The successful elimination of most pathogens requires
crosstalk between the innate and adaptive arms of the
immune system. The innate immune system recognizes
pathogen-associated molecular patterns1 through
pattern-recognition receptors, such as Toll-like recep-
tors (TLRs) and nucleotide-binding oligomerization
domain (NOD) receptors, and through the activa-
tion of complement by lectins (carbohydrate-binding
proteins) and natural antibodies2,3. These interactions
are followed by the release of cytokines, chemokines,
opsonins, anaphylatoxins and defensins.
The complement system was identified more than
100 years ago as an effector arm of the antibody response
that destroys bacteria by lysis4,5. The complement cascade
is initiated through three pathways: the classical path-
way, the lectin pathway and the alternative pathway2,3
(FIG. 1a). The classical, C1q (complement component 1q)-
dependent pathway is activated by the binding of C1q to
complement-fixing antibodies, which are bound to antigen
on the surface of bacteria, whereas the lectin pathway
is activated by proteins, such as mannan-binding lec-
tin (MBL), in association with MBL-associated serine
proteases (MASPs), attaching to carbohydrate patterns
on bacteria. Activation of the alternative pathway occurs
when C3b covalently binds to hydroxyl or amino groups
on the surface of a target microbe. Low-level activa-
tion of the alternative pathway takes place continu-
ously through the spontaneous hydrolysis (known as
tickover) of C3 in plasma and does not involve specific
recognition molecules. This pathway also amplifies the
activation of C3 (amplification loop).
Although triggered differently, these pathways
culminate in the formation of the C3 convertases (C3bBb
and C4bC2a) and C5 convertases (C3bBbC3b and
C4bC2aC3b), which involves cleavage of C2 and C4
(classical and lectin pathways) or the serine proteases
factor B and factor D (alternative pathway). This then
results in the generation of the main effector molecules of
the complement system: the opsonins C3b and C4b, the
anaphylatoxins C3a and C5a, and the membrane-attack
complex (MAC; membrane-bound C5b–C6–C7–C8–C9,
denoted as C5b–C9) (FIG. 1a). Deposition of clusters of
C3b (or C4b) on a pathogen leads either to immune
adherence and subsequent ingestion by phagocytic cells
(opsonization), or to lysis by engagement of the MAC,
a process known as the lytic mechanism. In addition, the
release of C3a and C5a mediates an acute inflammatory
reaction, including the activation and directed migration
of a wide range of immunocompetent cells2,3,6.
The coating of the pathogen with opsonic fragments
derived from C3 and C4 (REF. 6) is commonly a robust
process and is minimally influenced by complement
inhibitors (TABLE 1). However, such a powerful effec-
tor system requires tight regulation. This is achieved
through plasma and membrane regulatory proteins
(referred to as complement regulators) that inhibit
complement activation in the fluid phase (no target)
and on self (wrong target)2,3. At least three different
mechanisms of regulation are known: proteolytic
cleavage of deposited C3b and its cousin C4b (a proc-
ess known as cofactor activity) by the serine protease
factor I in conjunction with CD46 and complement
receptor 1 (CR1; also known as CD35), or by factor H
and C4b binding protein (C4BP); the disassembly of
the C3 and C5 convertases (a process known as decay-
accelerating activity) that involves CD55, CR1, factor H
Washington University School
of Medicine, Department of
Internal Medicine, Division
of Rheumatology, Campus
Box 8045, 660 South Euclid
Avenue, Saint Louis,
Missouri 63110, USA.
Correspondence to J.P.A.
1 December 2006
Proteins that bind to the
surface of a particle and
enhance its uptake by a
phagocyte. Opsonins include
IgG and complement activation
fragments (including C4b, C3b,
iC3b, C3dg and C3d).
fragments C3a and C5a.
These mediate an
through cell activation to
induce, for example,
chemotaxis and histamine
T-cell regulation: with complements
from innate immunity
Claudia Kemper and John P. Atkinson
Abstract | The complement system was traditionally known as an effector arm of humoral
immunity. Today we also recognize it as a main element of the innate immune system.
In blood and other body fluids complement is a first line of defence against pathogens,
because it becomes fully active within seconds. Active complement fragments attach to
the invading pathogen to promote opsonization and lysis, triggering a local inflammatory
response. This Review focuses on the evolving role of the complement system in the
regulation of T-cell responses, from directing the initiation phase, through driving lineage
commitment, to regulating the contraction phase.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 7 | JANUARY 2007 | 9
© 2007 Nature Publishing Group
C3 and C5
a Activation and amplification
CD59, S protein
Factor I, CR1
Factor I and CD46,
factor H or CR1
CD55, CR1, factor H
CD55, CR1, C4BP
Factor I and CD46,
C4BP or CR1
Decay-accelerating activity for C3 convertases
Inhibition of lysis
Not all antibodies fix or
activate complement. In
humans, IgM and the IgG
subclasses IgG1 and IgG3
readily fix complement,
whereas IgG2 is less effective.
The IgG subclass IgG4
and other classes of
immunoglobulin do not
fix complement or activate
the classical complement
and C4BP; or inhibition of lysis through the blockage of
MAC insertion by CD59 (REFS 6–8) (FIG. 1b).
The complement system is also a main player in
the handling of altered self. In response to injury, for
example during apoptosis or necrosis, complement acti-
vation occurs in a more targeted and restricted manner
compared with its interaction with foreign materials9–12.
Here, the goal is the safe disposal of cellular debris in
the absence of an immune response and with minimal
During the past three decades, the complement sys-
tem has been firmly identified as an instructor of the
humoral immune response13–17. It serves as a natural
adjuvant, lowers the threshold for B-cell activation18–20,
facilitates the localization of antigen to follicular den-
dritic cells (FDCs) in lymphoid follicles21, promotes
the development of optimal B-cell memory22,23 and
maintains B-cell tolerance23. These functions are mostly
mediated by the binding of opsonized antigens to CR1
and CR2 (also known as CD21). In view of this impres-
sive repertoire of activities, involvement of the comple-
ment system in the regulation of T-cell responses was
T-cell activation is induced through the presentation
of antigen by mature antigen-presenting cells (APCs) in
lymph nodes or secondary lymphoid structures to the
T cell. The nature of the antigen, the APC and the micro-
environment largely determines which type of T cell will
predominate (T helper 1 (TH1) cells, TH2 cells or regula-
tory T cells) and whether the activated T cells will then
migrate to an inflammatory site.
Recent research has shown that complement can
modulate T-cell responses during the induction and
effector phases, as well as in the contraction phase, of
an immune response24–26. These effects arise through
the direct modulation of the T cell itself or indirectly
through the alteration of immunomodulatory cells, par-
ticularly APCs. This Review discusses the emerging roles
of the complement system in the initiation, effector and
termination phases of the T-cell response.
Figure 1 | Activation and regulation of the complement system. a | Complement can be activated through three
pathways: the classical, lectin and alternative pathways. Complement component 1 (C1), composed of C1q , C1r and C1s,
and mannose-binding lectin (MBL)-associated serine proteases (MASPs) link the complement system to classical and lectin
pathways, respectively. These molecules also contain proteases that cleave C4 and C2, which then form the C3 and C5
convertases for the classical and lectin pathways. Factor B is the C2 equivalent for the alternative pathway. It is cleaved by
factor D. Factor P (also known as properdin) stabilizes the alternative pathway convertases. All three pathways culminate
in the formation of the C3 and C5 convertases that, in turn, generate the anaphylatoxins C3a and C5a, the membrane-
attack complex (MAC; C5b–C9) and the opsonin C3b. These effectors function as chemokines, chemoattractants and
activators of immunocompetent cells (C3a and C5a), mediate direct lysis of target cells (C5b–C9) or induce immune
adherence and phagocytosis of the pathogen (C3b). C3b also amplifies the alternative pathway (through the amplification
loop). b | Self tissue is protected from inappropriate complement deposition by fluid-phase and cell-bound regulators.
C3b and C4b undergo limited proteolytic cleavage by the serine protease factor I. This enzyme requires a cofactor protein
(membrane proteins CD46 and complement receptor 1 (CR1) or fluid-phase regulators factor H and C4-binding protein
(C4BP)). The C3 and C5 convertases are also regulated through disassembly by regulators that have decay-accelerating
activity (such as CD55, CR1, factor H and C4BP). Only the decay-accelerating activity for C3 convertases is shown.
The formation of the MAC is controlled by CD59 and S protein (vitronectin).
Table 1 | Complement interactions with pathogens and self
Activation profiles OutcomesExamples
Pathogen Robust and
Limited and targeted
and no immunity
Bacteria and viruses
Apoptotic and injured
cells and tissues; lipid and
Healthy cells and tissues Normal self Baseline (through
10 | JANUARY 2007 | VOLUME 7
© 2007 Nature Publishing Group
Figure 2 | Complement receptors and regulators on antigen-presenting cells and T cells. Expression profiles
and immunomodulatory functions of complement-binding proteins on human antigen-presenting cells (APCs) (a) and
T cells (b). C1qR, complement component C1q receptor; C3aR, complement component 3a receptor; CR, complement
receptor; CRIg, complement receptor of the immunoglobulin superfamily; SIGNR1, a mouse homologue of dendritic-
cell-specific ICAM3-grabbing non-integrin (DC-SIGN); TH1, T helper 1.
cytokine modulation and
CR2CR4 C3aRC5aRC1qRPCD59 CD55CD46
CR1CR2 CR3 CR4CRIg SIGNR1C3aR C5aR C1qR CD59 CD55CD46
The binding of antigens or
immune complexes, opsonized
with complement ligands, to
expressed on cells such as
erythrocytes, B cells, follicular
dendritic cells, monocytes and
The lysis of microbes or cells
through the formation of the
by the terminal components
of the complement cascade
Role of complement during T-cell activation
Modulation of APC function. APCs, including dendritic
cells (DCs), FDCs and macrophages, express a remark-
able repertoire of complement receptors and regulators
on their surfaces (FIG. 2a). Therefore, these cells are
poised to recognize and interact with antigens that have
been opsonized by complement27. The engagement of
complement receptors and regulators on APCs modu-
lates their maturation status and their chemokine and
cytokine expression profiles, which, in turn, influences
the T-cell response induced during antigen presenta-
tion16,25,26,28. So, MBL, C1q, C3b and C4b, which are
tightly attached to the antigen, engage their respective
receptors on APCs during antigen recognition and
uptake, and then initiate changes in APC function.
For example, in the absence of C1q or C3, antigen
uptake is suboptimal2,3,29–33, resulting in reduced matura-
tion of the APC, and leads to suboptimal T-cell activ-
ation2,3,29–32. Likewise, the anaphylatoxins C3a and C5a
are liberated at sites of complement activation, where
they positively modulate APC function by triggering
their seven-transmembrane G-protein-coupled recep-
tors C3a receptor (C3aR) and C5aR, respectively34
(TABLE 2). The biological consequences of C3aR and
C5aR activation on APCs includes the migration of
these cells and modulation of interleukin-12 (IL-12)
production34–39. Induction of IL-12 leads to the devel-
opment of a TH1 response, whereas suppression of
IL-12 production favours TH2-cell development.
However, both the induction and the suppression of
IL-12 production has been shown to occur after C3aR
and C5aR activation, depending on the disease model,
the route of delivery of the antigen to be opsonized
and the maturation status of the APC used34,37–40.
A related area of expanding research is the crosstalk
between the complement system and TLRs27,41. In a
recent study, Hawlisch et al. showed that C5a nega-
tively regulates TLR4- and CD40-induced production
of the IL-12 family of cytokines (IL-12, IL-23 and
IL-27) in mouse macrophages41. Because most patho-
gens activate both of these innate immune surveillance
systems simultaneously, an integrated analysis of their
Table 2 | Complement proteins and ligands
C3b, complement component 3b; C3aR, C3a receptor; CR, complement receptor; CRIg,
complement receptor of the immunoglobulin superfamily; DAF, decay-accelerating factor; iCb3,
inactivated form of C3b; MAC, membrane-attack complex; MCP, membrane cofactor protein;
SIGNR1, a mouse homologue of dendritic-cell-specific ICAM3-grabbing non-integrin (DC-SIGN).
NATURE REVIEWS | IMMUNOLOGY
VOLUME 7 | JANUARY 2007 | 11
© 2007 Nature Publishing Group
Mixed lymphocyte reaction
An in vitro assay to measure
the reactivity of alloreactive
T cells from one donor to the
MHC antigens on peripheral
blood cells or antigen-
presenting cells from another
An experimental model of the
human disease multiple
sclerosis. Autoimmune disease
is induced in experimental
animals by immunization with
myelin or peptides derived
from myelin. The animals
develop a paralytic disease
with inflammation and
demyelination in the brain and
signalling pathways might shed light on the conflicting
data regarding the effect of the anaphylatoxin receptors
on cytokine production by APCs.
Two membrane-bound complement regulators,
CD46 and CD55, also participate directly in modulat-
ing the function of APCs. The crosslinking of CD46 on
human macrophages with antibodies or with pathogenic
ligands (such as pili from Neisseria spp. or haemag-
glutinin from the measles virus) leads to calcium flux42
and the suppression of IL-12 (REF. 43). Failure to syn-
thesize this cytokine is one reason for the suppressed
state of T-cell responses during infection with the
measles virus43,44. How these regulators modulate APC
function is not fully understood, but Heeger and col-
leagues proposed that CD55 decreases APC maturation
by controlling complement deposition45. They suggest
that the decay-accelerating activity of CD55 decreases
the rate of formation of the C3 convertase and the rate
of C3b deposition on the APC surface, thereby reducing
the numbers of complement receptors engaged45. This,
in turn, affects the maturation status of the APC and,
consequently, T-cell priming.
Two recent studies46,47 describe previously unknown
receptors for complement fragments on macrophages
and indicate novel connections among complement,
pathogen recognition, clearance and immune modula-
tion. Helmy et al. identified CRIg (complement recep-
tor of the immunoglobulin superfamily; also known as
Z39Ig) as a receptor for C3b and the inactivated form of
C3b (iC3b) on tissue-resident macrophages — including
Kupffer cells in the liver — which mediates clearance
of C3-opsonized pathogens46. Kang and colleagues
observed that the lectin receptor SIGNR1 (a mouse
homologue of dendritic-cell-specific ICAM3-grabbing
non-integrin (DC-SIGN)) binds both C1q and the
Streptococcus pneumoniae polysaccharide on splenic
marginal-zone macrophages47. This binding process
results in SIGNR1-dependent C3 fragment deposition on
bacteria and their efficient clearance47. The generation of
CRIg- and SIGNR1-deficient mice will allow analysis
of their place in the regulation of adaptive immunity
during infections and in autoimmunity.
Direct modulation of T-cell activation. Compared with
APCs, T cells express a more limited range of comple-
ment receptors and regulators (FIG. 2b). Although the
complement receptors CR1 and CR2 have a central role
in the induction and regulation of B-cell responses20,23,
they do not seem to have a similar place in T-cell biology.
Only ~15% of human peripheral-blood T cells express
CR1 (REFS 48,49) and ~5% express CR2, CR3 or CR4
(REFS 48,50). However, CR1 is upregulated on human
peripheral-blood T cells on activation49, and crosslinking
CR1 inhibits T-cell proliferation and IL-2 production50.
No definitive function has been shown for CR2, CR3
and CR4 on CD4+ T cells48. CR3 is also expressed by
differentiated CD8+ T cells51.
C1q has been proposed to bind to a number of cell-
surface receptors52. The C1q receptor P (C1qRP) is
expressed by most T cells, and C1q-bearing immune
complexes might induce T-cell activation with concurrent
secretion of interferon-γ (IFNγ) and tumour-necrosis fac-
tor (TNF)53. C5aR is also expressed by most T cells. On
T-cell activation, the expression levels of C5aR increase
and these cells respond to C5a with directed chemo tactic
migration54. These and other data on the C5a–C5aR
interactions on T cells indicate a role for these proteins in
T-cell trafficking34,55,56. By contrast, naive CD4+ and CD8+
T cells do not express C3aR but its expression is induced
on T-cell activation57. The limited data available indicate
a possible regulative effect of C3a during T-cell activa-
tion, as addition of this anaphylatoxin decreases T-cell-
dependent antibody responses in a mixed lymphocyte
reaction25. In addition, T cells from C3aR-deficient mice
are characterized by increased cytokine production on
Unexpected roles are also beginning to be defined
for complement regulators during T-cell activation. For
example, the crosslinking of CD46 during CD4+ T-cell
priming induces strong proliferation and the synthesis
of large amounts of IL-10 and granzyme B24,58,59. In addi-
tion, the activation of CD46, in conjunction with phor-
bol 12-myristate 13-acetate, induces high IFNγ secretion
by T cells60. Furthermore, a new role for another com-
plement regulator in modulating T-cell immunity was
recently described in CD55-deficient mice45,61. These
animals have increased numbers of IFNγ-producing
T cells after immunization with ovalbumin or the myelin
oligodendrocyte glycoprotein (MOG) peptide in a model
of experimental autoimmune encephalomyelitis45,61. Finally,
crosslinking the MAC regulator CD59 on human T cells
transduces intracellular signals and leads to increased
proliferation and IL-2 production62.
Role of complement in the T-cell effector phase
Shaping the TH1/TH2-cell response. As discussed in the
previous section, complement affects T-cell activation
indirectly through modulating APC function or directly
by altering T-cell priming. Through these activities,
complement shapes the subsequent TH1/TH2 effector
response. Support for such a crucial role in protective
T-cell responses comes primarily from experiments
using C3-deficient mice in influenza and lymphocytic
choriomenigitis viral infection models63–65. In both cases,
the CD4+ T-cell response to the virus was impaired in
C3–/– mice. In addition, the CD8+ T-cell response was
decreased in the influenza system64. How complement
is activated in these models and the mechanism(s) of
C3 dependency remain unanswered. One possibility is
that natural antibodies bind the virus and initiate C3
deposition through the classical pathway. In line with
this hypothesis is the dependency of an optimal CD8+
T-cell response on natural IgM to activate complement
after immunization against visceral leishmaniasis66.
The absence of C3 probably results in reduced APC
maturation and limited T-cell activation.
Another possibility — and the two mechanisms are
not exclusive — is that the anaphylatoxins C3a and C5a
and their respective receptors are necessary for induc-
ing optimal adaptive immunity. Informative studies by
Wetsel and colleagues showed that C3a has a central
role in the priming and instruction of T-cell responses37.
12 | JANUARY 2007 | VOLUME 7
© 2007 Nature Publishing Group
In these experiments, C3aR-deficient mice showed
decreased TH2-cell responses, including reduced IL-4
production, and were protected against airway hyper-
reactivity, a TH2-dependent process, in a mouse model of
asthma37. By contrast, in a mouse model of atopic derma-
titis, C3aR-deficient mice showed an enhanced TH2-cell
response and no disease protection40. The predominant
TH2-cell response was dependent on C3aR-induced IL-4,
IL-5 and IL-10 synthesis by DCs40. The reason for these
contradictory results is not known.
The other anaphylatoxin, C5a, also regulates T-cell
responses. Mice lacking C5aR or treated with a C5aR
antagonist have a reduced ability to clear an infection
with Pseudomonas aeruginosa67 and to mount virus-
specific CD8+ T-cell responses68. In addition, C5-deficient
animals have exacerbated TH2-cell responses in an
experimental allergic asthma model41,69. Interestingly,
the C5 gene was identified as a susceptibility locus
for human allergen-induced asthma69. Although C5a
induces TH1-cell responses in these models, a role for
C5a in the induction of a TH2-cell phenotype has also
been shown70. Therefore, these data suggest complex
and pleomorphic effects of the anaphylatoxins on the
production of the key cytokines that drive T-cell effector
The explanation for the observed phenotype of
Cd55-knockout mice used in studies by Liu61 and
Heeger45 is controversial. The key finding of both
studies was an enhanced TH1-cell response in CD55-
deficient mice, including increased IFNγ production.
However, one group attributes the observed negative
regulation of T cells by CD55 to a direct effect on the
T cell itself61, whereas the other favours a mechanism
that involves alteration of APC function45. Future stud-
ies will clarify whether one or other, or both, of these
cell types contribute to the phenotype.
In an in vivo experimental system, CD46, a struc-
tural and functional cousin of CD55, also regulated
T-cell effector responses. Marie and colleagues gen-
erated mice expressing human CD46 with either of
its two regularly expressed cytoplasmic tails, CYT1
or CYT2 (REF. 71). CYT1 and CYT2 differ in size and
amino-acid sequence, and both contain motifs neces-
sary for signalling71. The researchers found that CD4+
T cells from mice expressing CD46 with the CYT1
cytoplasmic tail proliferated strongly, produced IL-10
and inhibited the contact-hypersensitivity reaction
after concurrent T-cell receptor (TCR) and CD46 acti-
vation. By contrast, TCR- and CD46-activated T cells
bearing CD46 with its CYT2 cytoplasmic tail showed
weak proliferation and low IL-10 production but a
heightened contact-hypersensitivity reaction71. This
study was the first to confirm a direct in vivo T-cell
regulative function for CD46 and suggests that CYT1
is the cytoplasmic domain that mediates the develop-
ment of IL-10-producing regulatory T cells after CD46
crosslinking (see later section).
A similar regulative role in virus-induced T-cell
responses was discovered for CD59. Mice deficient
for CD59 showed enhanced virus-specific CD4+ T-cell
responses after immunization with recombinant vaccinia
virus72. Notably, the observed effect in this study was
shown to be independent of complement activation and
does not therefore involve regulation of MAC forma-
tion. Such downregulation of T-cell activity by CD59 in
mice contrasts with findings in human T cells, in which
CD59, when crosslinked with antibodies, functions as a
co-stimulatory molecule by inducing T-cell proliferation
and IL-2 production independent of MAC formation62.
The above data are consistent with the emerging under-
standing that crosslinking or activating complement
receptors and/or regulators on T cells induces signal-
ling events that influence proliferation and cytokine
production by these cells.
However, these studies also raise an important issue:
namely that there are substantial differences between
mouse and human (and even other primate) comple-
ment receptors and regulators. Although CR1 and CR2
are two separate proteins in humans, mice express them
as one protein derived from a single gene in a more
limited array of cell types7,8. Moreover, human CR1 is a
250-kDa protein with three C3b and C4b binding sites,
whereas mouse CR1 is a 60-kDa amino-terminal attach-
ment to CR2 with one binding site for C3b and C4b7,8.
In addition, the complement regulatory proteins CD55
and CD59 are present in mice as two different protein
forms, each with distinct expression profiles, whereas
in humans CD55 and CD59 are only expressed in one
form7,8. Furthermore, CD46 is not expressed by somatic
cells in the mouse73,74, and another protein, complement-
receptor-related protein (CRRY), apparently replaces the
role of CD46 as a cofactor in the cleavage of C3b and
C4b (REF. 75). CRRY has co-stimulatory properties for
mouse CD4+ T cells76 and crosslinking of this protein
on the surface of these cells induces proliferation and
Overall, the complement-activation system does
not seem to be as robust in mice as it is in humans.
For example, the ability of mouse complement to lyse
sheep red blood cells is one-tenth to one-hundredth
as efficient as human complement. Most of the studies
regarding the role of complement in T-cell function
— specifically in vivo work — have been carried out in
mouse models. On account of these issues, the results
obtained should be transferred to the human system
with caution. Information on the affect of complement
on signalling in effector T cells is limited. The comple-
ment-mediated signalling pathways activated during
the APC–T-cell interactions are largely unknown and
probably complex. Available data indicate, however,
that these responses might not follow a pre-set, fixed
pathway but are likely to be customized to pathogen
classes and to vary considerably from one tissue type
Role of complement in the contraction phase
An exciting development in the field of T-cell immunity
is the idea that the complement system affects the termi-
nation of the T-cell response. Two main mechanisms for
the termination of the T-cell response by complement
are emerging: the modulation of apoptosis and induction
of regulatory T cells.
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© 2007 Nature Publishing Group
Low granzyme B
No suppressive activity
No IL-2 dependency
IL-2 (low IL-10)
High granzyme B
IL-10 (no IL-2)
Classical T-cell activation (CD3/CD28 activation)
T-cell activation in the presence of complement
Modulation of apoptosis. During the contraction phase
of the effector T-cell response most of the cells undergo
apoptosis, leaving only a small number of viable T cells
to constitute the memory pool. Efficient uptake and safe
disposal of these apoptotic cells are necessary to avoid
inflammation and autoimmune disease. C1q binds to late
apoptotic cells and initiates the activation of the classi-
cal pathway, which leads to their opsonization by C3b
(REFS 9,10). C1q therefore aids in the uptake of these cells
by macrophages. In addition, CD46 has an unanticipated
function in recognizing apoptotic T cells77. Elward et al.
observed that apoptotic T cells rapidly lose CD46 from
their surfaces77. CD46 was shown to cluster in the apop-
totic blebs and then shed in microparticles. The authors
proposed that expressing CD46 on the surface of a T cell
prevents the cell from being phagocytosed and that losing
CD46 on the induction of apoptosis removes this pro-
tective signal and allows engulfment by phagocytes. In
addition, losing this major complement regulatory mol-
ecule allows for greater C3b deposition, which, in turn,
increases phagocytic uptake of the apoptotic cells78.
An additional role for complement, beyond providing
assistance in the safe removal of apoptotic cells, has been
suggested. In this work, CD55 and CD59 were shown to
directly modulate CD95 (also known as FAS)-mediated
apoptosis of human CD4+ T cells79. Localization of CD28,
CD55 and CD59 into lipid rafts was observed on T-cell
activation; CD28 was concentrated into microdomains,
which are enriched with ganglioside GM1, within the
lipid rafts, whereas CD55 and CD59 were excluded from
these microdomains79. Whereas co-ligation of CD28 with
CD95 amplified the CD95 signalling pathway, co-ligation
of CD95 with CD55 or CD59 inhibited the apoptotic sig-
nal79. Although the biological significance of this finding
is not clear, it will be of interest to investigate whether
these events are linked to the inhibitory role of CD55 in
TCR-mediated T-cell activation45,61.
Induction of regulatory T cells. Downregulation of the
effector T-cell response through the development of a
lineage of T cells with suppressive properties is a recently
described role for complement in the contraction of
an immune response. The concurrent crosslinking
of the TCR and CD46 on naive peripheral-blood CD4+
T cells with specific antibodies, C3b dimers or a patho-
genic ligand (for example, the streptococcal M protein,
which interacts with CD46 on human CD4+ T cells)
induces the development of T cells with regulatory
properties24,59,80–83 (FIG. 3).
Active suppression of autoreactive T cells by regu-
latory T cells has emerged as an essential process to
prevent autoimmunity and mediate peripheral toler-
ance. In addition, the suppression of resident effec-
tor CD4+ TH1 and TH2 cells directed against enteric
commensals and other foreign but benign factors at
the host–environment interface is a crucial factor in
mucosal immune homeo stasis84,85. Regulatory T cells
are currently divided into two main subsets. Natural
CD4+CD25+ T regulatory (TReg) cells originate in the thy-
mus, are specific for self-antigens and act predominantly
through a contact-dependent mechanism that probably
involves granzyme A in humans59,80–82. However, in mice
it is thought that natural TReg cells might use granzyme B
for their suppressive activity86. These natural TReg cells
constitutively express the transcription factor forkhead
box P3 (FOXP3) and the IL-2 receptor α-chain (CD25),
and require exogenous IL-2 for their function and expan-
sion81,82,87. Inducible T regulatory 1 (TR1) and TH3 cells
are generated in the periphery against both self and
foreign antigens81,82. They also require exogenous IL-2
and mediate their suppressive effect primarily by the
secretion of IL-10 (TR1 cells) or transforming growth
factor-β (TGFβ; TH3 cells)84,88. Inducible regulatory
T cells might or might not express FOXP3 and show
variable expression of CD25 (REFS 59,81).
Figure 3 | Characteristics of complement-induced
regulatory T cells. Functional differences between
CD3- and CD28-stimulated compared with CD3- and
CD46-stimulated naive CD4+ T cells are summarized. The
activation of T cells in the presence of complement ligands
induces cells with a cytokine- and granzyme-profile that is
distinct from those activated through the classical CD28
co-stimulatory pathway. Importantly, CD46 activation
does not lead to interleukin-2 (IL-2) production24. GM-CSF,
granulocyte/macrophage colony-stimulating factor;
sCD40L, secretory CD40 ligand; TCR, T-cell receptor.
14 | JANUARY 2007 | VOLUME 7
© 2007 Nature Publishing Group
and uptake by APCs
Generation of C3a and C5a
Crosslinking CD46 during TCR activation leads
to the development of T cells with the ability to regulate
the activation of classically activated (CD3 and CD28)
bystander T cells, similar to inducible T regulatory
cells24. The CD46-mediated signalling pathways lead-
ing to this phenotype have not been defined. However,
these cells express normal levels of many activation
markers, including CD25, CD69, CD62 ligand (CD62L)
and CD152, and acquire a normal memory phenotype
(expression of CD45RO)24. These CD46-induced regu-
latory T cells proliferate strongly and suppress the acti-
vation of bystander T cells through the secretion of the
immunosuppressive cytokine IL-10 (REFS 24,74). They
require no pre-existing basal expression of FOXP3
(REF. 59) but their induction, function and expansion
is, as it is for other inducible regulatory T cells, highly
dependent on an exogenous source of IL-2 (REF. 24)
(FIG. 3). CD46-induced regulatory T cells also synthesize
granzyme B and perforin, and show contact-dependent
cytotoxicity towards autologous immunocompetent
T cells, including activated CD4+ and CD8+ T cells59,80.
Therefore, regulatory T cells generated through CD3
and CD46 activation have three distinct mechanisms
for effector T-cell suppression: secretion of IL-10,
synthesis of granzyme B and competition for IL-2 as
a growth factor.
T cells with these properties are predicted to aid in the
control and contraction of an effector T-cell response.
After the clonal expansion of effector T cells, sufficient
amounts of IL-2 and CD46 ligand (C3b- or C4b-
opsonized immune complexes) would become available
to induce IL-10-secreting, granzyme-B-expressing regu-
latory T cells. We propose that these regulatory T cells
then downregulate effector T-cell function to prevent
immunopathology caused by an overexuberant immune
response (FIG. 4). In this manner, complement-induced
regulatory T cells might participate in terminating an
effector immune response to an invading pathogen and
in preventing chronic inflammation.
Generally, adaptive IL-10-producing regulatory T-cell
populations do not allow for DC maturation on antigen
encounter, because IL-10 not only inhibits T-cell activa-
tion but also DC activation89. By contrast, CD46-induced
regulatory T cells permit DC activation90. This distin-
guishing feature is achieved through their simultaneous
secretion of granulocyte/macrophage colony-stimulating
factor (GM-CSF) and soluble CD40, in addition to IL-10
(REF. 90). Soluble CD40 and GM-CSF neutralize the sup-
pressive effect of IL-10 on DCs, but not on T cells, and
thereby allow the differentiation of DCs. So, the cytokine
profile of CD46-induced regulatory T cells suppresses
T-cell responses through IL-10 but allows for DC matu-
ration in the presence of this cytokine. Such ‘DC-sparing’
complement-induced regulatory T cells could be desir-
able at the host–environment interfaces. In the airway,
skin and gastrointestinal tract, the cytokine profile of
these regulatory T cells might ensure unresponsiveness
to commensals and innocuous antigens (by suppressing
an unwanted T-cell response through IL-10) while main-
taining reactivity to invading pathogens (by allowing DC
maturation on encounter with pathogenic antigens).
Intestinal bacteria are a constant source of antigen
that provides inflammatory signals for cells of the innate
immune system and a nidus for complement activation.
A portion of T cells that encounter their cognate antigen
at this location might be induced towards a regulatory
T-cell phenotype through CD46 stimulation. Such a
regulatory T-cell pool could control effector T-cell-
mediated inflammation through local IL-10 secretion85.
Indeed, both effector and regulatory T cells specific for
the same Escherichia coli-derived antigen are present
in the intestine91 and mice that are deficient for the Il10 or
Figure 4 | Complement in the T-cell response continuum. A model for how complement regulates the three phases of
a T-cell immune response. During the initiation phase, the activation of complement (the generation of the opsonins
complement component 3a (C3a) and C5a) facilitates antigen recognition and the maturation of antigen-presenting cells
(APCs). Antigen-experienced mature APCs induce effector T-cell responses to produce interleukin-2 (IL-2), which is
necessary for the induction of complement (CD46)-induced regulatory T cells. Ligands for CD46, such as opsonized
immune complexes (ICs), are also generated at this time. Clonal expansion of antigen-specific effector T cells leads to the
clearance of the pathogen, and the balance between effector T cells and CD46-induced regulatory T cells prevents
excessive immunopathology. With continuous expansion of CD46-induced regulatory T cells (which proliferate more
strongly than effector T cells24), IL-10 secretion and the number of granzyme B-expressing cells might become sufficient59
to shut down the successful effector T-cell response. The inactivation of effector T cells leads to the simultaneous
contraction of the regulatory T-cell pool — as these cells are dependent on IL-2 produced by effector T cells — and the
generation of an effector T-cell and regulatory T-cell memory pool24. The timescale chosen for this model is based on an
acute viral or bacterial infection.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 7 | JANUARY 2007 | 15
© 2007 Nature Publishing Group
Primarily vascularized graft
A type of transplantation
in which the recipient’s
vasculature is connected to
the vessels of the donor graft.
Cellular damage caused by
the return of a blood supply
to a tissue after a period of
inadequate blood supply.
The absence of oxygen and
nutrients causes cellular
damage such that restoration
of the blood flow results in
Il2 gene succumb to colitis92,93. However, allowing DCs to
function normally at this location also guarantees protec-
tion against invading pathogens. That the human lamina
propria contains T cells with a cytokine expression pro-
file that is characteristic of CD46-induced regulatory
T cells supports the hypothesis that complement-induced
regulatory T cells are involved in mucosal immunity90.
The immunomodulatory properties of CD46 on
T cells and macrophages probably account for the use
of CD46 as a receptor by numerous human pathogens
(for example, strains of the measles virus, herpes simplex
virus 6 and certain adenoviruses, as well as Streptococci
pyogenes and pathogenic Neisseria spp.)44,73,83. We have
speculated that pathogens that bind to CD46 might abuse
this complement receptor to induce a local suppressive
milieu74,83. This concept of abusing regulatory T-cell
functions has been shown for several other pathogenic
The results of studies of CD46-induced regulatory
T cells that can regulate a bystander T-cell response
make an appealing case for a role of complement in the
contraction phase of an immune response24,74. However,
this concept awaits verification in an in vivo system. In
addition, the circumstances that lead to the induction of
these cells in vivo are poorly understood. Although C3b
dimers induce regulatory T-cell development through
their interactions with CD46, the observation that a
CD46–human IgG4 fusion protein binds to human cell
lines as well as to polymorphonuclear leukocytes77 makes
the idea of an unidentified new ligand or receptor for
CD46 — perhaps expressed by specialized (possibly
tolerogenic) APCs — intriguing. Furthermore, the recent
identification of novel complement receptors (CRIg and
SIGNR1) on APCs46,47 shows that there is still much to be
discovered about the complement system.
Complement-induced signalling in T cells
Complement activation fragments such as C3b, C4b,
C3a and C5a interact with complement receptors and
regulators to modulate T-cell lineage commitment
and cytokine, granzyme and perforin production.
However, relatively little is known about the signal-
ling pathways involved in these effects compared with,
for example, CR2-induced signalling in B cells20,23.
Although the activation of CD46 induces intracellular
signalling events in several cell types25,26,73,96,97, these
pathways are largely undefined. The situation is com-
plicated by the fact that CD46 expresses two distinct
cytoplasmic domains (CYT1 and CYT2), both of which
have signalling capacities73. CD46 activation in macro-
phages induces calcium flux from intracellular stores
and the recruitment of SH2-domain-containing protein
tyrosine phosphatase 1 (SHP1) to the CD46 cytoplasmic
domain(s)98. On epithelial cells, the phosphorylation of
the intracellular domains of CD46, as well as association
of CYT1 with discs large 4 (DLG4), a protein involved
in the formation of cell-adherent junctions, has been
shown42,99. Activation of CD46 on T cells induces the
phosphorylation of the cytoplasmic tail domains of both
CD46 and the scaffolding molecule LAT, as well as the
activation of the guanine-nucleotide-exchange factor
VAV, the GTPase RAC and the extracellular-signal-
regulated kinase 1 (ERK1)/ERK2 mitogen-activated
protein kinase pathway58,100.
A direct signalling role in T cells has also been
described for the two glycosylphosphatidylinositol-
anchored complement regulators, CD55 and CD59
(REFS 8,25,26,62,101). Crosslinking of these molecules
enhances T-cell proliferation and, in the case of CD59,
IL-2 production62. These biological outcomes involve
SRC-family kinase LCK-mediated activation and phos-
phorylation events102. The signalling pathways for C3aR
and C5aR have been studied in human peripheral-blood
mononuclear and neutrophil populations34. These
complement receptors signal through G proteins34 and
downstream events include the activation of impor-
tant signalling molecules such as phosphatidylinositol
3-kinase (PI3K), protein kinase C (PKC), ERK and
signal transducers and activators of transcription 3
(STAT3) (REF. 34). The processes that occur between
the initial events that are mediated by the activation of
complement receptors and regulators and the induction
of proliferation, cytokines and granzymes remain to be
revealed. The current understanding of the signalling
pathways induced by complement receptors and regula-
tors in T cells have been recently reviewed by Hawlisch34,
Morgan25,26 and Russell96.
Complement and T-cell-mediated pathologies
Because an important role for complement in regu-
lating T-cell-mediated immunity is emerging, it is
not surprising that the complement system has been
studied in connection with transplantation rejec-
tion103,104. The main obstacle to successful allograft
transplantation is rejection of the donor graft, a prin-
cipally T-cell-mediated process104,105. Complement is
likely to have a more central role in this process than
has previously been suspected. Mice deficient in dif-
ferent complement components (mainly C3 or C4)
or animals treated with complement inhibitors show
prolonged survival of skin allografts and primarily
vascularized grafts104. This is related to a reduction in
ischaemia-reperfusion injury and vessel wall inflamma-
tion and the decreased recruitment of effector cells104.
The mechanisms underlying complement-mediated
rejection are complex and include the induction of
alloantibody responses and effector T-cell activation
and infiltration. Local synthesis of complement com-
ponents by epithelial and vascular tissue in the graft
might also contribute to this response103. Therefore,
to improve the success rate of organ and tissue trans-
plantation, a better understanding of these processes is
needed, and therapeutic manipulation of complement
in parallel with the more standard immunosuppressive
regimens should be considered. It is likely that comple-
ment deficiencies or dysfunctions are also associated
with human T-cell-mediated diseases. Indeed, mice
deficient for the complement regulator CD55 develop
more severe experimental autoimmune encephalo-
myelitis than wild-type mice in this disease model45 and
CD46-transgenic mice show abnormal T-cell responses
in the contact-hypersensitivity reaction71.
16 | JANUARY 2007 | VOLUME 7
© 2007 Nature Publishing Group
Interaction between the complement system and T cells
is a new area of research. Additional complement lig-
ands and receptors on T cells await discovery. Analysis
of their actions and of those reviewed in this update
should clarify conflicting opinions in the literature (for
example, the roles of the anaphylatoxins in cytokine
production, the mechanism(s) of T-cell modulation by
CD55 and to what extent we should or can apply results
obtained in mouse models to humans) and could lead to
new models of how T-cell responses are affected by com-
plement. An improved understanding of the parameters
that ultimately shape the interplay between T cells and
complement will become the basis for developing new
therapies that centre on manipulating complement to
control T-cell responses.
Medhzitov, R. & Janeway, C. A. Jr. Decoding the
patterns of self and non-self by the innate immune
system. Science 296, 298–300 (2002).
Walport, M. J. Complement. First of two parts.
N. Engl. J. Med. 344, 1058–1066 (2001).
Walport, M. J. Complement. Second of two parts.
N. Engl. J. Med. 344, 1140–1144 (2001).
Metschnikoff, E. Sur la lutte des cellule de l’organisme
contre l’invasion des microbes. Ann. Inst. Pasteur
1, 321 (1887) (in French).
Bordet, J. & Gengou, O. Sur l’existence de
substances sensibilisatrices dans la plupart des serum
antimicrobien. Ann. Inst. Pasteur 15, 289–302 (1901)
Volanakis, J. E. in The Human Complement System in
Health and Disease 10th edn (eds Volanakis, J. E. &
Frank, M. M.) 9–32 (Marcel Dekker, New York, 1998).
Morgan, B. P. & Harris, C. L. Complement Regulatory
Proteins (Academic, New York, 1999).
Kim, D. D. & Song, W.-C. Membrane complement
regulatory proteins. Clin. Immunol. 118, 127–136
Korb, L. C. & Ahearn, J. M. C1q binds directly
and specifically to surface blebs of apoptotic
human keratinocytes: complement deficiency
and systemic lupus erythematosus revisited.
J. Immunol. 158, 4525–4528 (1997).
10. Botto M. et al. Homozygous C1q deficiency causes
glomerulonephritis associated with multiple apoptotic
bodies. Nature Genet. 19, 56–59 (1998).
11. Riley-Vargas, R. C., Lanzendorf, S. & Atkinson, J. P.
Targeted and restricted complement activation
on acrosome-reacted spermatozoa. J. Clin. Invest.
115, 1241–1249 (2005).
12. Harris, C. L., Mizuno, M. & Morgan, B. P. Complement
and complement regulators in the male reproductive
system. Mol. Immunol. 43, 57–67 (2006).
13. Nussenzweig, V., Bianco, C., Dukor, P. & Eden, A.
in Progress in Immunology Vol. 59 (ed. Amos, B.)
73–81 (Academic, New York, 1971).
14. Carroll, M. C. The complement system in regulation
of adaptive immunity. Nature Immunol. 10, 981–986
15. Mastellos, D. & Lambris, J. D. Complement:
more than a ‘guard’ against invading pathogens?
Trends Immunol. 23, 485–491 (2002).
16. Nielsen, C. H., Fischer, E. M. & Leslie, R. G. The role
of complement in the acquired immune response.
Immunology 100, 4–12 (2000).
17. Pepys, M. B. Role of complement in induction of
antibody production in vivo. Effect of cobra factor and
other C3-reactive agents on thymus-dependent and
thymus-independent antibody responses. J. Exp. Med.
140, 126–145 (1974).
18. Carter, R. H., Spycher, M. O., Ng, Y. C., Hoffman, R. &
Fearon, D. T. Synergistic interaction between
complement receptor type 2 and membrane IgM
on B lymphocytes. J. Immunol. 141, 457–467
19. Dempsey, P. W., Allison, M. E., Akkaraju, S.,
Goodnow, C. C. & Fearon, D. T. C3d of complement
as a molecular adjuvant: bridging innate and acquired
immunity. Science 271, 348–350 (1996).
20. Fearon, D. T. & Carter, R. H. The CD19/CR2/TAPA-1
complex of B lymphocytes: linking natural to acquired
immunity. Ann. Rev. Immunol. 13, 127–149 (1995).
21. Fang, Y., Xu, C., Fu, Y., Holer, V. M. & Molina, H.
Expression of complement receptors 1 and 2 on
follicular dendritic cells is necessary for the generation
of a strong antigen-specific IgG response. J. Immunol.
160, 5273–5279 (1998).
22. Molina, H. et al. Markedly impaired humoral immune
response in mice deficient in complement receptors 1
and 2. Proc. Natl Acad. Sci. USA 93, 3357–3361
23. Carroll, M. C. The complement system in B cell
regulation. Mol. Immunol. 41, 141–146 (2004).
24. Kemper, C. et al. Activation of human CD4+ cells
with CD3 and CD46 induces a T-regulatory cell 1
phenotype. Nature 421, 388–392 (2003).
Provides evidence that a complement inhibitor
influences T-cell responses through the generation
of IL-10-producing regulatory T cells.
25. Morgan, B. P., Marchbank, K. J., Longhi M. P.,
Harris, C. L. & Gallimore, A. M. Complement:
central to innate immunity and bridging to adaptive
responses. Immunol. Lett. 97, 171–179 (2005).
26. Longhi, M. P., Harris, C. L., Morgan, B. P. &
Gallimore, A. Holding T cell in check — a new
role for complement regulators? Trends Immunol.
27, 102–108 (2006).
27. Hawlisch, H. & Köhl, J. Complement and Toll-like
receptors: key regulators of adaptive immune
responses. Mol. Immunol. 43, 13–21 (2006).
28. Köhl, J. et al. A regulatory role for the C5a
anaphylatoxin in type 2 immunity in asthma.
J. Clin. Invest. 116, 783–96 (2006).
29. Castellano, G. et al. Maturation of dendritic cells
abrogates C1q production in vivo and in vitro.
Blood 103, 3813–3820 (2004).
30. Jiang, K., Chen, Y., Xu, C. S. & Jarvis, J. N.
T cell activation by soluble C1q-bearing immune
complexes: implications for the pathogenisis of
rheumatoid arthritis. Clin. Exp. Immunol. 131, 61–67
31. Jacquier-Sarlin, M. R., Gabert, F. M., Villiers, M. B. &
Colomb, M. G. Modulation of antigen processing and
presentation by covalently linked complement C3b
fragment. Immunology 84, 164–170 (1995).
32. Kerekes, K. et al. Adjuvant effect of γ-inulin is mediated
by C3 fragments deposited on antigen-presenting
cells. J. Leuk. Biol. 69, 69–74 (2001).
33. Marth, T. & Kelsall, B. L. Regulation of interleukin-12
by complement receptor 3 signaling. J. Exp. Med.
185, 1987–1995 (1997).
34. Hawlisch, H., Wills-Karp, M., Karp, C. L. & Köhl, J.
The anaphylatoxins bridge innate and adaptive
immune responses in allergic asthma. Mol. Immunol.
41, 123–131 (2004).
35. Sozzani, S. et al. Migration of dendritic cells in
response to formyl peptides, C5a, and a distinct
set of chemokines. J. Immunol. 155, 3292–3295
36. Wetsel, R. A. Structure, function and cellular
expression of complement anaphylatoxin receptors.
Curr. Opin. Immunol. 7, 48–53 (1995).
37. Drouin, S. M., Corry, D. B., Kildsgaard, J. &
Wetsel, R. A. Cutting edge: the absence of C3
demonstrates a role for complement in TH2 effector
functions in a murine model of pulmonary allergy.
J. Immunol. 167, 4141–4145 (2001).
This report, along with references 38–41 and 56,
delineates the impact of the anaphylatoxins
on T-cell lineage commitment during APC–T-cell
38. Drouin, S. M., Corry, D. B., Hollman, T. J., Kildsgaard, J.
& Wetsel, R. A. Absence of the complement
anaphylatoxin C3a receptor suppresses TH2 functions
in a murine model of pulmonary allergy. J. Immunol.
169, 5926–5933 (2002).
39. Gerard, N. P. & Gerard, C. Complement in allergy
and asthma. Curr. Opin. Immunol. 14, 705–708
40. Kawamoto, S. et al. The anaphylatoxin C3a
downregulates the TH2 response to epicutaneously
introduced antigen. J. Clin. Invest. 114, 399–407
41. Hawlisch, H. et al. C5a negatively regulates Toll-like
receptor 4-induced immune responses. Immunity
22, 15–425 (2005).
42. Källström, H., Islam, M. S., Berggren, P. O. &
Jonsson, A. B. Cell signaling by the type IV pili
of pathogenic Neisseria. J. Biol. Chem. 273,
43. Karp, C. L. et al. Mechanisms of suppression
of cell-mediated immunity by measles virus.
Science 273, 228–231 (1996).
Measles virus uses the immunomodulatory
properties of a complement regulator to suppress
the immune response.
44. Cattaneo, R. Four viruses, two bacteria, and one
receptor: membrane cofactor protein (CD46) as
pathogens’ magnet. J. Virol. 78, 4385–4388
45. Heeger, P. S. et al. Decay-accelerating factor
modulates induction of T cell immunity. J. Exp. Med.
201, 1523–1530 (2005).
Shows that complement components produced by
APCs on antigen encounter modulate subsequent
cytokine production by T cells.
46. Helmy, K. Y. et al. CRIg: a macrophage complement
receptor required for phagocytosis of circulating
pathogens. Cell 124, 915–927 (2006).
47. Kang, Y.-S. et al. A dominant complement fixation
pathway for pneumococcal polysaccharides initiated
by SIGN-R1 interacting with C1q. Cell 125, 47–58
48. Wagner, C. & Hänsch, G. M. Receptors for
complement C3 on T-lymphocytes: relics of evolution
or functional molecules. Mol. Immunol. 43, 22–30
49. Wilson, J. G., Tedder, T. F. & Fearon, D. T.
Characterization of human T cells that express
the C3b receptor. J. Immunol. 134, 684–689
50. Wagner, C. The complement receptor 1, CR1 (CD35),
mediates inhibitory signals in human T-lymphocytes.
Mol. Immunol. 43, 643–651 (2006).
51. Muto, S., Vetvicka, V. & Ross, G. D. CR3 (CD11b/
CD18) expressed by cytotoxic T cells and natural
killer cells is upregulated in a manner similar to
neutrophil CR3 following stimulation with various
activating agents. J. Clin. Immunol. 13, 175–184
52. Eggleton, P., Tenner, A. J. & Reid, K. B. M. C1q
receptors. Clin. Exp. Immunol. 120, 406–412
53. Chen, A. et al. Human T cells express specific sites
for C1q: role in T cell activation and proliferation.
J. Immunol. 153, 1430–1440 (1994).
54. Nataf, S., Davoust, N., Ames, R. S. &
Barnum, S. A. Human T cells express the C5a
receptor and are chemoattracted to C5a. J. Immunol.
162, 4018–4023 (1999).
55. Tsuji, R. F. et al. Early local generation of C5a initiates
the elicitation of contact sensitivity by leading to early
T cell recruitment. J. Immunol. 165, 1588–1598
56. Grant, E. P. et al. Essential role for the C5a receptor
in regulating the effector phase of synovial infiltration
and joint destruction in experimental arthritis.
J. Exp. Med. 196, 1461–1471 (2002).
57. Werfel, T. et al. Activated human T lymphocytes
express a functional C3a receptor. J. Immunol.
165, 6599–6605 (2000).
58. Astier, A. L., Trescol-Biemont, M.-C., Azocar, O.,
Lamouille, B. & Rabourdin-Combe, C. Cutting edge:
CD46, a new costimulatory molecule for T cells, that
induces p120CBL and LAT phosphorylation. J. Immunol.
164, 6091–6095 (2000).
Establishes that signalling through CD46
modulates T-cell proliferation. This paper laid
the ground work for the subsequent studies
of the effects on T-cell function induced by CD46
NATURE REVIEWS | IMMUNOLOGY
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© 2007 Nature Publishing Group
59. Grossman, W. J. et al. Human T regulatory cells Download full-text
can use the perforin pathway to cause autologous
target cell death. Immunity 21, 589–601 (2004).
Establishes a simple paradigm for how
regulatory T cells might influence immune
responses. In humans, natural TReg cells
synthesize granzyme A, whereas adaptive
regulatory T cells produce granzyme B. On
CD46 activation both cell types can kill activated,
60. Sanchez, A., Feito, M. J. & Rojo, J. M. CD46-mediated
costimulation induces a TH1-biased response and
enhances early TCR/CD3 signaling in human CD4+
T lymphocytes. Eur. J. Immunol. 34, 2439–2448
61. Liu, J. et al. The complement inhibitory protein
DAF (CD55) suppresses T cell immunity in vivo.
J. Exp. Med. 201, 567–577 (2005).
This report, together with reference 45,
shows that complement deposition on APCs and
T cells influences T-cell proliferation and cytokine
production during APC–T-cell interactions.
62. Korty, P. E., Brando, C. & Shevach, E. M. CD59
functions as a signal-transducing molecule for human
T cell activation. J. Immunol. 146, 4092–4098
63. Kopf, M., Abel, B., Gallimore, A., Carroll, M. &
Bachmann, M. F. Complement component C3
promotes T-cell priming and lung migration to
control acute influenza virus infection. Nature Med.
8, 373–378 (2002).
References 63–68 indicate that complement
activation (and natural antibodies) are required
for optimal CD4+ and CD8+ T-cell responses to
64. Suresh, M. et al. Complement component 3 is
required for optimal expansion of CD8 T cells during
a system viral infection. J. Immunol. 170, 788–794
65. Verschoor, A., Brockman, M. A., Gadjeva, M.,
Knipe, D. M. & Carroll, M. C. Myeloid C3 determines
induction of humoral responses to peripheral herpes
simplex virus infection. J. Immunol. 171, 5363–5371
66. Stager, S. et al. Natural antibodies and complement
are endogenous adjuvants for vaccine-induced CD8+
T cell responses. Nature Med. 9, 1287–1292 (2003).
67. Hopken, U. E., Lu, B., Gerard, N. P. & Gerard, C.
The C5a chemoattractant receptor mediates
mucosal defence to infection. Nature 383, 86–89
68. Kim, A. H. et al. Complement C5a receptor is essential
for the optimal generation of CD8+ T cell responses.
J. Immunol. 173, 2524–2529 (2004).
69. Karp, C. L. et al. Identification of complement factor 5
as a susceptibility locus for experimental allergic
asthma. Nature Immunol. 1, 221–226 (2000).
70. Wittman, M. et al. C5a suppresses the production
of IL-12 by IFN-γ-primed and lipopolysaccharide-
challenged human monocytes. J. Immunol.
162, 6763–6769 (1999).
71. Marie, J. C. et al. Linking innate and acquired
immunity: divergent role of CD46 cytoplasmic
domains in T cell induced inflammation. Nature
Immunol. 3, 659–666 (2002).
This in vivo study supports a role for CD46
in the regulation of T-cell responses. The authors
used mice transgenic for human CD46 to modulate
T-cell responses in a contact-hypersensitivity
72. Longhi, M. P., Sivasankar, B., Omidvar, N.,
Morgan, B. P. & Gallimore, A. Cutting edge: murine
CD59a modulates antiviral CD4+ T cell activity
in a complement-independent manner. J. Immunol.
175, 7098–7102 (2005).
73. Riley-Vargas, R. C., Gill, D. B., Kemper, C.,
Liszewski, M. K. & Atkinson, J. P. CD46: expanding
beyond complement regulation. Trends Immunol.
25, 496–503 (2004).
74. Kemper, C., Verbsky, J. W., Price, J. D. &
Atkinson, J. P. T cell stimulation and regulation:
with complements from CD46. Immunol. Res.
32, 31–43 (2005).
75. Foley, S., Li, B., Dehoff, M., Molina, M. & Holers, V. M.
Mouse Crry/p65 is a regulator of the alternative
pathway of complement activation. Euro. J. Immunol.
23, 1381–1384 (1993).
76. Fernandez-Centeno, E., de Ojeda, G., Rojo, J. M. &
Portoles, P. Crry/p65, a membrane complement
regulatory protein, has costimulatory properties on
mouse T cells. J. Immunol. 164, 4533–4542 (2000).
77. Elward, et al. CD46 plays a key role in tailoring innate
immune recognition of apoptotic and necrotic cells.
J. Biol. Chem. 280, 36342–36354 (2005).
Shows that the expression profile of complement
receptors and regulators can send inhibitory (or
inducing) phagocytic signals. Proposes, together
with reference 79, new roles for complement
in the apoptotic process in addition to its
function in the safe removal of dead cells.
78. Cole, D. S., Hughes, T. R., Gasque, P. & Morgan, B. P.
Complement regulator loss on apoptotic neuronal
cells causes increased complement activation and
promotes both phagocytosis and cell lysis. Mol.
Immunol. 43, 1953–1964 (2006).
79. Legembre, P. et al. Cutting edge: modulation of Fas-
mediated apoptosis by lipid rafts in T lymphocytes.
J. Immunol. 176, 716–720 (2006).
80. Grossmann, W. et al. Differential expression of
granzymes A and B in human cytotoxic lymphocyte
subsets and T regulatory cells. Blood 104, 2840–2848
81. Bluestone, J. A. & Abbas, A. K. Natural versus
adapative regulatory T cells. Nature Rev. Immunol.
3, 253–257 (2003).
82. Jonuleit, H. & Schmitt, E. The regulatory T cell family:
distinct subsets and their interrelations. J. Immunol.
171, 6323–6327 (2003).
83. Price, J. D. et al. Induction of a regulatory phenotype
in human CD4+ T cells by streptococcal M protein.
J. Immunol. 175, 677–684 (2005).
84. Groux, H. et al. A CD4+ T-cell subset inhibits
antigen-specific T-cell responses and prevents
colitis. Nature 389, 737–742 (1997).
85. Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L.
& Powrie, F. An essential role for interleukin-10 in the
function of regulatory T cells that inhibit intestinal
inflammation. J. Exp. Med. 190, 995–1004 (1997).
86. Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S.
& Noelle, R. J. Cutting edge: contact-mediated
suppression by CD4+CD25+ regulatory cells involves
a granzyme B-dependent, perforin-independent
mechanism. J. Immunol. 174, 1783–1786 (2005).
87. Sakaguchi, S. Naturally arising Foxp3-expressing
CD25+CD4+ regulatory T cells in immunological
tolerance to self and non-self. Nature Immunol.
6, 345–352 (2005).
88. Fukaura, H. et al. Induction of circulating myelin basic
protein and proteolipid protein-specific transforming
growth factor-β1-secreting TH3 T cells by oral
administration of myelin in multiple sclerosis patients.
J. Clin. Invest. 98, 70–77 (1996).
89. O’Garra, A. & Vieira, P. Regulatory T cells and
mechanisms of immune system control. Nature Med.
10, 801–805 (2004).
90. Barchet, W. et al. Complement-induced regulatory
T cells suppress T cell responses but allow for dendritic
cell activation. Blood 107, 1497–1504 (2006).
91. Cong, Y., Weaver, C. T., Lazenby, A. & Elson, C. O.
Bacterial-reactive T regulatory cells inhibit pathogenic
immune responses to enteric flora. J. Immunol.
169, 6112–6119 (2002).
92. Kuhn, R., Lohler, J., Rennick, D., Rajewski, K. &
Müller, W. Interleukin-10-deficient mice develop
chronic enterocolitis. Cell 75, 263–274 (1993).
93. Sadlack, B. et al. Ulcerative colitis-like disease in mice
with a disrupted interleukin-2 gene. Cell 75, 253–261
94. McGuirk, P., McCann, C. & Mills, K. H. Pathogen-
specific T regulatory 1 cells induced in the respiratory
tract by a bacterial molecule that stimulates
interleukin 10 production by dendritic cells:
a novel strategy for evasion of protective T helper
type 1 responses by Bordetella pertussis. J. Exp. Med.
195, 221–231 (2002).
95. Lavelle, E. C. et al. Cholera toxin promotes the
induction of regulatory T cells specific for bystander
antigens by modulating dendritic cell activation.
J. Immunol. 171, 2384–2392 (2003).
96. Russel, S. CD46: a complement regulator and
pathogen receptor that mediates links between
innate and acquired immune function. Tissue Antigens
64, 111–118 (2004).
97. Wang, G., Liszewski, M. K., Chan, A. C. &
Atkinson, J. P. Membrane cofactor protein (MCP;
CD46): isoform-specific tyrosine phosphorylation.
J. Immunol. 164, 1839–1846 (2000).
98. Kurita-Taniguchi, M. et al. Functional modulation of
human macrophages through CD46 (measles virus
receptor): production of IL-12 p40 and nitric oxide
in association with recruitment of protein-tyrosine
phosphatase SHP-1 to CD46. J. Immunol.
165, 5143–5152 (2000).
99. Ludford-Menting, M. J. et al. A functional
interaction between CD46 and DLG4: a role
for DLG4 in epithelial polarization. J. Biol. Chem.
277, 4477–4484 (2002).
100. Zaffran, Y. et al. CD46/CD3 costimulation induces
morphological changes of human T cells and
activation of Vav, Rac, and extracellular signal-
regulated kinase mitogen-activated protein kinase.
J. Immunol. 167, 780–6785 (2001).
101. Davis, L. S., Patel, S. S., Atkinson, J. P. & Lipsky, P. E.
Decay-accelerating factor functions as a signal
transducing molecule for human T cells. J. Immunol.
141, 2246–2252 (1988).
102. Loertscher, R. & Lavery, P. The role of glycosyl
phosphatidyl inositol (GPI)-anchored cell surface
proteins in T-cell activation. Transpl. Immunol.
9, 93–96 (2002).
103. Pratt, J. R., Basher, S. A. & Sacks, S. H. Local
synthesis of complement component C3 regulates
acute renal transplant rejection. Nature Med.
8, 582–587 (2002).
Complement mediates graft rejection through
mechanisms that include increases in pro-
inflammatory cytokine secretion by vessel walls
and the recruitment of effector T cells.
104. Sacks, S. H., Chowdhury, P. & Zhou, W. Role of the
complement system in rejection. Curr. Opin. Immunol.
15, 487–492 (2003).
105. Makrides, S. C. Therapeutic inhibition of the
complement system. Pharm. Rev. 50, 59–87
We thank K. Murphy, S. Virgin, W. Barchet and the Immunology
community at Washington University for their support. We also
thank M. Bogacki and L. Whiteley for secretarial assistance.
Competing interests statement
The authors declare no competing financial interests.
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
C1qRP | C3 | C3aR | C4b | C4BP | C5aR | CD28 | CD46 | CD55 |
CR1 | CR2 | CRRY | DC-SIGN | factor H | FAS | FOXP3 | IFNγ |
IL-2 | IL-10 | IL-12 | MBL | MOG | SIGNR1 | STAT3
The role of complement in the elimination of
Access to this links box is available online.
18 | JANUARY 2007 | VOLUME 7
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