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The CBR Institute for Biomedical Research, Harvard Medical School, 800
Huntington Ave., Boston, Massachusetts 02115, USA. Correspondence should
be addressed to M.C.C. (carroll@cbr.med.harvard.edu).
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cells (FDCs) within lymphoid follicles24. These findings, combined
with experimental results showing that a transient reduction in the
amount of circulating complement C3 led to an impairment in antibody response, suggested that the complement system was involved in
adaptive immunity25.
A fundamental event following activation of the complement system is covalent attachment of C3b to the foreign (or self) antigen26,27.
Conceptually, this is a key event in innate immunity because it provides a mechanism to mark or identify antigens (both foreign and
self) for uptake by phagocytic cells or retention on FDCs for recognition by cognate B lymphocytes (discussed in more detail below). Both
C3 and C4 components have an internal thioester that upon activation can form amide or ester linkage28. This usually follows proteolytic cleavage via the classical or lectin pathways. However, as
mentioned above, C3 can spontaneously form a covalent linkage and
provide a substrate for amplification via the alternative pathway29.
Complement enhances B cell immunity principally via complement receptors CD21 (which binds iC3b, C3d,g and C3d) and CD35
(which binds the same C3 products as CD21 but also binds C3b and
C4b)30. In mice, the two receptors seem to be coexpressed and represent splice products of a single locus (the Cr2 locus)31,32. They are
expressed mainly on B cells and FDCs. On B cells, CD21 forms a
receptor complex with the signaling protein CD19 and tetraspan
protein CD81 (ref. 33). Uptake of C3d-coated antigen by cognate B
cells results in an enhanced signal via the B cell antigen receptor34.
Thus, coengagement of the CD21-CD19-CD81 coreceptor with B
cell antigen receptor lowers the threshold of B cell activation and
provides an important survival signal. A second key mechanism by
which complement enhances B cell immunity is by localization of
antigen to FDCs within lymphoid follicles35. FDCs are specialized
stromal cells that secrete the B lymphocyte chemoattractant
chemokine36 and are important in organizing germinal centers
Peripheral compartment
Transitional
Mature
Activation
1
B1
B2
B2
Anergy or
apoptosis
Plasma cell
MHC peptide
C3d
Antigen
CD21, CD19
B1
B2
CD35
FDC
Figure 1 Complement receptors are important in the regulation of B lymphocyte differentiation at five
stages. Stage 1: B1 cells represent a subset of B cells that preferentially develop during early life and
are positively selected by self or microbial antigens, probably at the transitional stage. CD21-CD19CD81 coreceptor engagement by complement-coated antigens enhances positive selection. Stage 2:
Self-reactive B cells are eliminated in the bone marrow and at the peripheral transitional stage.
Coligation of the B cell antigen receptor (BCR) and CD21-CD19-CD81 coreceptor by C3- or C4-coated
self antigen alters negative signaling. Stage 3: Activation of naive mature follicular B cells by the
engagement of antigen coupled to complement C3d results in coligation of the B cell antigen receptor
and coreceptor; in the presence of T cell help, this leads to activation and expansion. Stage 4:
Activated B cells initiate the formation of a germinal center in the splenic follicles, which is organized
by FDCs. Complement receptors expressed on germinal center B cells enhance BCR signaling. In
addition, complement receptors expressed on FDCs retain antigen and promote the antigen selection
of high-affinity germinal center B cells. Stage 5: Post-GC B cells require complement and antigen
selection for the efficient maintenance of long-term memory B cells.
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keyhole limpet hemocyanin or bacteriophage40,55 developed apparently normal T cell responses, yet humoral responses were impaired.
Likewise, initial work with infectious herpes simplex virus or inactivated lymphocytic choriomeningitis virus in C3-deficient mice found
no alteration in the priming of CD4+ T cells, despite the impairment
of B cell immunity56,57. In addition, impairment of B cell responses by
blocking of Cr2 receptors did not alter priming of T helper cells58.
A report that the priming of both CD4+ and CD8+ T cells was
impaired in C3-deficient mice in an influenza virus model supports
the idea of more general involvement of the complement system in
adaptive immunity59. Although the mechanism remains unclear, C3
is required in the pulmonary T cell response to influenza. Challenge
of Cr2-deficient mice in a similar model indicates that T cell priming
is normal, suggesting that the CD21-CD19-CD81 B cell coreceptor is
not involved. One possible explanation is that APCs preferentially
take up C3-coated viral particles for the priming CD4+ and CD8+ T
cells via complement receptors such as CR3 (CD11b-CD18) or CR4
(CD11c-CD18). In the absence of C3, APC function could be
reduced, resulting in a limited priming of T cells. An alternative possibility that is not mutually exclusive of an APC defect is that the
chemokine-like C3a and C5a receptors are important in the pulmonary response.
A fundamental event following the activation of complement C3
and C5 is release of N-terminal peptides of approximately 9 kilodaltons. They are byproducts of all three complement activation pathways and serve as potent ligands for G proteincoupled
chemoattractant receptors referred to as C3aR and C5aR, respectively6062. They are expressed on a wide range of inflammatory cells,
such as mast cells, eosinophils, basophils and lymphocytes, as well as
smooth muscle cells. They seem to participate in inflammatory events
via direct cell activation and in the modulation of cytokine release by
macrophages and/or monocytes. In the influenza model, the absence
of C3a and C5a ligands could influence the infiltration of CD4+ and
CD8+ T cells, as is described in more detail below.
How complement is activated in the influenza model is not
known, but one strong possibility is that specific natural antibody
binds virus particles and activates complement via the classical
pathway. Studies showing involvement of natural antibody in the
humoral response to influenza support this possibility63. Further
support for the idea of involvement of natural IgM and complement
in priming CD8+ T cells comes from a leishmania recombinant antigen hydrophilic acylated surface protein B1 (HASPB-1) model64.
The investigators proposed a pathway in which the recognition of
HASPB-1 by natural IgM activates classical pathway complement,
leading to the production of interleukin 4 (IL-4) by a CD11b+
CD11clo population of macrophages and the stimulation of IL-12
release by DCs. How complement activation stimulates macrophage
release of IL-4 is not clear. One possibility is that it occurs by direct
opsonization via the CR3 receptor with C3-coated antigen.
Although crosslinking CR3 is not thought to stimulate the release of
IL-4 in general, coligation with a HASPB-specific TLR could provide a suitable stimulus.
Natural antibody and classical pathway complement also seem to
be involved in contact sensitivity. In a complex model, involving
natural killer T cell release of IL-4 and the stimulation of B1 cell
production of natural IgM, Askenase and colleagues observed that
the early stage of contact sensitivity is complement-dependent65.
Notably, complement is activated via the innate natural IgM pathway, similar to that of the HASPB-1 model discussed above66.
However, in the example of contact sensitivity, IL-4 production lies
upstream of B1 cell release of IgM.
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2 10 PFU
HSV-I
DC
1
DC
2
DC
Afferent
lymph
B B
7
B
DC
Lymph
node
B B
M
5
MHC
class II
C3
IFN-
Viral
antigen
Antibody
T cell
receptor
Phagocytic
cells
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advances in real-time imaging and the construction of conditional
knock-in mice, many of these types of questions can be answered.
Finally, the observations that complement in concert with natural
antibody participates in regulating T cell immunity, both in activation and in control, provides a rich area for further investigation. It is
likely that the complement receptor pathways intersect with other
innate pathways such as the TLRs, as might occur in response to
highly conserved microbial antigens or PAMPs. This topic provides
additional opportunities for exploration.
In summary, the complement system represents a complex component of innate immunity that has many functions, including the
regulation of adaptive immunity. Further study will no doubt lead
to the identification of additional pathways that link innate and
adaptive immunity.
ACKNOWLEDGMENTS
I thank R. Barrington for review of the manuscript, and current and past members
of the laboratory for their contributions to the understanding of how complement
influences adaptive immunity. The related work from my laboratory is supported
by grants from the National Institutes of Health (AI39246-09, AI36389-08,
AI52343-03 and AI53570-02).
COMPETING INTERESTS STATEMENT
The author declares that he has no competing financial interests.
Published online at http://www.nature.com/natureimmunology/
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