Control of Human Viral Infections by NK Cells

IY31CH07-Altfeld ARI 14 February 2013 21:16
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Stephanie Jost and Marcus Altfeld
by Instituto de Salud Carlos III on 12/02/13. For personal use only.
Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02129;

email: sjost@partners.org, maltfeld@partners.org
Annu. Rev. Immunol. 2013. 31:16394 Keywords

First published online as a Review in Advance on HIV-1, HCV, inuenza, CMV, KIR, NKG2D, NK cells
January 3, 2013
The Annual Review of Immunology is online at Abstract

immunol.annualreviews.org
Natural killer (NK) cells are effector cells of the innate immune system
This articles doi:
and are important in the control of viral infections. Their relevance is
10.1146/annurev-immunol-032712-100001
reected by the multiple mechanisms evolved by viruses to evade NK
Copyright c 2013 by Annual Reviews.
cellmediated immune responses. Over recent years, our understanding
All rights reserved
of the interplay between NK cell immunity and viral pathogenesis has
improved signicantly. Here, we review the role of NK cells in the
control of four important viral infections in humans: cytomegalovirus,
inuenza virus, HIV-1, and hepatitis C virus.
163
INTRODUCTION human viral infections: CMV, inuenza virus,

hepatitis C virus (HCV), and human immuno-
Natural killer (NK) cells are large granular lym-
deciency virus-1 (HIV-1).
phocytes that play a central role in the control
of viral infections. NK cells were initially iden-
tied through their ability to mediate cellular
cytotoxicity against tumor cells (1). Subsequent NK CELLS AND THEIR
studies illustrating activation of NK cells in RECEPTORS IN MICE
response to type I interferons (IFNs) also AND HUMANS
identied them as a component of the innate NK cells are generally described as large lym-
immune response against pathogens. The con- phocytes that lack the expression of the T cell
tribution of NK cells to the antiviral immune receptor (i.e., CD3 negative), but there is no
response has been extensively studied in mouse unifying receptor that identies all NK cells in
models of viral infections, demonstrating that different species. NK1.1 can be used to isolate
NK cells not only contain viral replication by NK cells in some mouse strains, but not all, in
killing infected cells during the earliest stages of which case CD49b (DX5) represents an alterna-
infection, prior to the development of adaptive tive. Murine NK cells can be further subdivided
immunity, but also play a critical immunoregu- into four subsets with distinct maturation levels
latory role during the development of adaptive according to their surface expression of CD27
immunity (2, 3). Although NK cells are and CD11b (12). Human NK cells have been
considered part of the innate immune system classically dened as CD3 CD56+ lympho-
and mediate their effector functions through cytes, representing about 15% of peripheral
a number of germ-line-encoded receptors, re- blood lymphocytes. CD3 CD56+ NK cells
cent studies have suggested that a subset of NK can be further subdivided into CD56bright NK
cells in mice can mediate immunological recall cells, which lack the expression of CD16 (Fc-
responses to a variety of different haptens and receptor) and KIR (killer immunoglobulin-like
viral pathogens (46). These data indicate that receptor), and CD56dim NK cells, which
NK cells might comprise a more heterogeneous express CD16 and KIR (1, 13). In addition,
cell population than initially assumed. a subset of CD56 CD16+ NK cells appears
In humans, several rare NK cell deciencies to be expanded in chronic viral infections and
have been described (7). Biron et al. (8) rst re- seems to represent an exhausted/anergic subset
ported a case of a young girl who lacked func- of NK cells (14, 15).
tional NK cells and experienced a series of viral The most prominent function of NK cells
infections during childhood and adolescence, is to lyse malignant or virally infected cells.
including infections by multiple herpes viruses. NK cells mediate cytolysis by a number of dif-
Several subsequent studies have associated hu- ferent mechanisms, including (a) exocytosis of
man immunodeciency syndromes that result cytoplasmic granules containing perforin and
in complete or partial impairment of NK cell granzyme, (b) Fas ligandmediated induction of
numbers and functions with an increased sus- apoptosis, and (c) antibody-dependent cellular
ceptibility to viral infections, including herpes cytotoxicity (ADCC). NK cells, particularly
simplex virus (HSV), varicella zoster virus, cy- CD56bright NK cells, also play an important
tomegalovirus (CMV), and human papilloma role as immune regulatory cells, bridging the
virus, as well as more severe and progressive innate and adaptive immune responses as they
diseases during childhood (911). These stud- produce soluble factors including cytokines
ies established the critical role of functional and chemokines (16). In addition, NK cells can
NK cells in the control of viral infections in directly modulate adaptive immune responses,
humans. Here, we review the mechanisms by mainly via the interaction with dendritic cells
which NK cells participate in the control of viral (reviewed in Reference 2). The precise mech-
infections, with particular focus on four major anisms by which NK cells recognize virally
164 Jost Altfeld

infected target cells are complex and still not (17). It is beyond the scope of this review to
entirely understood. Unlike B and T cells, detail all NK cell receptors; therefore, only
NK cells do not appear to express unique those belonging to the three major families of
clonally distributed receptors for specic molecules involved in the regulation of human
antigens, but they do express an arsenal of and murine NK cell functions are described in
different stimulatory and inhibitory receptors discussion below and in Table 1.
Table 1 Major mouse and human NK cell receptorsa

Receptor family Species Receptor Known ligand Function
NCR M NCR1 Viral HA Activating
H NKp46 Viral HA, HSPG, PfEMP-1 Activating
NKp30 BAT-3, HCMV pp65, B7-H6, Activating
NKp44 HSPG, PfEMP-1
Viral HA, HSPG Activating

C-type lectin M Ly49A H-2Dd,k,p Inhibitory
H-2Kb,d , H-2Db,d,k
Ly49C Inhibitory
Ly49D H-2Dd Activating
Ly49H m157 Activating
Ly49I H-2K/Db,d,s,q,v Inhibitory
Ly49P H-2Dd Inhibitory
KIR H KIR2DL1 HLA-C2 (Lys 80) Inhibitory
KIR2DL2/3 HLA-C1 (Asn 80) Inhibitory
KIR2DL4 HLA-G Activating
KIR2DL5 Unknown Inhibitory
KIR2DS1 HLA-C2 (Lys 80) Activating
KIR2DS2 HLA-C1 (Asn 80) Activating
KIR2DS3 Unknown Activating
KIR2DS4 HLA-Cw4 Activating
KIR2DS5 Unknown Activating
KIR3DL1 HLA-Bw4 Inhibitory
KIR3DS1 HLA-Bw4?? Activating
KIR3DL2 HLA-A3/A11 Inhibitory
C-type lectin H, M CD94/NKG2A H: HLA-E, M: Qa1b Inhibitory
CD94/NKG2C H: HLA-E, M: Qa1b Activating
CD94/NKG2E H: HLA-E, M: Qa1b Activating
NKG2D H: MICA/B,ULBPs Activating
M: RAE-1, MULT-1, H60
M NKR-P1 Ocil/Clr-b Activating/Inhibitory
H NKR-P1A LLT1 Inhibitory
LILR H, M LILRB1/ILT2/LIR-1 H, M: MHC class I, H:UL18 Inhibitory
CD2 H, M 2B4 CD48 Activating/Inhibitory
CD2 H: CD58, M: CD48 Activating
NTB-A NTB-A Activating
CRACC CRACC Activating
DNAM-1 PVR, CD122 Activating
a
Abbreviations: M, mouse; H, human; BAT-3, HLA-B-associated transcript 3; H60, histocompatibility 60; HA, hemagglutinin; HLA, human leukocyte
antigen; HSPG, heparan sulfate proteoglycan; KIR, killer immunoglobulin-like receptor; LILR, leukocyte immunoglobulin-like receptor; MHC, major
histocompatibility complex; MULT-1, mouse UL16-binding-like transcript-1; NCR, natural cytotoxicity receptor; PfEMP-1, Duffy-binding-like
(DBL)-1 of Plasmodium falciparum erythrocyte membrane protein-1; RAE-1, retinoic acid early transcript-1; ULBP, UL16-binding protein.
www.annualreviews.org Control of Human Viral Infections by NK Cells 165

Table 2 Associations between KIR/HLA interactions and human viral diseases

Infection KIR/HLA association Observation Reference(s)
HIV KIR3DS1 and HLA-Bw4-80I Slower progression to AIDS 70
KIR3DL1high and HLA-Bw4-80I Slower progression to AIDS 71
KIR3DS1 Protection from infection 73, 78
HCV KIR2DL3 and HLA-C1 homozygosity Resolution of infection 126
KIR3DS1 and HLA-Bw4-80I Protection against development of HCC 138
CMV Fewer than one activating KIR in donor Reduced risk of CMV reactivation in 52, 53
recipient following bone marrow
transplant
KIR2DL1 expression on NK cells Recurrent CMV infection 51
Influenza virus KIR2DL2/3 and HLA-C1 Severe inuenza infection 198
KIR3DL1/S1 and HLA-Bw6 homozygosity
KIR2DL1 and HLA-C1 homozygosity 199
KIR3DS1, KIR2DS5, KIR2DL5

Abbreviations: CMV, cytomegalovirus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeciency virus; HLA, human
leukocyte antigen; KIR, killer immunoglobulin-like receptor.
RECEPTORS THAT CONTROL like receptors (KIRs) in humans share crucial

NK CELL FUNCTION characteristics, including common signaling
pathways, that can lead to inhibitory or
Natural Cytotoxicity Receptors activating outcomes depending on the trans-
The majority of human NK cells constitutively membrane residues or cytoplasmic motifs in the
express NKp46 and NKp30, two activating re- receptors, and the ability to primarily recognize
ceptors that belong to the family of natural cy- major histocompatibility complex (MHC) class
totoxicity receptors (NCRs). NCRs comprise a I and related surface molecules (reviewed in
third member, NKp44, which is only detected Reference 22). Activation or inhibition of NK
on the cell surface upon IL-2-mediated NK cell cells is signicantly affected by the strength
activation (18). The precise ligands for these of the binding between each Ly49 and KIR
receptors remain largely undened, yet several and their respective ligands, which itself can
viral- or tumor-associated molecules that can depend on the MHC class Ipresented peptide
interact with NCRs have been identied (re- and, at least in the case of Ly49 receptors, on
viewed in Reference 19) (Table 1). Of partic- the existence of cis rather than trans interactions
ular interest, NKp46 and NKp44 can interact with their ligands. Some of these molecules,
with inuenza hemagglutinin (HA) and medi- in conjunction with their ligands, have been
ate cytolysis of inuenza-infected NK cells (20, associated with protection against viral infec-
21). Only NKp46 has a mouse ortholog, NCR1, tion and other diseases (Table 2) and are thus
which seems to share the same antiviral and an- more extensively described in the following
titumoral properties as its human counterpart. paragraph.
Ly49 receptors bind specic allotypes of
H2D and H2K murine MHC class I molecules
Ly49 Receptors and Killer (22) (Table 1). One of these receptors, the
Immunoglobulin-Like Receptors activating Ly49H, does not have any known
Two large families of structurally distinct but MHC class I ligand but has a high afn-
functionally similar receptors in human and ity for the murine cytomegalovirus (MCMV)
mice play an important role in regulating NK protein m157 (reviewed below). KIRs inter-
cell function. The C-type lectin-like Ly49 react with specic allotypes of the classical (-A,
ceptors in mice and the killer immunoglobulin- -B, -C) and nonclassical (-G) human leukocyte
166 Jost Altfeld

antigen (HLA) class I receptors. In particular, HLA class I (Table 1). The murine receptors
KIR3DL1, and potentially KIR3DS1, binds to exert a similar function by binding to Qa1b .
HLA-B molecules that carry a distinctive sero- The activating receptor NKG2D is highly
logical motif, w4, that can be distinguished from expressed on human and murine NK cells and
the w6 motif on the basis of amino acids 77 is distinct from NKG2A/C/E based on se-
to 83 (23). HLA-Bw6 molecules do not serve quence alignments with other members of the
as known ligands for any KIR (24). Other re- superfamily and because it forms a homodimer
ceptors involved in the control of human vi- instead of a heterodimer with CD94. It exists
ral infections are KIR2DL1, KIR2DL2, and in a long and a short isoform in mice, favoring
KIR2DL3, all of which bind HLA-C molecules. cytotoxicity and cytokine production, respec-
HLA-C alleles can carry either an Asn at posi- tively, upon stimulation, but only the long
tion 80, and are classied as group 1 (HLA-C1), form of NKG2D is present in humans. Human
or a Lys, and then belong to group 2 (HLA- NKG2D recognizes human cytomegalovirus
C2). KIR2DL2/3 preferentially bind HLA-C1, (HCMV) glycoprotein UL16-binding proteins

and KIR2DL1 preferentially binds HLA-C2, (ULBPs) and the MHC class I chainrelated
with the binding afnity of the latter combi- molecules MICA and MICB. Ligands for the
nation being stronger than the former. Gen- mouse NKG2D include the retinoic acid early
erally, engagement of inhibitory Ly49/KIRs to transcript-1 (RAE-1) molecules , , , ,
their MHC class I ligands protects cells from and , mouse UL16-binding-like transcript-1
NK cellmediated lysis, and engagement of ac- (MULT-1) molecules, and histocompatibility
tivating Ly49/KIRs provides an activating sig- 60 (H60) molecules. All the receptors recog-
nal. Nevertheless, thus far only KIR2DS1 has nized by NKG2D are typically expressed by
been shown to interact directly with HLA-C, stressed or malignant cells, and viruses have
and ligands for the remaining activating KIRs evolved multiple mechanisms to evade recogni-
still remain to be identied (25). Finally, genes tion by NKG2D+ NK cells (reviewed below).
encoding Ly49 and KIR receptors display a
great diversity in number and sequence poly-
morphisms and are expressed in a stochastic NK CELLS IN CMV INFECTION
manner on NK cells, leading to unique subsets HCMV is a large double-stranded DNA virus
of NK cells with distinct properties and activa- of the subfamily Betaherpesvirinae and is
tion thresholds. Expression of Ly49 and KIR highly prevalent in humans, with 5090% of
not only depends on the repertoire of genes individuals in the United States, and as many
present in the genome, which altogether form as 100% of individuals in developing countries,
a haplotype, but also seems to be inuenced by being seropositive. Infection is usually acquired
the presence of the MHC ligand (26). early in life, and most immunocompetent hosts
are asymptomatic. However, CMV can cause
severe disease in immunocompromised individ-
NKG2 Receptors uals, such as patients with AIDS or recipients
Murine and human NK cells also express of transplants on immunosuppressive therapy,
CD94-NKG2A/C/E heterodimers, which resulting from the reactivation of latent infec-
belong to another family of C-type lectins. tion. Furthermore, maternal CMV reactivation
These highly conserved receptors can de- or primary infection during pregnancy causes
liver activating or inhibitory signals. Human congenital CMV, the most common congenital
inhibitory CD94-NKG2A and activating infection in the developed world, and is asso-
CD94-NKG2C/E heterodimers bind the non- ciated with long-term sequelae such as hearing
classical HLA-E loaded with peptides derived loss and developmental delay in about 50% of
from other HLA class I molecules, thereby these infants (27). HCMV establishes latent
monitoring the overall expression level of persistent infection in monocyte precursors

and tissue stroma cells, and persistent immune also renders infected cells more susceptible to
control is thought to be responsible for the recognition by NK cells, owing to the loss of lig-
control of the latent infection. HCMV has ands for inhibitory NK cell receptors. To com-
coevolved with its host for millions of years pensate for this, MCMV possesses several genes
(28), resulting in the evolution of a large that encode for MHC class Ilike molecules and
number of genes that prevent recognition of can engage inhibitory Ly49 receptors, thereby
infected cells by the immune system, including providing an inhibitory signal to NK cells.
NK cells, and enable the virus to establish These MHC class Ilike molecules include
persistent infection and dissemination. m157 and m144, yet in the case of m144, the
cognate Ly49 ligand and the precise mechanism
of action have not been identied. MCMV in-
NK Cells in the Mouse Model of fection also results in the expression of stress
MCMV Infection molecules on infected cells that serve as ligands
Because CMV infection is species specic, for activating NK cell receptors, particularly
no good animal models for HCMV infection NKG2D ligands (reviewed in References 29
currently exist. As a result, most animal studies and 30) (Table 1). Several of the MCMV pro-
of CMV infection have been performed teins interfere with the expression of NKG2D
using MCMV in mice. Although MCMV ligands, including m152, which reduces the ex-
and HCMV have similar tissue tropisms and pression of the RAE-1 gene products; m145,
similar pathogenesis, they have developed dif- which downregulates MULT-1; m155, which
ferences in the mechanisms they use to evade reduces H60 expression; and m138, which ap-
host-specic immunity (reviewed in Reference pears to reduce the expression of several of
29). This is reected by signicant primary these NKG2D ligands. Overall, MCMV ded-
genomic sequence diversity and less than icates multiple gene products toward evasion
50% homology in the open reading frames from recognition by NKG2D+ NK cells.
between MCMV and HCMV. Furthermore, In the process of coevolution with MCMV,
the highest sequence diversity is observed in some mouse NK cell receptors appear to have
those regions of CMV that encode for genes been selected for their ability to specically
dedicated toward immune evasion. The time recognize MCMV proteins expressed on
to complete a life cycle also distinguishes these infected cells. Genes encoding these receptors
viruses, with MCMV replicating signicantly (Cmv1r ) provide resistance to otherwise lethal
faster (approximately 30 h) than HCMV MCMV infection and are found in C57BL/6
(7296 h). Nevertheless, studies focusing on and MA/My strains of mice. In C57BL/6 mice,
MCMV have provided critical insights into the the activating Ly49H receptor on NK cells
basic mechanisms by which CMV evades the confers resistance to MCMV (3133). NK
hosts immune response (30). cells from Ly49H-decient C57BL/6 mice are
In an effort to avoid recognition of MHC unable to respond to MCMV, and these mice
class Ipresented viral epitopes by CD8+ T are susceptible to infection. Ly49H+ NK cells
cells, CMV encodes several gene products that recognize the MCMV-encoded glycoprotein
interfere with the presentation of viral pep- m157, which is expressed on infected cells. In
tides (reviewed in References 29 and 30). The support of this critical role of Ly49H-mediated
MCMV proteins m04, m06, and m152 are in- recognition of m157 in the immune protection
volved in the disruption of the MHC class I from MCMV, mutants that lack m157 are
synthesis pathway, resulting in the retention or signicantly more virulent in C57BL/6 mice
degradation of MHC molecules, and modulate (34). In addition to serving as a ligand for
antigen presentation. Although the reduction the activating Ly49H receptor, m157 is an
of MHC class I on the cell surface can allow MHC class I homolog that compensates for
evasion from virus-specic CD8+ T cells, it MHC class I downregulation. For example,
168 Jost Altfeld

m157 is recognized by high-afnity inhibitory in HLA degradation; US3 causes retention

Ly49I receptors expressed on NK cells in some of HLA class I in the endoplasmic reticulum;
strains of mice (33), potentially explaining why and US6 blocks the TAP-dependent transport
this MCMV gene product has persisted during of processed peptides into the endoplasmic
evolution despite the presence of an activating reticulum for loading on HLA class I. HCMV
receptor directed against it. Finally, the evolu- also encodes for several HLA class I homologs
tion of an antigen-specic receptor recognizing that engage inhibitory KIRs to avoid NK cell
m157 in C57BL/6 mice appears to have enabled activation. Additional HCMV proteins serve as
mice to develop NK cell memory responses to ligands for other inhibitory NK cell receptors,
MCMV, as described by Sun et al. (6). such as UL18, which binds to the inhibitory
Similar to Ly49H in C57BL/6 mice, Ly49P leukocyte immunoglobulin-like receptor
provides resistance to MCMV infection in 1 (LIR-1) expressed on NK cells, thereby
MA/My mice that do not possess the Ly49H dampening LIR-1+ NK cell function (37, 38).
gene (35). In contrast to Ly49H, the Ly49P gene Furthermore, HCMV infection results in
is not sufcient to confer resistance but needs to the upregulation of stress molecules, including
be encoded together with the MHC class I gene MICA, MICB, and ULBPs, on human cells.
for H2-Dk . Functional studies showed that the These molecules serve as ligands for the acti-
Ly49P response to MCMV is restricted by H2- vating NKG2D receptor and trigger strong ac-
Dk and can be blocked by antibodies against tivation of NKG2D+ NK cells (29, 30). HCMV
H2-Dk . Furthermore, it was dependent on the expresses several proteins that downregulate
MCMV-encoded m04 protein, as m04-deleted the expression of NKG2D ligands, including
mutants abrogated resistance to MCMV infec- UL16, which reduces the expression of MICB
tion in MA/My mice (36). However, the precise and ULBP1/2; UL142, which reduces the ex-
mechanisms by which Ly49P recognizes m04 in pression of MICA; and several additional pro-
the context of H2-Dk are not understood, as ad- teins (UL18, UL40, UL83, UL141) (as re-
ditional elements conferred by MCMV infec- viewed in Reference 30). In addition, HCMV
tion are required for this interaction. Taken to- encodes for microRNAs that target transcripts
gether, these detailed studies of the interaction of NKG2D ligands for degradation. Mandel-
between MCMV-encoded gene products and boim and colleagues (39, 40) demonstrated that
activating and inhibitory murine NK cell recep- the HCMV-encoded microRNA miR-UL112
tors have identied multiple immune recogni- downregulates the expression of MICB on in-
tion and immune evasion pathways and provide fected cells, leading to decreased binding of
important insights into the possible strategies NKG2D and reduced killing by NK cells. The
evolved in humans to control HCMV infection. description of viral microRNAs that participate
in evading immune recognition has opened a
new area of immune evasion pathways that is
NK Cells in HCMV Infection currently under intense investigation.
As described above, NK cells play a critical role Whereas specic NK cell receptors that
in the protection from herpesvirus infection in recognize MCMV proteins have been found
humans. Similar to MCMV, HCMV encodes in mice, no such receptors have been identied
for several gene products that enable it to in humans to date. HCMV encodes a peptide
evade the immune response in its natural host within the UL40 protein that is similar to those
(reviewed in References 29 and 30). HCMV found in many HLA class I molecules and leads
downregulates HLA class I expression by using to the upregulation of HLA-E on HCMV-
several different proteins in an effort to evade infected cells, resulting in the inhibition of
CMV-specic CD8+ T cell responses. US2 NKG2A+ NK cells (41). In contrast, NK cells
and US11 shuttle HLA class I from the endo- expressing the activating counterpart NKG2C,
plasmic reticulum to the cytoplasm, resulting which binds to HLA-E with less afnity than

NKG2A does, expand in response to HCMV negative. Similarly, an expansion of NKG2C+

infection. Cross-sectional studies showed NK cells was observed in HIV-1 infection (48)
that NKG2C+ NK cells, accounting for less and chikungunya virus infection (49), but again
than 2% of NK cells in CMV-seronegative only in those individuals also infected with
individuals, can represent more than 25% of HCMV, whereas such an expansion was not ob-
peripheral NK cells in individuals infected with served in recurrent HSV-2 infection (50). It re-
CMV (42, 43). More recently, Lopez-Verges mains to be elucidated whether prior exposure
et al. (44) characterized the changes in NK to HCMV primes NKG2C+ NK cells to ex-
cells longitudinally in a group of individuals pand more rapidly in response to other viruses,
with acute CMV infection and showed a or whether different viral infections can trig-
preferential expansion of NKG2C+ NK cells ger the expansion of these NKG2C+ NK cells.
that eventually acquired the expression of Finally, some studies have suggested that spe-
the maturation marker CD57 but lacked cic KIR genotypes are associated with protec-
the expression of the inhibitory receptors tion from CMV reactivation (5153) (Table 2);
NKG2A and KIR3DL1 (in those subjects however, their functional consequences remain
also encoding for the ligand HLA-Bw4). unclear. Overall, CMV has developed several
Furthermore, expansion kinetics of NKG2C+ evasion strategies against NK cellmediated

NK cells has been studied in individuals that immune pressure that have helped identify the
received umbilical cord blood transplantation principal mechanisms by which NK cells rec-
and subsequently reactivated CMV infection. ognize virally infected cells.
Della Chiesa et al. (45) observed an expansion
of NKG2C+ NK cells following HCMV NK CELLS IN HIV-1 INFECTION
reactivation that was associated with a more HIV-1 is a retrovirus that has infected more
rapid acquisition of the mature KIR+ NKG2A than 60 million individuals since its initial
NK cell phenotype. Similarly, Foley et al. (46) description in the mid-1980s and has killed
described an expansion of NKG2C+ CD57+ more than 30 million individuals. Although all
NK cells after CMV reactivation in adults parts of the world are affected by the epidemic,
receiving hematopoietic stem cell transplanta- most infected individuals live in sub-Saharan
tion. Taken together, these studies consistently Africa. HIV-1 is transmitted mainly through
describe the expansion of NKG2C+ NK cells mucosal routes during sexual exposure by
in response to CMV and demonstrate that an infected partner, by sharing needles with
these NKG2C+ NK cells acquire a more infected individuals during intravenous drug
differentiated and mature phenotype. use, and from mother to child at the time of
However, the precise mechanism by which birth and through breast-feeding. Following
this subset of NK cells recognizes HCMV acute infection, the virus establishes a chronic
remains unknown, and there is currently no infection and a persistent viral reservoir.
evidence that NKG2C directly binds to an HIV-1 preferentially infects CD4+ T cells
HCMV-encoded protein. Furthermore, it re- and macrophages and eventually leads to the
mains unclear whether these mature NK cells loss of CD4+ T cells and the development
represent a subset of memory NK cells in of AIDS in most infected individuals in the
humans, similar to the recent description of absence of antiretroviral therapy. However,
MCMV-specic memory NK cells expressing the speed of HIV-1 disease progression varies
Ly49H in mice (6). In this context, it is of inter- largely between infected individuals, with some
est that a rapid expansion and long-term per- individuals developing AIDS within one year of
sistence of NKG2C+ NK cells were also ob- infection, whereas others remain healthy with
served following human hantavirus infection no manifestations of HIV-1 disease even after
(47). However, this expansion was less impor- more than 25 years of infection. Apart from
tant in the three individuals that were HCMV differences in viral virulence and host genetic
170 Jost Altfeld

factors, differences in immune responses I/peptide complexes for NK cell function and
to the virus have been associated with the viral control in rhesus monkeys during SIV
heterogeneity of HIV-1 disease outcome (54). infection requires further investigation.
Of interest, almost all NK cells in rhesus
NK Cells in Animal Models monkeys express CD8, in contrast to humans,
of HIV-1 Infection in which only a relatively small subset of NK
HIV-1 infects humans, and there is currently cells expresses this marker (63). CD8 expression
no good animal model for HIV-1 infection. on NK cells in rhesus monkeys has complicated
However, several groups have developed the interpretation of studies that used anti-CD8
humanized mouse models, including irradiated antibodies for the depletion of CD8+ T cells,
NOD/SCID/IL-2Rc/ mice transplanted as these interventions also resulted in the re-
with human fetal liver hematopoietic stem moval of NK cells. Several studies have demon-
cells and autologous thymic grafts (55), and strated that CD8 depletion in SIV-infected rhe-
these models for HIV-1 infection have become sus monkeys results in a signicant increase in
more robust over the past few years (56). The viral replication, suggesting a critical role of
precise role of different immune cell subsets, CD8+ T cells, and potentially CD8+ NK cells,
including NK cells, in the restriction of HIV-1 in the control of SIV viremia (64, 65). In con-
replication in these mouse models remains to trast, the depletion of CD16+ cells in rhesus
be determined, but these models will probably monkeys has not resulted in changes in viral
become increasingly important tools for study- replication (66). However, anti-CD16 antibod-
ing immune responses to HIV-1 in upcoming ies depleted most (up to 90%) but not all pe-
years. In the absence of a well-characterized ripheral blood NK cells, for a very short pe-
animal model for HIV-1 infection, simian im- riod of time, and potentially spared CD16 NK
munodeciency virus (SIV) infection of rhesus cells endowed with immunoregulatory func-
monkeys has been used to study AIDS virus tions. Novel approaches aimed at more specif-
pathogenesis in nonhuman primates and to test ically depleting the NK cell population in rhe-
vaccine efcacy (57). SIV infection of rhesus sus monkeys are currently being evaluated and
monkeys leads to an acute infection with high will hopefully provide some insights into the
viremia that eventually declines to a subsequent role of NK cells in the control of SIV replica-
set point of viral replication that depends on tion in this model. Furthermore, recent studies
the SIV clone used for infection and on the have suggested that NK cells in rhesus monkeys
MHC class I genotype of the infected rhesus mediate ADCC against SIV-infected cells, and
monkeys (58). In addition, the KIR genotype that these ADCC responses might be inversely
of infected rhesus monkeys can be associated correlated with SIV viral loads (67, 68). Taken
with the level of viral control and the speed together, the precise role of NK cells in the con-
of SIV disease progression (59), suggesting trol of SIV replication in rhesus monkeys re-
a potential role for NK cells in that model. mains unclear. Optimizing the nonhuman pri-
Studies of the consequences of KIR and MHC mate and humanized mouse models for the
class I genotypes for SIV disease outcome have studies of the antiviral activity of NK cells might
been complicated by the complexity of the provide new insights into AIDS virus pathogen-
KIR genotype in rhesus monkeys (reviewed in esis and the correlates of protective immunity.
Reference 60). Inhibitory and activating KIRs
have been characterized as ligands for MHC Genetic Population Studies Suggest
class I molecules in rhesus monkeys, and poly- a Role of KIR+ NK Cells in
morphisms within these KIRs can modulate the HIV-1 Disease
peptide-dependent binding of KIRs to MHC Genetic studies in populations of HIV-1-
class I molecules (61, 62). The consequence infected individuals have provided evidence
of these KIR interactions with MHC class that NK cells might play a role in the control

of HIV-1 replication and disease outcome. of a single nucleotide polymorphism (SNP)

Initial studies by Flores-Villanueva et al. (69) 35 kb upstream of HLA-C (rs9264942) that is
showed that HIV-1-infected individuals with associated with the control of HIV-1 (80, 81).
HLA class I alleles encoding for molecules Further, SNP rs9264942 is associated with
carrying the Bw4 serological motif experience levels of HLA-C transcription and cell surface
signicantly better control of HIV-1 viremia expression. Kulkarni et al. (82) elegantly
and slower HIV-1 disease progression. In demonstrated the underlying mechanism,
subsequent studies, Carrington and colleagues showing that this SNP modulates the ability
(70) showed that HIV-1-infected individuals of microRNA hsa-miR-148 to bind to the
expressing KIR3DS1 and a subset of HLA-Bw4 promoter area of HLA-C and thereby en-
alleles encoding for an isoleucine in position hances HLA-C mRNA and protein expression.
80 (HLA-Bw4-80I) experienced signicantly HLA-C molecules serve as ligands for KIR2D
slower progression to AIDS compared with in- receptors, and variations in HLA-C expression
dividuals encoding for either HLA-Bw4-80I or might therefore have an impact on the function
KIR3DS1. Similarly, the interaction between of NK cells. Studies of HIV-1-specic CD8+
HLA-Bw4 molecules and their inhibitory lig- T cell responses have consistently shown
and KIR3DL1 appears to have an impact on the that most virus-specic T cell responses are
outcome of HIV-1 disease. Studies by Martin restricted by HLA-B and HLA-A and that
et al. (71) showed that the protective effect of HLA-C-restricted CD8+ T cells contribute
HLA-Bw4 alleles is further modulated by the only a little to the total HIV-1-specic CD8+ T
KIR3DL1 genotype. KIR3DL1 is highly poly- cell response (83). In this context, it is of interest
morphic, and expression of KIR3DL1 on NK that HIV-1 Nef (84) results in the downregula-
cells varies depending on the KIR3DL1 subtype tion of HLA-A molecules, which do not serve as
(71). A subset of KIR3DL1 alleles is associated ligands for inhibitory KIRs (except for HLA-A3
with high expression of the receptor on the NK and A11, which might serve in some situations
cell surface, whereas other KIR3DL1 alleles are as ligands for KIR3DL2) (85), and HLA-B
expressed at low levels. Individuals encoding molecules, which serve as ligands for KIR3DL1
for HLA-Bw4 and highly expressed KIR3DL1 (24). However, HLA-C molecules, which inter-
allotypes had signicantly lower levels of HIV- act with the large family of inhibitory KIR2DL
1 replication than did individuals encoding molecules, are not downregulated (84). HIV-1
for the same HLA-Bw4 alleles but KIR3DL1 Nef might therefore have evolved to evade
subtypes associated with low expression (71). strong virus-specic CD8+ T cell responses re-
Several studies have since then reported as- stricted by HLA-A and HLA-B while maintain-
sociations between the HLA-Bw4/KIR3DL1 ing the HLA-C ligand for the broadly expressed
genotype and protection from HIV-1 infection and inhibitory KIR2DL molecules on the sur-
or differential outcome of infection (7278). face of infected cells to provide an inhibitory
The number of KIR3DS1 genes, which vary signal to NK cells. Taken together, these
between individuals as a consequence of gene genetic studies suggest that KIR+ NK cells and
duplication, has also been associated with their interactions with the ligands, HLA class
better HIV-1 disease outcome in the context I molecules of the HLA-B and HLA-C family,
of HLA-Bw4 but not HLA-Bw6 (79). might play a critical role in the outcome of
In addition to the research that has revealed HIV-1 disease and have stimulated intensive
the protective interactions between HLA-Bw4 research into the underlying mechanisms.
and a subset of KIR3DS1/KIR3DL1 alleles,
several genome-wide association studies aimed Functional Studies of Human NK
at identifying host genetic polymorphisms Cells in HIV-1 Infection
associated with better control of HIV-1 viremia Although population genetic studies have
or disease outcome have led to the description provided strong indications suggesting that
172 Jost Altfeld

KIR/HLA interactions play a role in HIV-1 cated by several factors. First, a direct inter-
disease outcome, the functional correlates of action of KIR3DS1 with HLA-Bw4 molecules
these interactions are less well understood. NK has not been shown to date, and several studies
cells are expanded during acute HIV-1 infec- have failed to show any binding of KIR3DS1
tion, particularly prior to the development of to HLA class I molecules (24, 9395). Second,
detectable adaptive immunity, and this expan- in individuals expressing both KIR3DS1 and
sion of NK cells appears to be regulated to some KIR3DL1 receptors, it is currently difcult to
extent by KIR and HLA genotypes (86, 87). evaluate how each of these molecules inuences
KIR3DS1+ NK cells are highly enriched in the NK cell function. For instance, while inhibitory
peripheral blood of individuals with acute in- KIR receptors have been clearly demonstrated
fection, yet only in individuals that also encode as playing a determining role in the licensing
for HLA-Bw4 alleles and not in HLA-Bw6 ho- of NK cells, activating KIR receptors might
mozygous individuals (86). Furthermore, sev- also be involved in this process (96). However,
eral studies have suggested that KIR3DL1+ NK
in contrast to what has been observed for in-

cells from HLA-Bw4+ individuals are function- hibitory KIR receptors, interaction between ac-
ally superior to KIR3DL1+ NK cells from Bw6 tivating KIRs and their cognate ligand during
homozygous individuals (74, 75). These differ- NK cell development might lead to decreased
ences might reect differences in NK cell li- responsiveness of NK cells. Third, the genes
censing during development. Current models encoding KIR3DL1 and KIR3DS1 are found
of NK cell development suggest that NK cells in variable copy numbers among individuals,
need to receive an inhibitory signal through and it appears that protection against HIV-1
an inhibitory KIR during development to be- increases with the number of gene copies of
come functionally competent (8891). In line KIR3DL1, provided that at least one copy of
with this model, KIR3DL1+ NK cells from the KIR3DS1 gene and HLA-Bw4-80I are also
individuals that also encode HLA-Bw4 alleles present (79). Finally, KIR genes are located very
might be better licensed to kill infected cells close to each other in the KIR locus, leading to
than KIR3DL1+ NK cells from HLA-Bw6+ substantial linkage disequilibrium, notably be-
individuals. As the licensing of NK cells has tween KIR3DS1 and the activating KIR2DS1
also been suggested as being modulated by the receptor (97).
expression levels of KIRs and/or HLA class I Apart from the role of KIR/HLA class I
ligands, this model provides an attractive ex- interactions for the functional licensing of
planation for the protective effect of KIR3DL1 NK cells, the binding of KIR molecules to
alleles associated with higher KIR3DL1 expres- HLA class I is dependent on the sequence
sion in the context of HLA-Bw4 and of the SNP and structure of the HLA class Ipresented
rs9264942 associated with higher expression of epitopes (Figure 1). The role of the epitope
HLA-C molecules. However, convincing func- sequence in this interaction was postulated by
tional data demonstrating such a correlate are functional studies demonstrating that sequence
still pending. Furthermore, some studies have changes, particularly in the C-terminal part of
demonstrated that KIR3DS1+ NK cells have the epitope, signicantly modulated the ability
stronger activity in HIV-1-infected individu- of NK cells expressing the respective inhibitory
als encoding for HLA-Bw4 (77) and can in- KIR receptors to kill peptide-pulsed cell lines
hibit in vitro HIV-1 replication more potently (98, 99). These data suggested that HLA class
(92), but whether this is due to the ability of Ipresented peptides that did not allow for the
these KIR3DS1+ NK cells to better recognize binding of the inhibitory KIR resulted in a dis-
HIV-1-infected cells or to a general higher inhibition of NK cells and target cell lysis (100)
functional activity is not known. The identi- (Figure 1a,b). The recent characterization of
cation of functional correlates of the genetic crystal structures of HLA class I/peptide/KIR
associations described above is further compli- complexes has provided further structural

NK cell
Uninfected cell
a Inhib KIR HLA

Self-epitopes
NK cell promoting
inhibition strong KIR-HLA
interactions
Activ Activ
Rec Rec L
NK cell
Infected cell
b
Viral-epitopes
NK cell
activation not allowing
KIR-HLA binding
NK cell
Infected cell
c
Selected viral-
NK cell epitope variants
inhibition reconstituting
KIR-HLA binding
Figure 1
Simplied model displaying how individual HLA class Ipresented epitopes might affect binding of
inhibitory KIRs and NK cell function. (a) Under normal circumstances, HLA class I molecules present
self-peptides on the surface of cells that allow for binding of inhibitory KIRs and inhibit NK cell function.
(b) In the setting of viral infections, an increased number of viral epitopes or self-stress epitopes are
presented that do not allow for binding of inhibitory KIRs, resulting in disinhibition of NK cells. (c) Viruses
can select for epitope variants that reconstitute binding of inhibitory KIRs and enable the evasion from NK
cellmediated recognition. Inhib, inhibitory; Activ Rec, activating receptor; Activ Rec L, activating receptor
ligand.
evidence for this and has allowed for predic- signicantly modulate the binding of these
tions of the amino acids in the critical positions inhibitory KIRs (85, 102105) and result in
7 and 8 of the epitope that modulate KIR/HLA the activation of primary KIR+ NK cells (106).
binding (24, 101). These observations have Studies of the autologous viral sequences in
also stimulated research determining the large populations of HIV-1-infected individ-
consequences of changes in the HLA class uals have started to suggest that specic amino
Ipresented peptide repertoire that occur acids in the virus are selected at the popula-
during viral infections on KIR/HLA class tion level depending on the KIR molecules
I binding. In vitro studies investigating the expressed (107) (Figure 1c). In particular,
impact of sequence changes in HIV-1 epitopes HIV-1 viruses encoding for amino acids in
presented by HLA class I molecules on binding HLA class Ipresented peptides that allow
of KIRs showed that naturally occurring amino for the binding of an inhibitory KIR were
acid changes in HIV-1-encoded peptides can preferentially selected in individuals expressing
174 Jost Altfeld

the respective KIR but not in individuals who gression to chronic disease occurs in the major-
do not encode for the respective KIR, suggest- ity of infected individuals, about one-fourth of
ing that viruses encoding for these inhibitory de novo HCV infections are cleared during the
sequences might have a selective benet in acute phase. Resolved infection is characterized
infected individuals (107; C.F. Thobakgale & by the presence of HCV antibodies in the ab-
M. Altfeld, unpublished data). However, the sence of markers of active viral replication, such
precise functional consequences of these viral as HCV RNA. Viral clearance is thought to rely
sequence polymorphisms for the recognition largely on a broad, potent, and prolonged host
of infected cells by NK cells remain to be cellular immune response (112114). Accord-
elucidated. ingly, defective T cell immunity is strongly as-
Apart from the potential KIR-modulated sociated with viral persistence (115). No vaccine
recognition of HIV-1-infected cells by NK is currently available to prevent HCV infection,
cells, receptors that are less polymorphic, in- yet the rate of sustained virological responses to
cluding NKG2D, might play a role in the NK treatment has recently signicantly increased
cellmediated killing of HIV-1-infected cells. with the administration of HCV protease in-
Several viruses, particularly herpesviruses, such hibitors in addition to the conventional combi-
as CMV, have evolved elaborate mechanisms nation of pegylated INF- and ribavirin (116).
to evade this NKG2D-mediated recognition In individuals who spontaneously clear
(as reviewed above). The HIV-1 Nef protein HCV infection, viral control occurs within the
appears to downregulate not only HLA-A and rst few months of infection. Before the onset
HLA-B but also NKG2D ligands expressed of the adaptive immune response, innate im-
on infected cells (108), suggesting that this mune effector cells, such as NK and NKT cells,
specic pathway might play a signicant role are thought to release IFN-, which is directly
in the recognition of HIV-1-infected cells by responsible for the noncytopathic inhibition of
NK cells. HCV replication (117). IFN--mediated clear-
Overall, several key NK cell receptors ance of the virus might be more important than
have been associated with HIV-1 disease direct cytolysis of HCV-infected hepatocytes
progression and/or transmission, implying that by NK cells, as nearly all hepatocytes become
NK cells might contribute markedly to the infected and their elimination would lead to
control of HIV-1 infection. Besides, HIV-1- extensive liver damage. Type III IFN, such as
encoded proteins can facilitate evasion from IFN-, has received much attention recently,
NK cell recognition (as reviewed in Reference because not only does this cytokine inhibit
109). However, the extent to which these HCV replication in vitro (118), but specic
viral evasion mechanisms modulate HIV-1 polymorphisms located in the encoding gene,
pathogenesis and disease outcome remains IL28B, are strongly associated with HCV
incompletely understood. clearance, response to therapy, and disease
outcome (119122). Although the mechanisms
underlying IFN--mediated eradication of
NK CELLS IN HEPATITIS C HCV replication in vivo remain to be deter-
VIRUS INFECTION mined, it is possible that this cytokine plays a
Roughly 170 million people worldwide suf- crucial role in modulating NK cell responses
fer from chronic HCV infection, a condition to HCV, similarly to IFN- (118).
caused by an enveloped single-stranded RNA NK cells constitute 30% of resident lym-
virus of the Flaviviridae family (110, 111). Com- phocytes in the normal liver, which is higher
plications frequently arise from persistent HCV than their representation in the peripheral
infection, with liver cirrhosis and hepatocellu- blood, and percentages of NK cells in HCV-
lar carcinoma occurring in approximately 25% infected livers can reach as high as 90% (123).
and 15% of cases, respectively. Although pro- Compared to peripheral blood NK cells, NK

cells in healthy livers are characterized by a toward chronic HCV infection (132). A lack of
decreased ability to perform their cytotoxic and association between the KIR2DL3/HLA-C1
immunoregulatory functions, a functional state genotype and HCV clearance in HIV-1-
that might be maintained by high expression infected individuals has also been reported
of the inhibitory NKG2A receptor on NK (133) and might reect a general impairment
cells, and an increased local production of of NK cell function in these individuals. In
the immunosuppressive cytokine IL-10 (124, the future, it will be important to evaluate how
125). These features are required to avoid coinfections and allelic polymorphisms affect
immunopathology of the liver, in which tolero- the ability of NK cells expressing protective
genic conditions have to be maintained to KIRs to mediate their potentially benecial
avoid inammation in response to gut-derived effect on HCV infection.
antigens. In support of a possible increased ability
of NK cells to eliminate virally infected cells
in the context of the KIR2DL3/HLA-C1

Protective Effect Mediated by genotype, KIR2DL2/3+ NK cells display
KIR2DL3 in Combination with Its higher levels of activation than KIR2DL1+
Ligand HLA-C1 NK cells in the blood of individuals with acute

Compelling evidence for a role of human NK HCV infection, and particularly in those who
cells in HCV infection comes from epidemio- subsequently clear the infection (134). Because
logical studies, which led to the identication the afnity between the inhibitory KIR2DL3
of an association between homozygosity for and its ligand HLA-C1 is weaker than that
the KIR/HLA genotype KIR2DL3/HLA-C1 between KIR2DL1 and HLA-C2 or KIR2DL2
and viral clearance in intravenous drug users and HLA-C1, it is plausible that a lower
(126128). This genotype not only has been threshold of activation is required to trigger
suggested to protect from the establishment KIR2DL3+ NK cell responses (135). However,
of chronic disease, but also predominates in HCV infection does not lead to a signicant
HCV-exposed seronegative aviremic indi- downregulation of MHC class I molecules at
viduals and in HCV-infected patients with the surface of infected cells. Therefore, the
sustained responses to IFN--based therapies inuence of HLA-C1-presented epitopes on
(127, 129). Accordingly, the frequency of the avidity of the KIR-HLA interaction, rather
individuals encoding for HLA-C2 molecules than HLA-C1 disappearance from the cell
was higher among patients with chronic HCV surface, might explain the protective effect
infection than among healthy individuals (130), mediated by KIR2DL3+ NK cells, as suggested
and individuals with resolved HCV infection for HLA-Cw 0102 (136). Further experiments
had increased percentages of NK cells ex- are required to determine the mechanisms
pressing HLA-C-binding KIRs (including underlying KIR2DL3-mediated protection,
KIR2DL1, -2DL2, -2DL3, -2DS1, -2DS2) including the inuence of other KIRs.
compared to those with acute and chronic
HCV infection or to healthy controls (131).
There are a few specic situations in which Impact of Other KIRs on HCV
the positive effect of KIR2DL3 in conjunction Disease Outcome
with its HLA-C1 ligand seems to be lost. Expression of additional KIRs has been pro-
For instance, among all possible ligands for posed to also play a role in the prevention or
KIR2DL3, expression of HLA-Cw 07 has been outcome of HCV infection. For instance, in-
suggested to be associated with KIR2DL3+ creased frequencies of the activating KIR2DS3
NK cells with an increased ability to produce receptor and homozygosity for KIR3DS1 in
IFN-, yet this particular HLA-C1 allele conjunction with HLA-Bw4 were associated
does not confer protection from progression with poor prognosis for HCV infection (137),
176 Jost Altfeld

suggesting that liver damage in chronic HCV population also tends to coexpress inhibitory
infection might be explained, at least partly, self-KIRs, including KIR2DL3, and might rep-
by activating KIR-mediated NK cell overac- resent an important mean to limit NK cell
tivation. In contrast, in the context of hepa- mediated liver injury (142).
tocellular carcinoma development in patients
with chronic HCV infection, expression of
KIR3DS1 or HLA-C1 has been suggested to Studies of NK Cell Responses to HCV
be protective (138), but the potential mecha- Using In Vitro Systems
nisms underlying these protective associations Scientic progress in understanding HCV
remain unknown. Studies comparing cohorts of pathogenesis has been hampered severely by
chronically HCV-infected subjects and high- the lack of appropriate experimental in vivo
risk aviremic seronegative individuals showed or in vitro systems. Chimpanzees are the only
that expression of the activating KIR2DS4 re- immunocompetent animals that can be reliably
ceptor contributes to the KIR2DL3-mediated infected with HCV, but access to this model
protection against infection in exposed but has been limited owing to ethical considera-
uninfected HLA-C1+ intravenous drug users tions, high costs, and difculties inherent to
(139). However, because the known ligand for working with large animals and has thus been
KIR2DS4 is HLA-C2, the functional relevance stopped. As an attractive alternative, in vitro
of this nding will have to be addressed (140). HCV culture systems and humanized mouse
Finally, the failure of antiviral combination models that are permissive to HCV infection
therapy against HCV has been associated with have been recently developed (143). In 2005,
the presence of KIR2DL5 (141). It is cur- a robust HCV culture system was established
rently difcult to provide a mechanistic expla- by infecting the Huh7.5 hepatoma-derived cell
nation for this observation as the ligand for line with a full-length genotype 2a recombi-
the KIR2DL5 receptor has not been identi- nant HCV. This in vitro system established the
ed. It will also be important to assess whether ability of NK cells to abrogate HCV replication
KIR polymorphisms will be relevant for treat- in vitro (144) by demonstrating that incubation
ment outcome in the context of the recently im- of HCV-infected hepatocytes with NK cell
proved HCV treatments, which have markedly culture supernatant reduced HCV RNA and
enhanced the percentages of patients with a sus- protein production, an effect that depended on
tained virological response. IFN- produced by NK cells. Furthermore,
To clarify the role of KIRs in the outcome of in vitro experiments conducted in cell culture
natural HCV infection, it will be important to models uncovered several potential mecha-
determine whether linkage disequilibrium with nisms by which HCV might affect NK cell
other genes accounts for the associations with functions in vivo. One major nding was the
liver disease or protection from infection ob- ability of the HCV envelope 2 (E2) protein
served for activating KIR receptors. The pres- to interact directly with CD81, a cellular
ence of KIR/HLA compound genotypes that coreceptor for the virus, thereby blocking
allow for strong NK cell activation very early antiviral functions of CD81+ NK cells (145
in HCV infection might signicantly increase 147). However, experimental settings of these
the chances of clearing the virus, yet persistent studies involved plates coated with recombi-
innate immune activation during chronic in- nant truncated HCV-E2 proteins. When NK
fection might contribute to pathology. For in- cells are exposed to intact HCV virions, their
stance, HCMV infection leads to the expansion functions are preserved, whereas the presence
and long-term persistence of NK cells express- of anti-CD81 antibodies suppresses NK cell
ing the activating NKG2C receptor (43). In mediated IFN- production and cytotoxicity
HCMV-seropositive individuals with chronic (148). Therefore, it remains to be elucidated
HCV infection, this NKG2C+ NK cell sub- whether cross-linking of CD81 by HCV E2

affects NK cell function and provides a way NK cell responses in resolved and chronic HCV
for the virus to facilitate the establishment of infection. These studies have generated a sur-
chronic infection. Alternatively, in vitro studies prisingly high degree of controversial results,
suggested that NK cell function might be which are discussed below. Heterogeneity in
impaired upon enhanced expression of ligands cohorts and experimental protocols applied to
for inhibitory NK cell receptors on HCV- study NK cells might account for these discrep-
infected cells, including HLA class I (149), and ancies. However, the few existing studies focus-
specically HLA-E (150), or downregulation ing on NK cells in acute HCV infection point
of MICA, a ligand for the activating NKG2D toward a pivotal role for NK cells in the early
NK cell receptor (151). The contribution of control of HCV replication and in predicting
these different pathways to the outcome of subsequent disease outcome (131, 134, 163).
HCV disease, however, remains incompletely
understood and requires further evaluation. NK Cells in Acute HCV Infection
Redistribution of NK cell subsets occurs early

Changes in the NK Cell Compartment in acute HCV infection and is characterized
During HCV Infection by an increase in the percentages of CD56bright

and CD56neg NK cells, whereas percentages
One mechanism by which HCV establishes
of CD56dim NK cells are reduced. These data
chronic persistent infection might involve
suggest that the KIR-expressing cytotoxic
virus-induced alterations of NK cell functions
CD56dim subpopulation might be recruited
very early in the course of infection. This hy-
toward the acutely infected liver (131, 134).
pothesis is supported by increasing evidence
Overall, peripheral blood NK cells in acute
demonstrating that patients with chronic HCV
HCV infection display enhanced functions
infection have several peripheral blood and in-
compared with NK cells from uninfected or
trahepatic NK cell abnormalities, such as de-
chronically infected subjects, and importantly,
creased numbers of NK cells, and altered NK
natural cytotoxicity does not differ between
cell subset distribution and/or NK cell receptor
subjects who are subsequently able to clear the
expression (reviewed in Reference 152). How-
virus and those who develop chronic infection
ever, to what extent HCV-associated NK cell
(131, 134, 163). However, some differences
phenotypic changes affect NK cell function is
in NK cells during acute HCV infection have
not entirely clear, and although initial stud-
been suggested to be predictive of the outcome
ies observed impaired natural cytotoxicity in
of HCV infection. In particular, individuals
chronic HCV infection (147, 153155), more
who spontaneously clear HCV infection have
recent reports strongly suggest that NK cell
signicantly lower proportions of peripheral
functions are not reduced (131, 148, 156161).
blood NK cells expressing NKp46, NKp30,
Moreover, the eld has a limited understanding
NKG2D, and CD161 at the time of acute
of intrahepatic NK cell function in HCV in-
infection compared with those who develop
fection, and NK cells with decreased cytotoxic
chronic infection (131). Further studies looking
functions yet intact IFN- production might
at liver specimens during acute HCV infection
still be able to contribute to the clearance of
are required to conclude whether differences
the virus, as the antiviral effect mediated by
in NK cells during the initial stage of infection
IFN- has been proposed to be more efcient
can determine subsequent disease outcome.
at controlling HCV replication than is direct
lysis of infected hepatocytes (162). Finally, be-
cause acute HCV replication is mostly asymp- NK Cell Phenotypes in Chronic
tomatic, access to acute infection samples has HCV Infection
been challenging, and the majority of studies The distribution of circulating NK cell sub-
have focused on comparing peripheral blood sets is also skewed in chronic HCV infection,
178 Jost Altfeld

with percentages of CD56neg and CD56bright in several studies, contradictory data regarding
NK cells increased relative to CD56dim NK the frequency of NCR-bearing peripheral
cells (reviewed in Reference 164). An altered blood and intrahepatic NK cells have been
ratio of CD56dim to CD56bright NK cells in the reported (131, 157159, 166, 169). Of interest,
infected liver has also been reported, yet it is a recent study showed that NKp46high NK
not clear whether this observation is directly re- cells have potent anti-HCV activity in vitro
lated to HCV infection as there are no convinc- and accumulate in the liver of subjects with
ing data regarding the proportions of these NK chronic HCV infection, suggesting that func-
cell subsets in the healthy liver (165). Further- tionally competent NKp46+ NK cells might
more, chronic HCV infection is associated with be recruited to the site of infection (171).
an increased number of peripheral blood and Although the enhanced activity of this subset
intrahepatic NK cells bearing the inhibitory might contribute to liver damage, intrahepatic
heterodimeric receptor CD94/NKG2A (157, percentages of NKp46high inversely correlate
159, 165, 166). This feature has been pro- with HCV viral load. A potential role for
posed to result in reduced cytolytic activity NKp30 in the control of HCV infection has
and impaired dendritic cell activation, poten- been further suggested by the fact that NK cells
tially facilitating viral persistence (167169). In with high expression levels of NKp30 might
accordance with these observations, individu- have an increased potential to protect against
als with spontaneously resolved HCV infection HCV infection in vivo and in vitro (172).
have diminished numbers of NK cells express- Further investigations are required to link
ing NKG2A, -2C, and -2E compared with pa- alterations in NK cell phenotype to their anti-
tients with chronic infection (161). At least one HCV function, yet it can be speculated that low
HLA-E-restricted HCV peptide has been sug- expression of activating receptors on peripheral
gested to stabilize the ligand for NKG2A at NK cells during chronic HCV infection reects
the surface of infected hepatocytes and might anergy of NK cells, resulting from consistent
be responsible for the increased expression of activation through these receptors. Alterna-
NKG2A on NK cells (150). However, expres- tively, NK cells expressing activating receptors
sion of NKG2A on CD56dim NK cells is in- might be retained in the infected liver, and this
versely correlated to HCV viral load, suggest- hypothesis is supported by recent investigations
ing that the NKG2A+ NK cell subset, whose looking at both intrahepatic and peripheral
function is expected to be more inhibited, might blood NK cells in parallel (157, 159, 171).
actually be protective (165). Further investiga- Taken together, the current literature suggests
tions are required to determine whether other that increased and early expression of activating
receptors on NKG2A+ NK cells might partly receptors on hepatic NK cells, associated with
account for this observation. In particular, coex- enhanced NK cell function, might provide
pression of CD94, which can protect NK cells protection from infection in exposed individ-
from cell death, might contribute to this de- uals and might favor spontaneous resolution of
scribed association (170). Higher pretreatment infection, while the consequences of changes
frequencies of NKG2A+ KIR NK cells occur in the NK cell compartment during chronic
in patients who subsequently present a success- infection for disease outcome are less clear.
ful response to antiviral therapy compared with
those who fail to respond, further suggesting
that a protective effect might be mediated by a
NK CELLS IN INFLUENZA
subset of NKG2A+ NK cells that do not over-
VIRUS INFECTION
express inhibitory receptors (166). Orthomyxoviridae, a family of enveloped
Although the increase in percentages of single-stranded segmented RNA viruses that
NKG2A+ NK cells in subjects with chronic includes inuenza A, B, and C viruses, cause
HCV infection has been observed consistently annual inuenza disease outbreaks as well as

sporadic and devastating pandemics (reviewed of NK cells on the outcome of inuenza disease
in Reference 173). Seasonal inuenza epi- has been recently questioned by a study report-
demics result in an estimated 250,000500,000 ing an increased survival of mice devoid of IL-
deaths per year worldwide (174) and in an 15, or depleted of NK cells using antibodies,
average of 200,000 hospitalizations (175) and and challenged with a lethal dose of inuenza
36,000 deaths per year in the United States virus (189). These discrepancies with previous
alone (176, 177). Seasonal epidemics are observations might be explained by the amount
instigated by the quick spread of inuenza of virus used to infect the mice, and they sug-
virus variants generated by antigenic drift, a gest that at high infectious doses NK cells might
process that facilitates the escape of the virus signicantly contribute to inuenza-mediated
from the host immune system. As a result, immunopathology by enhancing pulmonary in-
inuenza vaccines need to be reformulated ammation. Beyond its role in NK cell homeo-
before each annual epidemic, and although stasis, IL-15 also has chemotactic properties,
yearly immunization has been the most ef- and its inuenza-induced release at the site of
cient way to prevent inuenza so far, vaccines infection might participate in recruiting NK
do not provide complete protection. Recovery cells to the lung airways of infected mice (190).
from acute inuenza infection and resistance Murine models and in vitro experiments
to reinfection rely both on the production of identied NCR1, the murine receptor corre-
neutralizing antibodies targeting the HA and sponding to human NKp46, as a potential NK
the neuraminidase glycoproteins and on the cell receptor that can interact with inuenza
killing of infected cells by inuenza-specic HA in a sialic aciddependent manner and is in-
cytotoxic CD8+ T lymphocytes that mostly volved in the elimination of inuenza-infected
target conserved viral proteins (178, 179). In cells (191, 192). Whereas the inuence of other
addition, several studies, reviewed below, have NK cell receptors in the recognition and killing
highlighted the early and potentially important of inuenza-infected cells remains unknown,
role of innate effector cells, particularly NK mice lacking NCR1 fail to clear the virus and
cells, in the control of inuenza infection. do not survive infection with a lethal dose of
inuenza. In this murine model, the presence
of the Ncr1 gene confers protection against
NK Cells in Mouse Models of challenge with inuenza H1 subtypes and the
Influenza Virus Infection highly pathogenic avian inuenza H5 subtype,
Most studies of inuenza virus infection have although in vitro, interaction between NKp46
been performed using mouse models. Mice are and H5 was not sufcient to trigger killing
naturally not susceptible to inuenza infection. of H5N1-infected cells (193). It is generally
However, inuenza disease and lethal infection accepted that NCR1 can interact with inuenza
can be achieved with viral strains that have been HA, yet the relevance of NCR1 expression at
adapted by serial passages in mice. In both hu- the surface of NK cells in mediating protection
mans and mice, NK cells initially represent a against inuenza infection in vivo remains
substantial portion of the lymphocyte popula- controversial. Indeed, Noe mice, which carry
tion that resides in the healthy lungs, and within a mutated Ncr1 gene that abolishes surface
days of inuenza infection, these innate im- expression of the receptor, display increased
mune cells are further recruited to the respi- resistance to inuenza infection (194). In
ratory tract (180183). Experimental inuenza addition to binding to viral HA via NCR1, NK
infection of NK celldepleted mice, or different cells might recognize and eliminate inuenza-
mice models with defects in NK cell activity, re- infected cells via binding to inuenza-specic
sulted in a delayed clearance of the virus from antibodies (195, 196). ADCC has been identi-
the lungs and augmented morbidity and mortal- ed as the main mechanism providing protec-
ity (184188). However, the benecial impact tion against lethal inuenza challenge in mice
180 Jost Altfeld

vaccinated with the extracellular part of the M2 In support of the role of NCR1 in the
inuenza protein (196). Taken together, stud- mouse NK cell response to inuenza, NKp46
ies using mouse models demonstrated that NK predominantly mediates human NK cell lysis
cell function, particularly NCR1-mediated NK of inuenza-infected cells in vitro by directly
cell activation, can have a signicant impact on binding to the HA proteins present at the sur-
the outcome of inuenza infection. face of infected cells (20, 21, 200). -2,6-linked
sialic acid residues play a crucial role in the
binding of both NKp46 and NKp44 to viral HA
NK Cells in Human (18, 20, 21). Furthermore, NKp46 blockade
Influenza Infection impairs NK cell responses to inuenza (201,
Humans are susceptible to several strains of 202). In particular, expression of both NKp46
inuenza, and the virus is normally eliminated and NKG2D has been suggested to be re-
within a few days following infection in quired for the recognition of inuenza-infected
immunocompetent individuals. Several studies dendritic cells and the subsequent activation
have suggested a role for NK cells in this of NK cells (201). Polyfunctional NK cell
process. As described above, NK cells require responses to inuenza rely on a combination
the interaction between an inhibitory KIR and of signals provided by dendritic cells, which
its ligand to become licensed during develop- include not only upregulation of NKp46- and
ment. Applying this model to NK cell responses NKG2D-ligands on dendritic cells but also the
against inuenza, Ahlenstiel et al. (197) showed production of IFN- and IL-12 (201). Finally,
in in vitro experiments that KIR2DL3+ NK NKp46 downregulation following inuenza
cells derived from individuals also encoding for exposure has been described in different in
its ligand HLA-C1 exhibited strong activity vitro experimental models, potentially reect-
in response to inuenza. However, to date ing inuenza-induced activation of NKp46+
there is no evidence for a KIR2DL3-mediated NK cells (202, 203). Altogether, these data
protective effect at the population level. Some suggest the importance of activating NK cell
genetic associations between KIR alleles and receptors in the response to inuenza. Future
increased control or susceptibility to severe experiments need to determine whether over-
and/or lethal inuenza infection with the 2009 activation of NK cells during acute infection
pandemic H1N1 virus have been described with highly pathogenic inuenza viruses, such
(198, 199). For instance, KIR2DL2 and/or as H5N1, might also contribute to increasing
KIR2DL3 in conjunction with their HLA-C1 morbidity and mortality.
ligands were enriched in subjects with severe
inuenza infection, whereas the absence of
HLA-Bw4 ligands for KIR3DL1/S1 or of Evasion from NK CellMediated
HLA-C2 ligands for KIR2DL1 prevailed in Immune Responses by Influenza Virus
patients with signicant inuenza-associated NK cell contribution to the immune control
pathology requiring intensive care treatment of inuenza infection has also been reected
(Table 2) (198). Moreover, the frequency by several studies describing strategies evolved
of KIR3DS1, KIR2DS5, and KIR2DL5 was by inuenza to specically evade NK cell
associated with increased severity in symptoms mediated immune responses, specically
(199). However, these studies were conducted NKp46-mediated responses. One strategy
in relatively small patient cohorts, and further consists of changing the glycosylation patterns
studies involving larger numbers of subjects of the HA protein (204, 205). These changes
are warranted to fully determine the clinical occur over time as the virus rapidly acquires
relevance of KIR alleles and their HLA mutations conferring resistance to antibody-
ligands in the immune response to inuenza mediated neutralization from one year to
infection. another. For instance, H3N2 inuenza viruses

that were isolated more than 16 years ago have NKp46 in recognizing inuenza-infected NK
a higher binding afnity for sialic acid, and cells (203). In addition, inuenza vaccination
therefore an increased ability to trigger NK was associated with an expansion of NK cells
cellmediated killing, than do contemporary expressing high levels of 2B4, which persisted
H3N2 inuenza strains isolated between 1999 for up to 150 days.
and 2003 (204). Further studies are required to Before the emergence of the 2009 pandemic
determine whether this reduced recognition by H1N1 inuenza virus, ex vivo studies charac-
NK cells is a reection of direct adaptation to terizing changes in human NK cell phenotype
NK cellmediated immune pressure, simply an and function in acute inuenza infection were
indirect consequence of escape from antibody scarce. However, increased mortality and mor-
responses, or both. bidity associated with the pandemic strain rein-
Evasion from NK cell effector functions by forced the need to further understand the role
increasing the signals delivered via inhibitory played by immune effector cells in inuenza-
NK cell receptors is another strategy em- associated pathology and to shed further light
ployed by inuenza viruses to escape NK cell on human NK cell responses to inuenza. No-
mediated lysis (206, 207). Prior to cell surface tably, clinical investigations reported marked
expression of ligands for NK cellactivating decreases in peripheral blood NK cell numbers

receptors, such as NKp46, inuenza infec- in inuenza-infected individuals, with severe
tion triggers the accumulation of MHC class I symptoms associated with a more dramatic de-
molecules into lipid raft microdomains, thereby crease or a complete absence of circulating NK
increasing the binding of inhibitory NK cell re- cells (210214). Reduced numbers of peripheral
ceptors, including KIR2DL1 and LIR-1, to the blood NK cells in patients with acute inuenza
infected cells (207). Altogether, these in vitro infection might reect homing of these cells
studies suggest that inuenza virus has devel- to other tissues, including those of the respi-
oped evasion strategies to escape recognition ratory tract. Alternatively, inuenza-mediated
by human NK cells. increased apoptosis and activation-induced cell
death might explain the observed decrease in
circulating NK cells (215, 216). In support of
Human NK Cell Responses to this latter hypothesis, lung inammatory inl-
Influenza in Vaccinated trates from one subject with fatal H1N1 in-
and Infected Individuals uenza infection were devoid of NK cells (210).
Several studies have assessed the NK cell re- Further investigation is required to evaluate the
sponses in individuals vaccinated with current role played by NK cell trafcking to infected
inuenza vaccines or infected with inuenza. tissues and/or immune cell death in inuenza-
About 30 years ago, increased NK cell cyto- associated lymphopenia.
toxic function and IFN- production were as-
sociated for the rst time with intranasal inocu-
lation of volunteers with a live H1N1 inuenza COMMON THEMES IN NK
virus (180). Since then, additional studies have CELLMEDIATED
reported an enhanced production of IFN- by RECOGNITION OF VIRALLY
NK cells in subjects vaccinated with live at- INFECTED CELLS
tenuated or inactivated inuenza vaccines (208, Viral infections trigger a panel of common
209). Longitudinal analysis of NK cell pheno- modications in their respective target cells,
types following immunization with inuenza which can be sensed by NK cells. These include
vaccines revealed a very early and transient de- ligands of several different families of NK cell
crease in the percentage of NKp46+ NK cells, receptors, probably to ensure that some will
further supporting a downmodulation of this still be efcient at eliciting NK cell responses
NCR upon engagement with HA, and a role for against viruses that have evolved multiple
182 Jost Altfeld

mechanisms to evade NK cell recognition. NK cell Infected cell

NK cell activation depends, on the one hand,
on the loss of inhibitory signals provided by a
MHC class I molecules and, on the other hand,
on the expression of stress- or virally induced ULBPs
ligands for activating NK cell receptors. The H NKG2D
MICA/B
best characterized of these ligands are those
engaging NKG2D (Table 1 and Figure 2a).
NKG2D
Interestingly, although many viruses express
proteins that counteract NKG2D-mediated
NK cell activation, no convincing escape
mechanisms have been described for viral es- RAE-1
cape from NCR-mediated recognition to date. M NKG2D MULT-1
H60
However, yet-to-be-discovered ligands for the

NCRs may play a role in the NK cell response
to viruses (Table 1, Figure 2b). Similarly,
natural ligands for most activating KIRs have

not been identied to date, and the precise role
of these receptors in the NK cell responses
b
against viruses remains to be determined. Host Viral HA
genetic-association studies with viral outcome HCMV pp65
H NCRs WNV/DV
have led to the suggestion that activating E glycoprotein
KIRs might recognize specic MHC class I ?
molecules when those molecules start present-
NCRs
ing epitopes derived from stress-induced or

viral proteins (Table 1 and Figure 2c) or that
activating KIRs might directly recognize viral
antigens, as described for Ly49H in the context Viral HA
of MCMV infection. Finally, both downmod- M NCRs
?
ulation of MHC class I and alterations of the

Figure 2
Expected changes in the expression of ligands for c
activating NK cell receptors at the surface of virally
infected cells in the absence of viral escape
mechanisms. (a) Upregulation of ligands for KIR2DS HLA-C
H
NKG2D. (b) Upregulation of cellular ligands and/or KIR3DS ?
expression of viral proteins recognized by NCRs.
(c) Upregulation of viral and/or cellular ligands
and/or changes in the repertoire of peptides
KlRs
presented by MHC class I that allow recognition by

activating KIRs. (Abbreviations: H, human; M,
mouse; NCR, natural cytotoxicity receptor; HA,
hemagglutinin; KIR, killer immunoglobulin-like
Ly49H m157
receptor; HLA, human leukocyte antigen; M
MULT-1, mouse UL16-binding-like transcript-1; Ly49D H-2Dd
RAE-1, retinoic acid early transcript-1; H60,
histocompatibility 60; ULBP, UL16-binding
protein; WNV/DV, West Nile virus/Dengue virus.)

repertoire of MHC class Ipresented peptides ral diseases, including human infections caused
may contribute to reducing the interactions by CMV, HIV-1, inuenza virus, and HCV. Al-
with NK cell inhibitory receptors (Table 1 and though NK cellmediated immunity can con-
Figure 1), resulting in NK cell disinhibition. tribute to viral control and viral clearance dur-
All the above-mentioned common features ing the initial acute phase of these infections,
of virally infected cells might act in concert to overly extensive activation of NK cells dur-
enhance NK cell antiviral responses. Further- ing acute infection and persistent stimulation
more, recent studies in Rag-decient mice have during chronic infections might contribute to
suggested that NK cells are endowed with the virus-associated pathology. Furthermore, there
ability to recognize virally infected cells in an are signicant limitations in our current under-
antigen-specic manner, in some cases through standing of the mechanisms by which human
receptors yet to be dened, allowing for subse- NK cells recognize different viruses and me-
quent NK cellmediated recall responses (46). diate their antiviral function. In particular, the
To determine the precise receptors and mech- human NK cell receptors that might enable NK
anisms underlying these NK cellmediated re- cells to directly recognize infected cells remain
call responses, and whether human NK cells unknown. Future studies will need to elucidate
possess this faculty, will surely become an in- in more detail the molecular mechanisms by
tense area of future investigation. which NK cells recognize infected cells, as well
as the receptor-ligand families involved. A more
precise understanding of these interactions will
CONCLUSIONS represent the basis for the development of even-
An increasing body of data suggests that NK tual targeted interventions to harness the antivi-
cells play a critical role in the control of many viral activity of human NK cells.
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
Work by the authors has been supported by the National Institutes of Health (R01AI066031
to M.A.), the Doris Duke Charitable Foundation (M.A.), the Philip T. and Susan M. Ragon
Foundation (M.A., S.J.), as well as the Swiss National Science Foundation and the Mas-
sachusetts General Hospital Executive Committee on Research (ECOR) Fund for Medical
Discovery (S.J.).
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200. Arnon TI, Achdout H, Lieberman N, Gazit R, Gonen-Gross T, et al. 2004. The mechanisms controlling
the recognition of tumor- and virus-infected cells by NKp46. Blood 103:66472
201. Draghi M, Pashine A, Sanjanwala B, Gendzekhadze K, Cantoni C, et al. 2007. NKp46 and NKG2D
recognition of infected dendritic cells is necessary for NK cell activation in the human response to
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202. Du N, Zhou J, Lin X, Zhang Y, Yang X, et al. 2010. Differential activation of NK cells by inuenza A
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in NKp46+ NK cells in response to inuenza. Immunology 132:51626
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binding properties of recent human inuenza H3N2 viruses are associated with reduced natural killer
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205. Zhang M, Gaschen B, Blay W, Foley B, Haigwood N, et al. 2004. Tracking global patterns of N-linked
glycosylation site variation in highly variable viral glycoproteins: HIV, SIV, and HCV envelopes and
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NK receptors after inuenza virus infection. J. Immunol. 171:91523
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through reorganization of major histocompatibility complex class I proteins. J. Virol. 82:803037
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children and adults receiving inactivated or live attenuated inuenza vaccines. J. Virol. 80:1175666
209. Long BR, Michaelsson J, Loo CP, Ballan WM, Vu BA, et al. 2008. Elevated frequency of gamma
interferon-producing NK cells in healthy adults vaccinated against inuenza virus. Clin. Vaccine Immunol.
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inuenza. J. Leukoc. Biol. 85:103643
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IY31-Frontmatter ARI 27 February 2013 7:16
Annual Review of
Contents Immunology
Volume 31, 2013
Years in Cologne
Klaus Rajewsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
The Biology of Recent Thymic Emigrants
Pamela J. Fink p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p31
Immunogenic Cell Death in Cancer Therapy
Guido Kroemer, Lorenzo Galluzzi, Oliver Kepp, and Laurence Zitvogel p p p p p p p p p p p p p p p p p51
Recognition of Bacteria by Inammasomes
Jakob von Moltke, Janelle S. Ayres, Eric M. Kofoed, Joseph Chavarra-Smith,

and Russell E. Vance p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p73
The Immunology of Fibrosis
Georg Wick, Cecilia Grundtman, Christina Mayerl, Thomas-Florian Wimpissinger,
Johann Feichtinger, Bettina Zelger, Roswitha Sgonc, and Dolores Wolfram p p p p p p p p p 107
Memory T Cell Subsets, Migration Patterns, and Tissue Residence
Scott N. Mueller, Thomas Gebhardt, Francis R. Carbone, and William R. Heath p p p p p 137
Control of Human Viral Infections by Natural Killer Cells
Stephanie Jost and Marcus Altfeld p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163
Functional T Cell Immunodeciencies (with T Cells Present)
Luigi D. Notarangelo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 195
Controlling Natural Killer Cell Responses: Integration of Signals for
Activation and Inhibition
Eric O. Long, Hun Sik Kim, Dongfang Liu, Mary E. Peterson,
and Sumati Rajagopalan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
Metabolic Regulation of T Lymphocytes
Nancie J. MacIver, Ryan D. Michalek, and Jeffrey C. Rathmell p p p p p p p p p p p p p p p p p p p p p p p p 259
Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche
and a Stepping-Stone for Regenerative Medicine
Paul S. Frenette, Sandra Pinho, Daniel Lucas, and Christoph Scheiermann p p p p p p p p p p p 285
Interleukin-4- and Interleukin-13-Mediated Alternatively Activated
Macrophages: Roles in Homeostasis and Disease
Steven J. Van Dyken and Richard M. Locksley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Brain-Reactive Antibodies and Disease
B. Diamond, G. Honig, S. Mader, L. Brimberg, and B.T. Volpe p p p p p p p p p p p p p p p p p p p p p p p 345
v
IY31-Frontmatter ARI 27 February 2013 7:16
Immunology of the Maternal-Fetal Interface

Adrian Erlebacher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 387
Regulation of Ligands for the NKG2D Activating Receptor
David H. Raulet, Stephan Gasser, Benjamin G. Gowen, Weiwen Deng,
and Heiyoun Jung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Pathways of Antigen Processing
Janice S. Blum, Pamela A. Wearsch, and Peter Cresswell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
The Immune Response in Tuberculosis
Anne OGarra, Paul S. Redford, Finlay W. McNab, and Chloe I. Bloom,
Robert J. Wilkinson, and Matthew P.R. Berry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 475
The Adaptable Major Histocompatibility Complex (MHC) Fold: Structure
and Function of Nonclassical and MHC Class ILike Molecules

Erin J. Adams and Adrienne M. Luoma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 529
The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and
Their Subsets in the Steady State and the Inamed Setting
Miriam Merad, Priyanka Sathe, Julie Helft, Jennifer Miller, and Arthur Mortha p p p 563
T CellMediated Host Immune Defenses in the Lung
Kong Chen and Jay K. Kolls p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 605
Human Hemato-Lymphoid System Mice: Current Use and Future Potential
for Medicine
Anthony Rongvaux, Hitoshi Takizawa, Till Strowig, Tim Willinger,
Elizabeth E. Eynon, Richard A. Flavell, and Markus G. Manz p p p p p p p p p p p p p p p p p p p p p p 635
Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells
Klaus Okkenhaug p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 675
Broadly Neutralizing Antiviral Antibodies
Davide Corti and Antonio Lanzavecchia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 705
Molecular Control of Steady-State Dendritic Cell Maturation and Immune
Homeostasis
Gianna Elena Hammer and Averil Ma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 743
Indexes
Cumulative Index of Contributing Authors, Volumes 2131 p p p p p p p p p p p p p p p p p p p p p p p p p p p 793

Cumulative Index of Articles Titles, Volumes 2131 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 800
Errata
An online log of corrections to Annual Review of Immunology articles may be found at

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Control of Human Viral Infections by NK Cells

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IY31CH07-Altfeld ARI 14 February 2013 21:16

Our comprehensive search

Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02129;

Annu. Rev. Immunol. 2013. 31:16394 Keywords

The Annual Review of Immunology is online at Abstract

INTRODUCTION human viral infections: CMV, inuenza virus,

164 Jost Altfeld

Table 1 Major mouse and human NK cell receptorsa

Viral HA, HSPG Activating

www.annualreviews.org Control of Human Viral Infections by NK Cells 165

Table 2 Associations between KIR/HLA interactions and human viral diseases

KIR3DS1, KIR2DS5, KIR2DL5

RECEPTORS THAT CONTROL like receptors (KIRs) in humans share crucial

166 Jost Altfeld

C2). KIR2DL2/3 preferentially bind HLA-C1, (HCMV) glycoprotein UL16-binding proteins

www.annualreviews.org Control of Human Viral Infections by NK Cells 167

168 Jost Altfeld

m157 is recognized by high-afnity inhibitory in HLA degradation; US3 causes retention

www.annualreviews.org Control of Human Viral Infections by NK Cells 169

NKG2A does, expand in response to HCMV negative. Similarly, an expansion of NKG2C+

Furthermore, expansion kinetics of NKG2C+ evasion strategies against NK cellmediated

170 Jost Altfeld

www.annualreviews.org Control of Human Viral Infections by NK Cells 171

of HIV-1 replication and disease outcome. of a single nucleotide polymorphism (SNP)

172 Jost Altfeld

in contrast to what has been observed for in-

www.annualreviews.org Control of Human Viral Infections by NK Cells 173

a Inhib KIR HLA

174 Jost Altfeld

www.annualreviews.org Control of Human Viral Infections by NK Cells 175

in the context of the KIR2DL3/HLA-C1

Ligand HLA-C1 NK cells in the blood of individuals with acute

176 Jost Altfeld

www.annualreviews.org Control of Human Viral Infections by NK Cells 177

Redistribution of NK cell subsets occurs early

During HCV Infection by an increase in the percentages of CD56bright

178 Jost Altfeld

www.annualreviews.org Control of Human Viral Infections by NK Cells 179

180 Jost Altfeld

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expression of ligands for NK cellactivating decreases in peripheral blood NK cell numbers

182 Jost Altfeld

mechanisms to evade NK cell recognition. NK cell Infected cell

However, yet-to-be-discovered ligands for the

natural ligands for most activating KIRs have

ing epitopes derived from stress-induced or

presented by MHC class I that allow recognition by

www.annualreviews.org Control of Human Viral Infections by NK Cells 183

184 Jost Altfeld

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186 Jost Altfeld

failure of the Merck HIV-1 vaccine in humans. Nat. Med. 14:61721

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190 Jost Altfeld

natural killer cell functions. J. Exp. Med. 195:4349

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192 Jost Altfeld

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194 Jost Altfeld

Jakob von Moltke, Janelle S. Ayres, Eric M. Kofoed, Joseph Chavarra-Smith,

Immunology of the Maternal-Fetal Interface

and Function of Nonclassical and MHC Class ILike Molecules