Molecular Immunology 41 (2004) 141146

Review
The complement system in B cell regulation
Michael C. Carroll

The Departments of Pediatrics and Pathology, The CBR Institute for Biomedical Research Inc.,
Harvard Medical School, 800 Huntington Ave., Boston, MA 02115, USA
Abstract
Early studies of animals bearing natural deciencies in complement C3 and C4 and mice transiently decient in C3 suggested that the
complement system played a role in humoral immunity. Identication and characterization of the complement receptors CD21 and CD35
and their expression on B lymphocytes provided evidence for a direct role for complement in linkage of innate and adaptive immunity.
More recent studies of mice bearing targeted deciencies in complement proteins C3, C4 or the receptors CD21/CD35 has conrmed
the importance of complement in B cell responses in vivo and extended our understanding to distinct stages in B cell differentiation in
which complement participates in humoral immunity. In this review, a role for complement is described in ve distinct stages of B cell
differentiation.
2004 Elsevier Ltd. All rights reserved.
Keywords: Humoral immunity; Complement receptors; Innate immunity; Germinal centers; Follicular dendritic cells
1. Introduction
The importance of the complement system in inamma-
tion is well appreciated; however increasing evidence sup-
ports its important role in regulation of B lymphocytes. In
this review, I will focus on efforts from my laboratory and
others to understand at what stages the complement system
is involved in regulation of humoral immunity. The early
observation by Nussenzweig and colleagues that B lympho-
cytes bound complement C3 raised the question of whether
the complement system was involved in adaptive immune
responses (Nussenzweig et al., 1971). The subsequent obser-
vation by Pepys that depletion of C3 could dampen or impair
humoral immunity to thymus-dependent antigens provided
more direct evidence that indeed the complement system
was required for efcient adaptive response to at least some
antigens (Pepys, 1972). Characterization of immune re-
sponses in humans (Jackson et al., 1979), guinea pigs (Ochs
et al., 1986) or dogs (ONeil et al., 1988) bearing natural de-
ciency in early complement proteins further substantiated
an important role for complement and implicated a role for
early classical pathway. In these earlier studies, it was noted
that an intact classical pathway of complement was essen-
tial for efcient trapping and retention of antigen within
lymphoid tissues (splenic follicles) (Papamichail et al.,
1975). Therefore, it was generally held that one major role

Tel.: +1-617-278-6660.
E-mail address: carroll@cbr.med.harvard.edu (M.C. Carroll).
of the complement system was to bind and localize foreign
antigens within sites important for lymphocyte responses.
The identication and characterization of complement
receptors CD21 and CD35 greatly expanded our under-
standing of how complement ligands inuenced localization
of antigen and suggested an additional mechanism by which
complement acted on B cells. In humans, the two receptors
are encoded by separate but linked genes; they are expressed
on all red cells, certain hematapoietic cells, B cells and
specialized stromal cells referred to as follicular dendritic
cells (FDC) (Fearon and Wong, 1983). In the mouse, the
two receptors are encoded at a single locus, i.e. Cr2, and
CD21 protein is a splice product of CD35 message, (Kurtz
et al., 1990). Moreover, expression is limited as they are
co-expressed primarily on B cells, FDC and probably a mi-
nor subset of myeloid and T cells (Molina et al., 1992). On
B cells, CD21 (and CD35 in the mouse) form a co-receptor
with signaling protein CD19 and the tetra-span receptor
CD81(Matsumoto et al., 1993). As rst proposed by Carter
and Fearon, co-ligation of the co-receptor and the Bcell anti-
gen receptor (BCR) substantially lowers the threshold for B
cell activation (Carter and Fearon, 1992). This important ob-
servation provided an alternative explanation for how com-
plement could inuence immune responses. To test directly
the effect of C3d ligand on B cells responses, Dempsey et al.
prepared fusion proteins of multimers of C3d and lysozyme
(Dempsey et al., 1996). Notably, they found that attachment
of antigen to multimeric C3d lowered the threshold of B
cell activation in vitro by several orders of magnitude. Thus,
0161-5890/$ see front matter 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.molimm.2004.03.017
142 M.C. Carroll / Molecular Immunology 41 (2004) 141146
complement appears to enhance humoral responses by both
localization of antigens to FDC and co-receptor signaling.
More recent studies suggest other complement receptors are
important in adaptive responses and in particular enhance-
ment of T cell responses (Kopf et al., 2002), (Kemper et al.,
2003).
Our own studies have focused on understanding the im-
portance of complement proteins C3 and C4 and receptors
CD21/CD35 in vivo using genetically modied strains of
mice bearing null alleles for the relevant complement com-
ponent (Carroll, 1999). Based on results from these animal
models and similar studies by other groups, it is becoming
apparent that complement acts at multiple stages to regulate
B cell responses. Thus, evidence is accumulating that com-
plement has a major affect on at least ve different stages
in B cell differentiation and these are outlines in more detail
below and in Fig. 1.
1.1. Repertoire of natural antibody is altered in Cr2-def
mice
Natural antibody is produced primarily by a subset of
B cells termed B-1. They are distinguished from conven-
tional B cells (B-2) by anatomical localization, repertoire,
cell surface phenotype, activation and life span. B-1 cells
are IgM-int, IgD-neg and CD21-int, CD23-neg and localize
primarily in the peritoneal tissues and at low levels in the
spleen and lymph nodes (LN). Two subsets have been iden-
tied based on expression of CD5, i.e. CD5+ termed B-1a
and CD5-neg termed B-1b. Both subsets express CD43 and
CD11b unlike conventional B cells. Although B-1 cells can
undergo isotype switch, they are not thought to enter germi-
nal centers or acquire extensive somatic mutation; however,
they are long-lived and appear to undergo self-renewal. Their
repertoire appears to be biased towards highly conserved
B
mature

+ +

+ +
CD21
+ +
CD23
+ +
B
B
T
B cell
compartment
T cell
compartment
Spleen
B
T
Germinal
Center
antigen
selection
FDC
long term
effector cells
IgG
lo
CD21
hi
CD23
-
memory
compartment
Spleen / Bone Marrow
B
B
CD21/
CD35
antigen TCR
C3d
CD19
MHC
peptide BCR
B B
Expansion
B
B
short term
effector cells
antigen
selection
FcR
Fig. 1. Complement receptors are important in regulation of B lymphocyte responses at multiple stages of the peripheral response. Activation of nave
B cells by engagement of antigen coupled to complement C3d results in co-ligation of BCR and co-receptor and in the presence of T cell help leads
to activation and expansion. Activated cells initiate a germinal center within the splenic follicles which is organized by ollicular dendritic cells (FDC).
Complement receptors expressed on GC B cells act to enhance BCR signaling. In addition, complement receptors expressed on FDC act to promote
antigen selection of high afnity GC B cells. Thus, CD21/CD35 are critical in retention of antigen complexes. Post-GC B cells continue to require
complement in continued antigen selection at least within the spleen as maintenance of long-term memory B cells is dependent on CD21/CD35 receptor.
antigens such as phosphoryl choline, phosphatidyl choline
and nuclear antigens such as DNA and nuclear proteins. This
bias might reect their development as they are selected
during early neonatal period in which terminal transferase
is not expressed and V to DJ gene rearrangement is biased
towards more proximal gene expression. Their repertoire is
also inuenced by positive selection by self and enteric bac-
terial antigens (Hardy and Hayakawa, 2001) (Herzenberg
and Kantor, 1993).
Development of B-1 cells requires an intact BCR as de-
fects in proteins involved in BCR signaling such as vav,
PI-3 kinase and CD19 result in a more profound loss of
B-1 relative to conventional B-2 cells (Cariappa and Pillai,
2002). Moreover, mutations leading to hyper-responsive
BCRsignaling can result in increased frequency of B-1 cells.
Whether this reects a general requirement for intrinsic
signaling of BCR or encounter with cognate antigen is not
clear. However recent studies identifying the requirement
of cognate antigen for certain B-1 cell specicities suggests
that interaction with self-antigens or enteric bacteria is im-
portant for initial positive selection or expansion and main-
tenance. Complement receptors CD21/CD35 also appear to
be important in selection or expansion/maintenance of B-1
cells as Cr2-def mice have an altered repertoire of natural
antibody to certain but not all self-antigens. For example,
both lines of Cr2-def mice are missing or have reduced lev-
els of natural antibody involved in induction of reperfusion
injury (I/R). I/R represents an acute inammatory response
against self following reperfusion of ischemic tissues. It is
mediated by natural IgM (and IgG) and classical pathway
complement. Cr2-def mice are protected from full injury to
a similar level as Ig-decient animals (Fleming et al., 2002)
(Reid et al., 2002). Thus, despite apparent normal levels of
serum IgM Cr2-def mice are protected in an intestinal model
of I/R. Injury can be restored by reconstitution with pooled
M.C. Carroll / Molecular Immunology 41 (2004) 141146 143
IgM prepared from WT mice. Alternatively, reconstitution
of Cr2-def mice with WT peritoneal B cells also restores
their susceptibility to I/R injury. Since engrafted Cr2+ B-1
cells are maintained in Cr2-def mice in the absence of stro-
mal expression of CD21/CD35 it seems most likely that
co-receptor signaling rather than FDC binding is important
in expansion/maintenance of the B-1 subset of cells.
In summary, B-1 cells are a major source of natural an-
tibody and are positively selected during early development
by cognate antigen. The interaction requires complement re-
ceptors for at least some antigens to enhance antigen recep-
tor signaling.
1.2. Activation of naive B cells
B cells, like T cells, must be tightly regulated to circum-
vent non-specic activation of bystander cells during an on-
going infection. Antigen specicity is insured in large part
by the requirement for two signals, i.e. BCR and CD40, to
promote activation and expansion against specic pathogens.
B cell encounters with antigen in the absence of T cell help
(CD40L co-stimulation) or vice versa can result in induc-
tion of anergy or cell death. A well-characterized pathway
for regulation of peripheral lymphocytes is via Fas recep-
tor (CD95). Trimerization of the Fas receptor on periph-
eral B cells stimulated by CD40 alone leads to assembly of
the caspase death pathway and B cell apoptosis. Efcient
cross-linking of BCR induces expression of Fas ligand in-
hibitor protein (cFLIP) that blocks the caspase pathway re-
sulting in cell survival and expansion. Antigen afnity is
important in this regulatory step as co-ligation of CD21 and
BCR can protect; whereas cross-linking of BCR alone by
moderate afnity antigen does not (Fischer et al., 1998).
Thus, as predicted by Carter and Fearon the co-receptor is
important in lowering the threshold for B cell activation in
vivo.
In summary, the Fas pathway regulates naive peripheral B
cells to limit bystander activation during an ongoing infec-
tion. Regulation is dependent on antigen afnity and com-
plement receptors as low-moderate afnity antigens require
co-receptor cross-linking to prevent Fas-dependent apopto-
sis. Thus, engagement of the BCR and co-receptor is impor-
tant for survival and expansion of naive B cells following
encounter with many T-dependent antigens.
1.3. Germinal center survival
Germinal centers (GC) represent a specialized micro-
environment within the B cell follicles of lymphoid tis-
sue (MacLennan, 1994). They are transient in duration
and disappear within 1521 days following immunization.
Within GC, activated B cells (termed centrocytes) undergo
rapid expansion, isotype switch and somatic hypermuta-
tion followed by antigen selection. As mutated centrocytes
emerge from the dark zone they encounter C3-coated anti-
gen retained on FDC primarily via CD21/CD35 but also
FcR. Survival of GC B cells within GC is dependent on
T cell help (CD40 ligand), antigen and interaction with
FDC.
Co-receptor expression is also required for survival of B
cells within GC based on several lines of evidence. Treat-
ment of immune mice with soluble CD21 receptor (sCR2)
results in rapid loss of the GC (Fischer et al., 1998). Thus,
contact between C3d-coated antigens localized on FDC is
essential for survival of GC B cells. Whether the B cells
are eliminated in a Fas- or FcRIIB-dependent mechanism
is not known. Further support comes from studies compar-
ing GC survival of Cr2+ and Cr2-def immunoglobulin (Ig)
transgenic (Tg) B cells (specic for hen lysozyme). In this
study, adoptive transfer of high afnity Ig-Tg B cells into
mice immunized with specic antigen identied participa-
tion of the Cr2+ but not Cr2-def Tg B cells within the GC.
Thus, expression of a high afnity BCR was not sufcient
to mediate survival of B cells in absence of co-receptor ex-
pression (Fischer et al., 1998).
In summary, the GC represents a specialized environment
within the lymphoid compartment for expansion, isotype
switch, somatic hypermutation and antigen-dependent selec-
tion of high afnity B cells. Survival requires presence of
antigen, T cell help and contact with FDC. Co-receptor sig-
naling independent of antigen afnity is also required and
explains at least part of the need for FDC.
1.4. Memory B cells and persistence of
antibody secretion
A hallmark of the adaptive immune response is formation
of memory B cells. These post-GC cells are antigen selected
and of relatively high afnity. A sub-population of memory
cells (B
mem
) differentiate into antibody forming cells (AFC)
or plasma cells that persist over long-term primarily in the
bone marrow (BM) but also in the secondary lymphoid com-
partment. The role of antigen in maintenance of AFC and
B
mem
is controversial. Earlier studies by Gray demonstrated
a critical role for antigen in long-term antibody secretion
and recall (Gray, 2002). These results combined with the ob-
servations that antibody afnity continues to increase long
after GC wane suggests that at least some post-GC AFC
precursors are continually selected by antigen such that the
higher afnity clones are preferentially maintained. More re-
cent adoptive transfer studies using chimeric mice in which
FDC are decient in CD21/CD35 or FcRIIB provide further
support that antigen is important in maintenance of B
mem
cells (Barrington et al., 2002). An alternative view is that
B
mem
, like memory T cells, are long-lived in the absence of
antigen. This view is supported by results that suggest that
B
mem
cells are non-dividing over long periods and recent el-
egant genetic experiments demonstrating that switching of
BCR specicity after formation of B
mem
did not appear to
alter their survival as functional memory cells (Maruyama
et al., 2000). A current view is that antigen is important for
afnity maturation and efcient maintenance of memory B
144 M.C. Carroll / Molecular Immunology 41 (2004) 141146
cells. However, sub-populations of long-lived plasma cells
and B
mem
cells persist in the absence of antigen.
In summary, antigen is retained over long periods on FDC
primarily via CD21/CD35 and appears to be essential for an
effective recall response. The presence of antigen is impor-
tant for both afnity maturation and efcient maintenance
of memory B cells.
1.5. Negative selection of self-reactive B cells
Systemic lupus erythematosus (SLE) is an autoimmune
disease characterized by antibodies specic for nuclear anti-
gens such as dsDNA. Although full development of disease
is due to multiple gene defects, dysregulation of B cells is
a major factor. Defects resulting in excess BCR signaling
such as loss of negative regulators like FcRIIB often lead
to production of anti-dsDNA or -nuclear antibodies (ANA).
One interpretation of these results is that breakdown in nor-
mal regulation of self-reactive B cells within the BM and
periphery results in survival of self-reactive cells that be-
come activated and secrete auto-antibodies in the presence
of T cell help.
Multiple checkpoints have evolved to limit develop-
ment and activation of self-reactive B cells. Within the
BM (central tolerance), B cells that rearrange and express
self-reactive receptors at the immature stage are either
edited (rearrangement of additional upstream Ig-light chain
variable region genes) or eliminated by apoptosis. How
immature B cells encounter self-antigen is not clear. How-
ever, it is most probable that mechanisms similar to ones
utilized in localization of environmental antigens within
the periphery are involved. The observation that deciency
in complement components Clq and C4 predispose to Lu-
pus suggests an important role for the complement system.
Thus, complement proteins Clq and C4 and the receptors
CD21/CD35 could protect from Lupus by enhancing pre-
sentation of Lupus antigens to self-reactive B cells at the
immature stage. At this stage encounter with antigen re-
sults in negative selection rather than activation. Defects
in retention of self-antigen could result in loss of efcient
negative selection and escape of self-reactive B cells to
the periphery. In addition, complement could participate in
peripheral tolerance at the transitional stage. CD21/CD35
are rst expressed at the T1T2 transitional stage in which
a threshold BCR signal can result in cell death rather than
activation. Co-cross-linking of BCR and co-receptor would
increase the sensitivity of the transitional B cell to C4b
coupled cognate self-antigens.
The human CD35 receptor binds both C1q and acti-
vated C4; whereas the mouse receptor only appears to
bind the latter. If CD21/CD35 participate in the uptake of
C4-bound lupus antigens, Cr2-def mice might be expected
to also display increased production of lupus autoantibod-
ies. Although Cr2-def mice (mixed background) do not
spontaneously develop signicant levels of anti-nuclear an-
tibodies (ANA), when combined with Fas-deciency they
develop an overt lupus-like phenotype characterized by
early (by 1520 weeks) onset of anti-dsDNA and ANA
and glomerular nephritis (Prodeus et al., 1998). Cr2-def
mice on the B-6 background bred with Fas-deciency also
develop ANA but their phenotype seems less severe than
on the mixed background (Molina et al, 2002). Additional
support for a role for CD21/CD35 receptors comes from
genetic mapping of susceptibility loci in a lupus-prone
strain of mice (NZM 2410/NZW) (Boackle et al., 2001).
One of the susceptibility loci, Sle-1c includes the Cr2 lo-
cus, suggesting that CD21 or CD35 might be involved in
the lupus phenotype. Structural analysis of the CD21 allele
(NZM2410/NZW) identied several nucleotide differences
one of which results in the addition of a carbohydrate at-
tachment site within the region of C3d binding. Functional
studies of B cells that express the mutant allele conrmed
that binding of C3d is reduced and that co-receptor activity
is diminished. The ndings from this study suggest that the
Cr2-locus encodes the Sle-1c susceptibility gene. Whether
the mutation affects C4b as well as C3d binding was not
reported.
Much of our understanding of negative selection of B
cells comes from studies with immunoglobulin transgenic
(Tg) mice in which the majority of B cells express a known
receptor for self-antigen. One model that is particularly
well-characterized is the hen lysozyme (HEL) model in
which the B cells express a conventional Ig-Heavy (Hc) and
Light (Lc) chain Tg which encodes a relatively high afnity
BCR. In the absence of the antigen, the B cells appear to
mature normally and are responsive to antigen both in vivo
and in vitro. However, when the mice are crossed with a
strain that expresses a soluble form of the antigen (sHEL)
the B cells undergo negative selection. In the BM, imma-
ture HEL-Tg B cells undergo limited receptor editing and
apoptosis in response to threshold levels of self-antigen.
Self-reactive Tg B cells that escape become anergized and
remain unresponsive when treated with antigen in vitro.
Moreover, the anergic B cells have a reduced half-life that
is reected by a reduced frequency of CD23+ mature B
cells within the lymph nodes.
The role of complement and its receptors was tested in
this model by crossing mice decient in C1q, C4, C3 or
CD21/CD35 with double Tg mice, i.e. HEL-Ig Tg sHEL
Tg. While no effect on anergy was observed in C1q- or
C3-def HEL double Tg mice, (Cutler et al., 2001) mice de-
cient in either C4 or CD21/C35 failed to develop the full
anergic phenotype (Prodeus et al., 1998). Characterization
of splenic B cells isolated from double Tg mice that were
decient either in C4- or CD21/CD35 revealed a phenotype
similar to that of single Tg mice. Thus, the B cells remained
responsive to antigen in vitro and the frequency of mature
cells within LNs was similar to that of single Tg mice. By
contrast, complement-sufcient controls and C3-def double
Tg mice expressed the normal anergic phenotype. The nd-
ing that C3-def mice were fully anergic was not unexpected
and is consistent with observations discussed above. The
M.C. Carroll / Molecular Immunology 41 (2004) 141146 145
results suggest that C4 functions via CD21/CD35 and
they both are involved in induction of anergy in the Ig Tg
model.
It is not clear at what stage complement and its recep-
tors are involved in tolerance in the lysozyme-double Tg
model. This model of autoimmunity is considered one of
peripheral tolerance since the majority of the B cells es-
cape to the periphery where they remain unresponsive. Al-
though, as noted above, a fraction of self-reactive B cells
undergo receptor editing and apoptosis within the BM that
indicates that the self-reactive B cells encounter antigen
prior to reaching the periphery. It is not known if C4 or
CD21/CD35 deciency alters editing or apoptosis. Since B
cells do not express CD21/CD35 until the late transitional
stage (splenic compartment), their role in central tolerance is
probably limited to binding antigen on stromal cells. Thus,
retention of C4-coated sHEL antigen on BM stroma via
CD35 could enhance encounter by developing B cells and
increase the efciency of threshold signaling by aggregation
of antigen. An alternative (but not mutually exclusive) ex-
planation is that complement affects the HEL-self-reactive B
cells at the transitional stage once they express CD21/CD35.
As discussed above, this is an important checkpoint and it
could involve CD21/CD35. B cells at this stage also require
BAFF ligand for survival; it is possible that BAFF receptor
signaling is affected by BCR cross-linking. One possibil-
ity is that co-receptor signaling at this stage via C4-coated
self-antigens enhances a negative BCR signal resulting in
cell death or anergy.
In summary, deciency in complement proteins C1q and
C4 leads to increased susceptibility of lupus and produc-
tion of auto-antibodies both in humans and murine models.
This striking observation supports a critical role for com-
plement and its receptors in protection from maturation
of self-reactive B cells. Deciency in CD21/CD35 when
combined with Fas-deciency results in earlier onset and
increased disease. Moreover, identication of a mutant Cr2
allele with reduced C3d binding correlates with increased
auto-antibodies and suggests a role for CD21/CD35 in
regulation of self-reactive B cells. The stage at which com-
plement participates in negative selection is not clear as it
could affect immature B cells within the bone marrow or
in the transitional stage in the spleen or both.
2. Conclusions
Over the past decade our understanding of how the com-
plement system inuences lymphocyte cell responses has
greatly expanded. However a number of important ques-
tions remain, such as how complement protects in lupus and
further dissection of the mechanisms in which complement
enhances survival and differentiation of distinct subsets of
B cells. The more recent observations of a role for comple-
ment in activation of T cells suggest another important area
for investigation over the next decade.
Acknowledgements
Work was supported by NIH grants (AI39246-09,
AI36389-08, GM52585-09, AI52343-02).
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