The immune response has evolved to protect the host
from a wide range of potentially pathogenic micro-
organisms, but parallel mechanisms to control over-
exuberant immune responses and prevent reactivity to
self are required to limit host damage. Interleukin-10
(IL-10) is an anti-inflammatory cytokine with a cru-
cial role in preventing inflammatory and autoimmune
pathologies
1–3
. IL-10-deficient mice
4
develop inflam-
matory bowel disease following colonization of the
gut with particular microorganisms
5
(BOX 1) and show
other exaggerated inflammatory responses to micro-
bial challenge. Although the absence of IL-10 leads to
better clearance of some pathogens with no enhanced
immuno pathology
6,7
, during other infections the
absence of IL-10 can be accompanied by an immuno-
pathology that is detrimental to the host but does not
necessarily affect the pathogen load
3,8–11
. This suggests
that an absence of IL-10 is not always compensated by
other regulatory mechanisms and thus that there is a
non-redundant role for IL-10 in limiting inflammatory
responses in vivo.
To inhibit inflammatory pathologies, IL-10 func-
tions at different stages of an immune response and
possibly at different anatomical locations. IL-10 was
initially described as a T helper 2 (T
H
2)-type cytokine
12
,
but further evidence suggested that the production of
IL-10 was associated with tolerant or regulatory T (T
Reg
)
cell responses
3,13,14
. It is now known that the expres-
sion of IL-10 is not specific to T
H
2 cells or T
Reg
cells but
instead that it is a much more broadly expressed cytokine
(FIG. 1). IL-10 is expressed by many cells of the adap-
tive immune system, including T
H
1, T
H
2 and T
H
17 cell
subsets, T
Reg
cells, CD8
+
T cells and B cells (reviewed in
REFS 3,10,11,14–16). It is also expressed by cells of the
innate immune system, including dendritic cells (DCs),
macrophages, mast cells, natural killer (NK) cells, eosino-
phils and neutrophils
3
(FIG. 1). Thus, IL-10 production
seems to be associated with many immune cells, affirming
its crucial role as a feedback regulator of diverse immune
responses, not only T
H
1 cell responses
10,11
but also T
H
2
cell responses to schistosome parasites
17
, Aspergillus spp.
18
and allergens
19
(reviewed in REF. 1).
Much is known about the function of IL-10. For
example, the induction of the anti-inflammatory
response mediated through the IL-10 receptor (IL-10R)
and activation of signal transducer and activator of
transcription 3 (STAT3) is reviewed in REFS 3,20. By
acting on DCs and macrophages, IL-10 inhibits the
development of T
H
1-type responses (reviewed in REF. 3)
but also leads to the suppression of T
H
2 cell and aller-
gic responses (reviewed in REF. 1). In addition to an
autocrine inhibitory effect of IL-10 on macrophages
and DCs, and because IL-10 can be produced by T
H
1,
T
H
2 and T
H
17 cells, an additional feedback loop exists
to limit the innate effector functions of macrophages
and DCs and their subsequent activation of T cells.
However, IL-10 enhances the differentiation of IL-10-
secreting T
Reg
cells, thus providing a positive regula-
tory loop for its induction
21
(reviewed in REFS 1,14).
In some situations, IL-10 also activates mast cells and
enhances the functions of CD8
+
T cells, NK cells and
B cells (reviewed in REFS 2,3), although these effects
have yet to be tested in infection models.
So, IL-10 is a cytokine with important effects on the
development of an immune response. An understanding
of how IL10 expression is regulated in different innate
*Microbiology and Infection
Research Domain, Life and
Health Sciences Research
Institute (ICVS), School of
Health Sciences, University of
Minho, Campus de Gualtar,
4710‑057 Braga, Portugal.
‡
Division of Immunoregulation,
Medical Research Council
National Institute for Medical
Research, The Ridgeway,
Mill Hill, London NW7 1AA,
UK.
Correspondence to A.O’G.
e‑mail:
aogarra@nimr.mrc.ac.uk
doi:10.1038/nri2711
Published online
15 February 2010
The regulation of IL‑10 production by
immune cells
Margarida Saraiva* and Anne O’Garra
‡
Abstract | Interleukin‑10 (IL‑10), a cytokine with anti‑inflammatory properties, has a central
role in infection by limiting the immune response to pathogens and thereby preventing
damage to the host. Recently, an increasing interest in how IL10 expression is regulated in
different immune cells has revealed some of the molecular mechanisms involved at the
levels of signal transduction, epigenetics, transcription factor binding and gene activation.
Understanding the specific molecular events that regulate the production of IL‑10 will
help to answer the remaining questions that are important for the design of new strategies
of immune intervention.
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|
AOP, published online 15 February 2010; doi:10.1038/nri2711
© 20 Macmillan Publishers Limited. All rights reserved10
Chromatin
Composed of nucleosomes,
this is the basic repeating unit
of eukaryotic genomes.
Nucleosomes consist of 146
base pairs of DNA wound
around an octamer of histone
proteins.
Plasmacytoid DC
A DC that lacks myeloid
markers such as CD11c and
CD33 but expresses high levels
of HLA-DR and CD123. These
cells produce high levels of
type I interferons in response
to viral infection.
and adaptive immune cells is therefore of importance
for the development of immune intervention strate-
gies in various pathologies. Several layers of regula-
tion of IL-10 expression exist, and this is a main focus
of this Review. First, regulation of IL-10 production
involves changes in the chromatin structure at the
IL10 locus. A second layer of regulation involves
the enhancement or silencing of IL10 transcription and
is controlled by specific transcription factors activated by
discrete signal-transduction pathways. In addition, post-
transcriptional mechanisms exist. Many of the molecu-
lar events leading to IL10 expression are common to
various IL-10-producing immune cells. However, there
are also cell-specific signals and molecular mechanisms
that allow IL-10 production by particular immune cells
and not by others.
In this Review, we discuss our current understand-
ing of the regulation of IL10 expression at the molecular
level in different cell types, from signal transduction
pathways to epigenetic regulation and the activation of
specific transcription factors involved in IL-10 produc-
tion. Throughout, we highlight the common and distinct
mechanisms of IL-10 regulation that exist in different
IL-10-producing immune cells.
IL‑10 production by immune cells
Induction by pathogen-derived products. Pathogen
activation of DCs and macrophages involves the rec-
ognition of pathogen-derived products by pattern
recognition receptors (PRRs), which triggers the expres-
sion of cytokines and other factors
22
. Both macro-
phages
23–27
and DCs
26,28–33
can express IL-10 in vitro
following activation of specific PRRs (FIG. 2a). In addi-
tion, DCs
31,34
, macrophages
35
and neutrophils
36
have been
reported to express IL-10 in vivo.
It has been suggested that Toll-like receptor 2 (TLR2)
agonists are specialized in inducing IL-10 expression
by antigen-presenting cells (APCs)
29,30,37,38
. For exam-
ple, TLR2 signalling is crucial for the induction of
IL-10 production by macrophages (M. Teixeira-Coelho,
J. Carmona, A. G. Castro and M.S., unpublished obser-
vations) or by DCs
39
stimulated with Mycobacterium
tuberculosis or with lipopeptides and the LcrV antigen
of Yersinia pestis
40
. IL-10 production by macrophages
following pneumoccocal cell wall stimulation mainly
depends on TLR2; however, in this case a role for
nucleotide-binding oligomerization domain 2 (NOD2)
signalling, independent of TLR2, has also been
described
41
. Significant amounts of IL-10 are also
produced by macrophages and myeloid DCs following
stimulation with TLR4 and TLR9 ligands
26
. Of note,
IL-10 production following TLR3 stimulation was only
observed in macrophages
26
. Interestingly, activation
of macrophages through TLRs results in high levels of
IL-10 production, whereas myeloid DCs only produce
intermediate amounts and plasmacytoid DCs (pDCs) do
not produce detectable levels of IL-10 (REF. 26) (FIG. 1).
In addition, IL-10 can be induced by TLR-independent
stimuli, such as the C-type lectins DC-specific ICAM3-
grabbing non-integrin (DC-SIGN; also known as
CLEC4M)
33
and dectin 1 (also known as CLEC7A)
32
(FIG. 2a). Ligation of CD40 enhances IL-10 production by
TLR-stimulated
28
or dectin 1-stimulated DCs
32
and liga-
tion of Fc receptors (FcRs) enhances IL-10 production
by TLR-stimulated macrophages
25
.
Signalling pathways for innate IL-10 production.
Following TLR ligation, signalling cascades are activated
through Toll/IL-1 receptor (TIR)-domain-containing
adaptor molecules, such as myeloid differentiation pri-
mary-response protein 88 (MYD88) and TIR-domain-
containing adaptor protein inducing IFNβ (TRIF; also
known as TICAM1), leading to the production of IL-10
and pro-inflammatory cytokines
26,30,42
. TLR signalling
through MYD88 leads to the activation of mitogen-
activated protein kinases (MAPKs) and nuclear factor-κB
(NF-κB)
43
(FIG. 2a).
Additional signals that are required for IL-10 pro-
duction by macrophages have also been reported. Of
note, optimal lipopolysaccharide (LPS)-induced IL-10
production by macrophages requires both the activa-
tion of the TRIF- and MYD88-dependent pathways
26,27
and the production of and signalling by type I inter-
ferons (IFNs)
27
. This secondary induction of IL-10 by
type I IFNs has important implications for the use
of type I IFNs as potential anti-inflammatory drugs.
Moreover, this study is in line with the observation
that TNFR-associated factor 3 (TRAF3), an important
component of the type I IFN production pathway, is
also involved in LPS-induced upregulation of IL-10
expression
42
.
The MAPK cascade is composed of three major
groups of kinases: extracellular signal-regulated kinases
(ERKs) (comprising ERK1 (also known as MAPK3)
and ERK2 (also known as MAPK1), which are collec-
tively referred to here as ERK); JUN N-terminal kinases
Box 1 | IL‑10 expression and gut homeostasis
The intestine is continuously exposed to bacterial flora, dietary antigens and
potential pathogens. To prevent chronic intestinal inflammation, various regulatory
lymphocyte populations keep the immune response in check. These populations
use several regulatory mechanisms, the best characterized of which involves
interleukin-10 (IL-10) and transforming growth factor-β (TGFβ)
15,155
. IL-10- or IL-10
receptor-deficient mice do not develop severe autoimmune disorders but develop
colitis in the presence of microorganisms
4,156
. Many studies unequivocally identify
CD4
+
T cell-derived IL-10 as a key mediator of intestinal immune homeostasis
157–161
.
Coeliac disease and inflammatory bowel disease (IBD) are the most common causes
of non-infectious intestinal inflammation in humans, with recent reports identifying
IL10 as a susceptibility locus for the development of IBD
162
. Polymorphisms in
nucleotide-binding oligomerization domain 2 (NOD2) have also been associated
with IBD in humans
163
, which is interesting considering that NOD2 has been
associated with IL-10 production
41
. IL-10 seems to function not directly on T cells,
but instead on myeloid cell populations in a similar manner to that observed in the
immune response to pathogens
3
. In vivo IL-10 production by forkhead box P3
(FOXP3
+
) regulatory T (T
Reg
) cells and FOXP3
–
regulatory T cells in the gut seems to
be mediated by TGFβ, independently of endogenous IL-10 (REF. 97). This IL-10
independence is in contrast to that reported in vitro for human IL-10-producing
regulatory T cells
14
. Retinoic acid was identified as a cofactor for TGFβ in the
induction of FOXP3
+
T
Reg
cells
164–166
, although retinoic acid itself downregulates the
expression of IL-10 by inducible FOXP3
–
regulatory T cells
92
. Although the exact
mechanisms of IL-10 induction in the intestine remain elusive, the protective role
of intestinal T
Reg
cells mostly depends on their expression of IL-10, suggesting that
local IL-10 expression might be a therapy for IBD
2
.
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Nature Reviews | Immunology
Naive
T cell
b
c
a
T
H
2 cellIL-10-producing
T
H
1 cell
IL-10-producing
FOXP3
+
T
Reg
cell
IL-10-producing
FOXP3
–
regulatory T cell
T
H
17 cellT
H
1 cell
FOXP3
+
T
Reg
cell FOXP3
–
naive T cell
DC
DC
High
antigen
dose
or IL-12
High antigen dose
High antigen
dose and IL-12
STAT4
ERK
STAT6
ERK
STAT3
ERK
TGFβ, IL-6, IL-21
and/or IL-27
TGFβ
TGFβ
TGFβ and
retinoic acid
Signalling pathways?
IL-4
Low ERK expression
High ERK expression
Intermediate ERK
expression
IL-10
IL-10
IL-10
Intermediate IL-10
production
High IL-10 production
No IL-10 production
IL-10
IL-12
IL-10
IFNγ
Microbial
products
Plasmacytoid DC
Myeloid DC
Macrophage
(JNKs) (comprising JNK1 (also known as MAPK8)
and JNK2 (also known as MAPK9)); and p38 (REF. 44).
Following TLR stimulation, activation of ERK modulates
IL-10 expression
30,45–47
, and in the presence of chemi-
cal inhibitors of ERK
30,45,47
or in ERK-deficient cells
46
IL-10 production by TLR-activated DCs is decreased.
Furthermore, the differences in IL-10 production by
macrophages, myeloid DCs and pDCs have been shown
to correlate with the strength of ERK activation in each
of these cell types
47
. Following TLR stimulation, ERK is
most highly activated in macrophages, with lower activa-
tion of ERK in myeloid DCs and the lowest amount of
activated ERK in pDCs
47
(FIG. 1).
Further studies using cells deficient for tumour
progression locus 2 (TPL2) or NF-κB1 (also known as
p105) support the role of ERK in the induction of IL-10.
TPL2 is an upstream activator of ERK and, following
TLR stimulation, TPL2 dissociates from the TPL2–
NF-κB1 complex and activates ERK. In the absence
of NF-κB1, TPL2 is rapidly degraded in the cell and,
as a consequence, ERK activation by TPL2 is compro-
mised
48
. In TPL2-deficient macrophages and myeloid
DCs the amounts of TLR-induced IL-10 were lower
than in wild-type cells owing to the absence of ERK
activation
47
. Similarly, NF-κB1-deficient macrophages
have lower levels of IL-10 expression than control cells
Figure 1 | Interleukin-10 expression in the immune system. a | Interleukin‑10 (IL‑10) is expressed by macrophages
and myeloid dendritic cells (DCs), but not by plasmacytoid DCs, in response to microbial products. The extracellular
signal‑regulated kinase 1 (ERK1) and ERK2 (which are collectively referred to here as ERK) pathway is one of the signalling
cascades that is activated in these cells that results in IL‑10 expression. For other immune cells, such as B cells, mast cells
and eosinophils, the exact signalling pathways that lead to IL‑10 production remain elusive. b | In T helper (T
H
) cells, the
expression of IL‑10 is accompanied by the expression of the signature cytokines for each subset, with the exception of
regulatory T (T
Reg
) cells, which normally lose the capacity to express other cytokines. Although the differentiation of T
H
cells from naive CD4
+
T cells requires T cell receptor triggering and the activation of distinct signal transducer and
activator of transcription (STAT) pathways, activation of the ERK pathway is a common requirement for IL‑10 expression by
these cells. High doses of antigen presented by DCs to naive T cells or IL‑12 favours the development of T
H
1 cells, which
produce interferon‑γ (IFNγ). IL‑10‑producing T
H
1 cells require high antigen dose and IL‑12 and STAT4 signalling for the
expression of maximum levels of IL‑10 following re‑stimulation. In T
H
2 cells, IL‑4 and STAT6 signalling pathways are
required for IL‑10 expression. Induction of IL‑10‑producing T
H
17 cells is not well understood, but transforming growth
factor‑β (TGFβ), IL‑6, IL‑21 and/or IL‑27 and STAT3 signalling are likely to be involved. c | TGFβ can induce the production
of IL‑10 by forkhead box P3 (FOXP3)
+
T
Reg
cells and this cytokine can also promote the development of IL‑10‑producing
FOXP3
–
regulatory T cells from naive T cells. Conversely, FOXP3
+
IL‑10‑producing T
Reg
cells can differentiate from naive
T cells in vitro in the presence of TGFβ and retinoic acid.
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IL-10
IL-10
IL-10
IL-10
TLR4TLR2 TLR2 TLR2
TLR9
TLR3
Endosome
Macrophage
TPL2
TPL2
TRIF
MSK1
MSK2
NF-κB
NF-κB
p38
p38
IFNγ
IFNγ
TLR-dependent signal
Nature Reviews | Immunology
PI3K
AKT
DC-SIGN
Myeloid DCs Macrophages and myeloid DCs Macrophages
Dectin 1
ERK
ERK
ERK
SYK
TRAF3
Through IL-10R
and STAT3
Through IL-10R
and STAT3
MYD88 MYD88
NOD2
RIP2
RAF1
Cytoplasm
a
b
MSK1
MSK2
CREB
AP1
DUSP1
GSK3
MEK1
MEK2
following TLR activation
49
. IL-10 expression was only
partially restored following rescue of ERK activation in
these cells
49
, indicating that NF-κB-mediated regulation
of IL-10 production involves both ERK-dependent and
ERK-independent mechanisms, as had been suggested
by previous studies
50,51
. Furthermore, pathogen trigger-
ing of DC-SIGN in human DCs resulted in the activation
of RAF1, leading to acetylation of the NF-κB p65 subunit
and to prolonged and increased IL10 transcription
52
. This
effect was only observed after TLR-dependent NF-κB
activation, suggesting that activation of DC-SIGN can
modulate TLR-induced IL-10 production
52
.
The regulation of IL-10 production in response to
dectin 1 ligation depends on spleen tyrosine kinase
(SYK)
32
. SYK is recruited to phosphorylated dectin 1
(REF. 53) and initiates a signalling cascade that induces
IL-2 and IL-10 production
32
. IL-10 production down-
stream of dectin 1 also requires signalling through the
ERK pathway, despite being independent of TLR activa-
tion
54
(FIG. 2a). Furthermore, IL-10 production by FcR
ligation in the presence of TLR signals in macrophages
can also lead to ERK activation
55
. Therefore, ERK activa-
tion is common to several signalling pathways upstream
of IL10 in macrophages and DCs.
IL-10 expression can also be compromised by inhibi-
tion of p38 signalling in LPS- or CpG-activated macro-
phages
45,56–58
, primary DCs
59
and human peripheral
blood monocytes
60
. Primary cells lacking the p38 regula-
tor dual-specificity protein phosphatase 1 (DUSP1) have
prolonged p38 activation and increased levels of IL-10
expression following TLR stimulation
61–63
. This could be
reversed by chemically inhibiting p38 signalling
61,62
.
Interestingly, abrogation of either ERK or p38 activa-
tion leads to a reduction, but not abrogation, of IL-10
expression, which suggests that these two pathways might
cooperate in TLR-induced IL-10 production. Supporting
this hypothesis, inhibition of both the ERK and p38
pathways in LPS- or CpG-stimulated macrophages leads
to an almost complete abrogation of IL-10 production
(A.O’G., unpublished observations). Furthermore, defi-
ciency of mitogen- and stress-activated protein kinase 1
(MSK1; also known as RPS6Kα5) and MSK2 (also known
as RPS6Kα4), which are activated downstream of the p38
and ERK pathways, correlated with a loss of IL-10 expres-
sion by LPS-stimulated macrophages
64
.
The production of IL-10 by macrophages and DCs
is also regulated by the activation of certain inhibitory
pathways. ERK- and p38-dependent IL-10 production
is inhibited by IFNγ
38
(FIG. 2b). In addition to directly
blocking TLR-induced MAPK activation, IFNγ induces
the release of glycogen synthase kinase 3 (GSK3) by
antagonizing phosphoinositide 3-kinase (PI3K)–AKT
activation. This leads to inhibition of TLR-induced
IL-10 production by suppressing the binding of acti-
vator protein 1 (AP1) to the Il10 promoter
38
. Another
negative feedback loop controlling IL-10 production by
macrophages is mediated by IL-10 itself. IL-10 induces
the expression of DUSP1, which negatively regulates p38
phosphorylation and thus limits IL-10 production
65
. By
contrast, IL-10 positively feeds back to upregulate Tpl2
expression
66
, thus providing a positive amplification
Figure 2 | Signals that induce interleukin-10 expression by cells of the innate immune
response. a | The expression of interleukin‑10 (IL‑10) can be induced by Toll‑like receptor
(TLR) or non‑TLR signalling in macrophages and myeloid dendritic cells (DCs). Activation of
TLRs and their adaptor molecules — myeloid differentiation primary‑response protein 88
(MYD88) and TIR‑domain‑containing adaptor protein inducing IFNβ (TRIF) — results in
the activation of the extracellular signal‑regulated kinase 1 (ERK1) and ERK2 (which are
collectively referred to here as ERK), p38 and nuclear factor‑κB (NF‑κB) pathways.
Activation of these pathways results in the induction of IL‑10 expression, in addition to
pro‑inflammatory cytokines. In myeloid DCs, non‑TLR signals through DC‑specific
ICAM3‑grabbing non‑integrin (DC‑SIGN) and RAF1 can augment TLR2‑induced IL‑10
production. Furthermore, activation of dectin 1 and the signalling molecules spleen
tyrosine kinase (SYK) and ERK results in IL‑10 production. In macrophages, a role for
nucleotide‑binding oligomerization domain 2 (NOD2) signalling in IL‑10 induction, in
crosstalk with TLR2, has been described. b | Positive and negative feedback loops for IL‑10
regulation in macrophages. The p38 and ERK pathways leading to IL‑10 expression by
macrophages are tightly controlled by interferon‑γ (IFNγ) and IL‑10 itself. IL‑10 feeds back
to induce the expression of dual‑specificity protein phosphatase 1 (DUSP1), which
negatively regulates p38 phosphorylation and thus limits IL‑10 production. IL‑10 can also
positively feed back to upregulate tumour progression locus 2 (TPL2) expression, thus
providing a positive amplification loop for its own production. In addition, IFNγ can also
interfere with the phosphoinositide 3‑kinase (PI3K)–AKT pathway, releasing glycogen
synthase kinase 3 (GSK3). As GSK3 normally blocks IL‑10 expression by acting on the
transcription factors cAMP response element‑binding protein (CREB) and activator
protein 1 (AP1), IL‑10 production is inhibited by IFNγ through its effects on PI3K. IL‑10R,
IL‑10 receptor; MEK, MAPK/ERK1 kinase; MSK, mitogen‑ and stress‑activated protein
kinase; RIP2, receptor‑interacting protein 2; STAT3, signal transducer and activator of
transcription 3; TRAF3, TNFR‑associated factor 3.
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Notch
A signalling system
comprising highly conserved
transmembrane receptors that
regulate cell fate choice in the
development of many cell
lineages. Therefore, they are
crucial in the regulation of
embryonic differentiation
and development.
loop for its own production. IL-10 was also described
to induce its own transcription in human monocytes in
a STAT3-dependent manner
67
, which may result from
its upregulation of TPL2 and thus ERK activation
66
.
However, the mechanisms dictating the balance between
IL-10-mediated negative and positive feedback loops are
currently not clear. Furthermore, the inhibition of IL-10
production by NK cell- or T cell-derived IFNγ in vivo
will also influence these loops.
Various pathogen-derived products induce IL10
expression by macrophages and DCs through the acti-
vation of signalling cascades that, although common
to various stimuli and different cells, have distinct
thresholds of activation depending on the cell type,
which reflect the distinct amounts of IL-10 produced
by these cells.
IL-10 production by T
H
cells. IL-10 production was first
described in T
H
2 cells
12,68
, where its expression accom-
panies that of the T
H
2-type cytokines IL-4, IL-5 and
IL-13. T
H
1 cells can also be induced to produce IL-10,
but, in contrast to T
H
2 cells, only under certain condi-
tions
10,11,15,69–76
(FIG. 1). Furthermore, T
H
17 cells have
recently been shown to produce IL-10 (REFS 72, 77–79).
The fact that T
H
1, T
H
2 and T
H
17 cells are dependent on
DC- and macrophage-derived factors that are downregu-
lated by IL-10, but these subsets can all be induced to
produce IL-10, is indicative of a negative feedback loop
that ensures that effector T cell responses do not result
in immunopathology. It is of interest to note that IL-9-
producing T
H
cells, which have recently been suggested to
be a unique T
H
cell subset (T
H
9 cells), also express IL-10
(REF. 80).
Molecular signals for IL-10 induction in T
H
cells.
IL-10-inducing signalling cascades have been studied
less thoroughly in T
H
cells than in macrophages and
DCs. IL-10-producing T
H
1 cells have been described
in infectious diseases, human CD4
+
T cell clones and
mouse CD4
+
T cells. T
H
1 cells that produce both IFNγ
and IL-10 can be generated by inducing T cells to pro-
liferate with high levels of antigen-specific or polyclonal
stimulation in the presence of IL-12 (REFS 10,11,69,70)
(FIG. 1). However, until recently the signals that determine
whether T
H
1 cells produce IL-10 were not known. Strong
T cell receptor (TCR) triggering (high antigen dose)
71
and
endogenous IL-12 have now been shown to be essential
for the differentiation of IL-10-producing T
H
1 cells, as
well as for maximal expression of IL-10 following re-
stimulation of these cells
72
. IL-10 induction in T
H
1 cells
is STAT4 and ERK dependent
72
(FIG. 1). Notch signalling
can also induce IL-10 expression by T
H
1 cells, a process
that requires STAT4 (REF. 81). In T
H
2 cells, IL-10 produc-
tion seems to be regulated by the main T
H
2 type-associ-
ated signalling pathways and transcription factors: IL-4,
STAT6 and GATA binding protein 3 (GATA3)
82–84
. IL-10
expression by T
H
17 cells seems to occur in a STAT3- and,
in some cases, STAT1-dependent manner
79,85
(FIG. 1).
Thus, to induce IL-10 expression, T
H
1, T
H
2 and T
H
17
cells require the same signals needed for each T
H
cell
differentiation programme. However, IL-10 production
by all these subsets requires ERK activation
72
, indicating
that a common molecular mechanism exists for IL-10
production by T
H
cells. Chemical inhibition of the p38
signalling pathway did not compromise the production
of IL-10 by T
H
1, T
H
2 or T
H
17 cells
72
, suggesting that in T
H
cells the role of ERK is dominant over that of p38. This
observation is in contrast to a joint role for ERK and p38
in IL-10 induction in macrophages and DCs.
IL-21 can enhance IL-10 expression by CD4
+
T cells
in the context of different stimuli
86
, and IL-27 enhances
IL-10 expression by T
H
1, T
H
2 and T
H
17 cells
78,79,85,87,88
.
By contrast, IL-27 attenuates TLR-induced IL10 expres-
sion by human monocytes
89
. Of interest, it has recently
been shown that both IL-21 and IL-27 induce ERK
activation
90,91
, but it is currently not clear whether this
explains the ability of these cytokines to upregulate IL-10
production. Also, both IL-21 and IL-27, in addition to
ERK, activate STAT3, which seems to be involved in
IL-27-mediated IL-10 upregulation by T cells
79
.
Undoubtedly, all T cell subsets can produce IL-10, as
well as their hallmark cytokines, following TCR trigger-
ing, but this depends on the environmental context and
strength of stimulus
10,11,69–73,92–94
.
IL-10 and regulatory T cells. T
Reg
cells, which are char-
acterized by their specific expression of the transcrip-
tion factor forkhead box P3 (FOXP3), do not express
IL-10 following stimulation directly after ex vivo isola-
tion
95,96
, unless isolated from the gut
97
(BOX 1). Although
FOXP3
+
T
Reg
cells inhibit naive T cell proliferation in vitro
independently of IL-10, in some cases, T
Reg
cells mediate
their regulatory function in vivo through IL-10 (reviewed
in REFS 1,14,16,98–100). Therefore, T
Reg
cells must receive
signals in vivo to induce the expression of this suppressive
cytokine. Both IL-2 and IL-4 have been shown to induce
IL-10 production after culture of T
Reg
cells in vitro
101,102
.
However, in these studies, the T
Reg
cell population analysed
might have contained some effector T cells and therefore
the source of IL-10 cannot be confirmed. So far the signals
that induce IL-10 expression by FOXP3
+
T
Reg
cells remain
elusive, although transforming growth factor β (TGFβ)
has been shown to be required in vivo
97
(FIG. 1).
Several populations of antigen-driven FOXP3
–
IL-10-producing T cells with regulatory activity that are
distinct from naturally occurring T
Reg
cells have been
described (reviewed in REFS 1,2,13,14). These cells pro-
duce IL-10, but not IL-2, IL-4 or IFNγ, and can be gen-
erated in vitro using various stimuli, such as cytokine
cocktails (TGFβ, IL-10 and IFNα) or immunosuppres-
sive drugs (vitamin D3 and dexamethasone)
1,2,13,14,21
, or
in vivo by repeated stimulation with soluble antigen
71,103
.
Additional signals for IL-10 expression by these FOXP3
–
regulatory T cells include co-stimulation through CD2
or CD46 and stimulation with type I IFNs or with
immature DCs (reviewed in REFS 1,14,104). Signals
delivered through inducible T cell co-stimulator (ICOS)
have also been suggested to induce IL-10 expression by
FOXP3
–
regulatory T cells
105,106
; a similar effect has been
observed in T
H
2 cells
107,108
, suggesting that, although it
is involved in the induction of IL-10, ICOS is not a cell
type-specific inducer of IL-10.
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