Autoimmune inflammation from the Th17 perspective
Janette Furuzawa-Carballeda, María Inés Vargas-Rojas, Antonio R. Cabral⁎
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,
Vasco de Quiroga 15 Tlalpan, Mexico City, 14000, Mexico
Accepted 12 October 2006
Available online 14 November 2006
Recent studies demonstrated an IL-17-producer CD4+T cell subpopulation, termed Th17, distinct from Th1 and Th2. It
represents a different pro-inflammatory Th-cell lineage. This notion is supported by gene-targeted mice studies. Mice lacking
IL-23 (p19−/−) do not develop experimental autoimmune encephalomyelitis (EAE) or collagen-induced arthritis (CIA), while
knockout mice for the Th1 cytokine IL-12 (p35−/−) strongly develop both autoimmune diseases. Disease resistance by IL-23
knockout mice correlates well with the absence of IL-17-producing CD4+T lymphocytes in target organs despite normal
presence of antigen-specific-IFN-γ-producing Th1 cells. This finding may thus explain previous contradictory reports showing
that anti-IFN-γ-treated mice, IFN-γ- or IFNR-deficient mice develop CIA or EAE. TGF-β, IL-6 and IL-1 are the differentiation
factors of Th17 cells. IL-23 is dispensable for this function, but necessary for Th17 expansion and survival. The master
regulator that directs the differentiation program of Th17 cells is the orphan nuclear receptor RORgt. IL-27, a member of the IL-
12/IL-23 family, potently inhibits Th17 development. Evidence suggesting rheumatoid arthritis and multiple sclerosis as
primarily IL-17 autoimmune inflammatory-mediated diseases is rapidly accumulating. The IL-17/23 axis of inflammation and
related molecules may rise as therapeutic targets for treating these and perhaps other autoimmune diseases.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Th1/Th2/Th17 lineages; IL-17; IL-23; Rheumatoid arthritis
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
The Th1/Th2 paradigm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
The Th17 lineage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.1.Th17 cell is a distinct CD4+effector cell lineage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.2.TGF-β, IL-6 and IL-1 induce Th17 differentiation, while IL-27 inhibits this function . . . . . . . . . . . . . 172
3.3. Transcription factors in Th17 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
IL-17, IL-12 and IL-23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
IL-17 in human rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Autoimmunity Reviews 6 (2007) 169–175
⁎Corresponding author. Tel.: +52 55 5485 0079; fax: +52 55 5573 2096.
E-mail address: email@example.com (A.R. Cabral).
1568-9972/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .173
Men whose research is based on shared paradigms
are committed to the same rules and standards for
Thomas S. Khun
The classical T helper (Th)1 and Th2 CD4+T cell
effector paradigm has recently been challenged. Studies
from various laboratories have shown the existence of a T
cell subpopulation, dubbed Th17, not only distinct from
Th1 and Th2, but a different pro-inflammatory Th-cell
with the IL-17/IL-23 axis, particularly in the pathogenesis
of collagen-induced arthritis (CIA) and experimental
autoimmune encephalomyelitis (EAE). We focus our dis-
cussion on the role of the IL-17/IL-23 axis in the path-
ogenesis of human rheumatoid arthritis (RA). Taken
together, these data promise to change our understanding
of immune regulation and pathogenesis and maybe our
approach to treat some human autoimmune diseases.
2. The Th1/Th2 paradigm
Two decades ago, Mosmann et al. proposed that Th
cells could be subdivided in two subpopulations, Th1
and Th2, based upon their cytokine expression profiles
. Th1 cells produce IL-2 and interferon-γ (IFN-γ),
while Th2 cells synthesize IL-4, IL-5 and IL-10 
(Fig. 1). These mutually inhibitory cytokine-function
profiles are mediated by lineage-specific transcription
the transcription factor signal transducer and activator of
transcription 4 (STAT4), which results in the expression
of T-bet (also known as Tbx-21), the master regulator of
Th1 differentiation . Th2 polarization is initiated via
TCR signaling acting in concert with IL-4 receptor
signaling via STAT6, which, in turn, up-regulates the
expression of GATA-binding protein 3 (GATA3), the
master regulator of Th2 differentiation  (Fig. 1).
3. The Th17 lineage
The Th1/Th2 paradigm is paradoxical because anti-
IFN-γ-treated mice, IFN-γ- or IFNR-deficient mice
indeed develop CIA [3–6] or EAE [7–9], two classical
Th1 associated-diseases . Similarly, Infante-Duran
et al. recently demonstrated that Th cells primed with a
synthetic peptide in the presence of Borrelia burgdor-
feri, the causative agent of Lyme disease, primarily
express mRNA encoding IL-17 (IL-17A) at significant-
ly higher levels than Th cells primed with IL-12, while
IL-4 and IL-10 mRNA are depressed under the same
conditions . In addition, these authors elegantly
showed that intracellular IL-17 and IL-17 production are
not significantly increased under Th1 or Th2 polarizing
conditions. Instead, almost all IL-17-producing-Th
cells, identified as CD4+/CD8−, simultaneously produce
TNF-α and GM-CSF. Infante-Duarte et al. therefore
reasonably concluded that IL-17-producing T cells
could not be categorized as either Th1 or Th2 .
Later, Aggarwal et al. showed that memory T cells
produce great amounts of IL-17A/F in response to IL-23
from activated dendritic cells, while IL-12 has only
marginal effects on IL-17 production  (Fig. 1).
The notion that the IL-17-producing T cell may be a
distinct T cell lineage that emerged from gene-targeted
mice studies. Langrish et al. demonstrated that IL-23-
deficient mice are EAE-resistant, that the numbers of
IFN-γ-positive CD4+cells infiltrating the central
nervous system (CNS) or from draining lymph nodes
are equivalent to wild-type (WT) mice, and that TNF-α,
IL-17 and IL-6-positive cells are undetectable at both
sites . The recognition that IL-12 and IL-23 share
the p40 subunit and that IL-23 is paired with a distinct
chain (IL-23p19 instead of IL-12p35) helped to
consolidate these notions . Cua et al. studied mice
lacking only IL-23 (p19−/−), IL-12 (p35−/−), or both
(p40−/−), and found that mice lacking IL-23 (p19−/−) are
resistant to EAE while IL-12 (p35−/−) knockout animals
are highly susceptible to EAE . Furthermore, when
p19−/−or p40−/−mice (both IL-23-deficient) received
intracerebral injections of a vector carrying the IL-23
gene, all acquired EAE . The same group also
showed that IL-23-deficient mice do not develop CIA,
correlating well with the absence of IL-17-producer
CD4+T cells despite normal induction of collagen-
specific-IFN-γ-producing Th1 cells. In contrast, IL-12-
deficient (p35−/−) mice have more IL-17-producing
CD4+T cells and elevated mRNA expression of TNF-α,
IL-1β, IL-6 and IL-17 in the affected tissues of arthritic
mice . These findings concur with reports showing
170J. Furuzawa-Carballeda et al. / Autoimmunity Reviews 6 (2007) 169–175
that CIA is suppressed in IL-17-deficient mice and that
administration of neutralizing anti-IL-17 antibodies at
preclinical and advanced clinical stages significantly
reduces the severity of CIA (reviewed in Ref. ).
3.1. Th17 cell is a distinct CD4+effector cell lineage
Convincing arguments pointing the IL-17-produc-
ing CD4+Tcells (Th17 or ThIL-17) as a distinct effector
lineage, arose simultaneously from two laboratories
[16,17]. Harrington et al. and Park et al. showed that
development of Th17 cells from naïve cells is potently
inhibited by IFN-γ and IL-4, whereas already com-
mitted Th17 cells are resistant to suppression by Th1
or Th2 cytokines . This differentiation of Th17
cells is suppressed by IFN-γ and IL-4 in an STAT1-, T-
bet-, STAT4- and STAT6-independent manner .
Under Th1 or Th2 polarizing conditions (anti-IL-4 or
anti-IFN-γ, respectively), both groups also demon-
strated that IL-23 does not induce Th1 or Th2 pro-
liferation. Contrarily to Th1 development, antigen-
specific Th17 differentiation depends not only on
CD28 but also on ICOS co-stimulatory molecules .
Fig. 1. T-helper-cell differentiation. Th1 cells produce IL-2 and interferon-γ (IFN-γ), while Th2 cells synthesize IL-4, IL-5, IL-10 and IL-13. IL-12
activates STAT1 which results in the expression of T-bet, the master regulator of Th1 differentiation. Th2 differentiation signaling via STAT6
regulates the expression of GATA3, the master regulator of Th2 differentiation. Development of Th17 cells from naïve cells is inhibited by IFN-γ and
IL-4 whereas committed Th17 cells are resistant to suppression by Th1 or Th2 cytokines. Differentiation of Th17 cells from naïve precursors is
induced by IL-1, TNF-α, IL-17 A/F and IL-6 in STAT1-, T-bet-, STAT4- and STAT6-independent manners. The master regulator of the Th17
differentiation program is the orphan nuclear receptor RORgt. The Th17 cytokine profile is IL-17A/F, TNF-α, IL-1, IL-6 and GM-CSF. Under Th1 or
Th2 polarizing conditions (anti-IL-4 or anti-IFN-γ, respectively) the development of antigen-specific Th17 cells depends on ICOS co-stimulatory
signals. TGF-β1 alone is sufficient to promote Th17 development via IL-23R expression, while IL-23 proper does not elicit this response. TGF-β1
also induces the differentiation of a distinct subpopulation of post-thymic T cells to express Foxp3, Tregcells. IL-27, a member of the IL-12/IL-23
family, is a potent IFN-γ-independent inhibitor of the Th17 development in a STAT1- and SOC3-dependent manner.
171J. Furuzawa-Carballeda et al. / Autoimmunity Reviews 6 (2007) 169–175
3.2. TGF-β, IL-6 and IL-1 induce Th17 differentiation,
while IL-27 inhibits this function
Mangan et al. found that exogenous TGF-β induces
suppression of intracellular IFN-γ+cells compared to
IL-23 alone and that TGF-β1 markedly increases the IL-
17+cell-fraction . Naïve CD4 T cells from ifng−/−
mice cultured with anti-CD3, anti-IL-4 and anti-IFN-γ,
respond well to TGF-β1, which by itself is sufficient to
promote robust Th17 development via IL-23R expres-
sion , even in IL-23-deficient naïve CD4+T cells
. Although dispensable for the development of Th17
cells in vitro and in vivo [11,19], Mangan et al. showed
that IL-23 is necessary for host protection against the
bacterial enteropathogen, Citrobacter rodentium .
In agreement with a previous report , these
investigators also found that TGF-β1 induces the
expression of Foxp3 (Treg) or IL-17 (Th17) and that
levels of TGF-β1 inversely correlate with those of IL-6
to an extent that the latter cytokine almost totally
abolishes the expression of Foxp3 . In a back to
back paper, albeit with a different model, Betelli et al.
also reported that IL-6 inhibits the generation of Foxp3+
Tregcells induced by TGF-β and that IL-23 is not the
differentiation factor of Th17 cells . (Fig. 1).
Knowledge that IL-1 also plays a role in the differ-
entiation of Th17 cells comes from a study by Sutton et
cells, but not Th1 or Th2 cells, is abrogated in IL-1
receptor type I-deficient (IL-1RI−/−) mice which are also
protected against EAE, but become ill after adoptive
transfer of antigen-specific Th17 cells from WT mice
with advanced EAE. Sutton et al. showed that the IL-23-
mediated IL-17 production is amplified by IL-1α, IL-1β
and TNF-α and is inhibited by PI-3k, NF-κB, and novel
PKC isoforms .
IL-27, a member of the IL-12/IL-23 family, is a
potent inhibitor of the Th17 development [23,24] that is
dependent of STAT1, independent of IFN-γ [23,24] and
of cytokine signaling protein 3 (SOCS3) . (Fig. 1).
3.3. Transcription factors in Th17 cells
The master regulator that directs the differentiation
program of Th17 cells is the orphan nuclear receptor
RORgt . GATA-3 and T-bet are not required for this
function . Similarly, the negative regulator for TGF-
β signaling, Smad7, is dispensable for Th17 develop-
ment  (Fig. 1). Th SOCS3-deficient-T cells
stimulated with IL-23 express increased tyrosine phos-
phorylation of STAT3 that binds preferentially to IL-
17A/F promoters, irrespective of IL-23R mRNA
expression . More importantly, naïve CD4+
SOCS3 null T cells cultured under Th1, Th2 or Th17
polarizing conditions and in the presence of TGF-β and
IL-6, all express increased amounts of IL-17 mRNA
. (Fig. 1).
4. IL-17, IL-12 and IL-23
Interleukin-17 (IL-17A) is the prototypic IL-17 family
E. The IL-17F isoforms 1 and 2 (ML-1) have the highest
degree of homology with IL-17A (55 and 40%,
respectively), IL-17E is the most distant (17%). IL-17A
is co-expressed with TNF-α and GM-CSF [16,17] by
Th17 cells [16,17], and to a lesser extent by neutrophils,
eosinophils, and CD8+memory CD45RO+T cells
(reviewed in Ref. ).
The IL-17 receptor (IL-17RA), a type I transmem-
brane protein with a ubiquitous cell and tissue distri-
bution, has no homology with any known cytokine
receptor family. Its mRNA can be detected in epithelial
cells, fibroblasts, B and T lymphocytes, myelomonocy-
tic cells, marrow stromal cells and vascular endothelial
cells. The biologic activity of IL-17 is dependent on a
multimeric (homotypic and heterotypic) preformed (in
the plasma membrane) receptor complex composed of
IL-17RA and IL-17RC. More recently, four additional
IL-17-like receptors (IL-17RB–E) have been identified
. Similar to IL-17R, they are type I transmembrane
proteins but display significant alternative splicing.
Binding of IL-17A to its unique receptor, IL-17RA,
results in activation of the adapter molecule TNFR-
associated factor 6 (TRAF-6) but not TRAF-2. IL-17
shares transcriptional pathways with IL-1 and TNF-α at
the level of the 24p3 promoter . A summary of the
key molecular characteristics and tissue distribution of
IL-17 and IL-17R is presented in the Table 1.
IL-12, is formed by p35 and p40 subunits, the
latter is structurally related to the soluble IL-6 receptor
(IL-6Rα). By comparison, novel subunits comprising
IL-23 (p19) and IL-27 (p28) were identified in a
homology search of the human DNA sequence database,
using IL-6-related cytokines as probes. These studies
revealed that IL-23 is a heterodimer of IL-23p19 and IL-
12p40 . IL-12p35, IL-23p19 and IL-27p28 are
poorly secreted unless co-expressed with their respec-
tive partners (IL-12p40 for IL-12p35 and IL-23p19, and
EBI3 for IL-27). (Recently reviewed in Ref. ).
Patterns of ligand and receptor expression are similar
. Functional cloning of the other IL-23 receptor
172J. Furuzawa-Carballeda et al. / Autoimmunity Reviews 6 (2007) 169–175
this chain is present in memory and/or activated T cells
(CD4+CD45RBloorCD4+CD45RO).At least sixspliced
isoforms of IL-23R, named IL-23R1-6, can be generated
through alternative splicing in normal lymphoid cells and
numerous tumor cell lines .
5. IL-17 in human rheumatoid arthritis
IL-17 and IL-23p19 are present in the sera, synovial
fluids and synovial biopsies of most RA patients, while
both are absent in osteoarthritis (OA) [29–33]. Similar-
ly, IL-17 is produced by T cell clones developed from
RA patients  and human RAT cells primed in vitro
with type II collagen, stimulate IL-15, TNF-α and IL-18
production by RA synovial fibroblasts, in turn, T cells
respond to fibroblasts by secreting high levels of IL-17
and IFN-γ . It is also known that IL-17 activates RA
synovial fibroblasts to synthesize IL-6, IL-8  and
vascular endothelial growth factor , the former via
NF-κB and PI3-K/Akt-dependent pathways . IL-17
also enhances IL-6 production, collagen destruction and
collagen synthesis by RA synovial explants, causes
bone resorption by RA bone explants , increases
osteoclastogenesis  and fetal cartilage destruction
. Patients with early inflammatory arthritis who
subsequently develop RA appear to have a distinct but
transient synovial fluid cytokine profile characterized by
increased levels of IL-2, IL-4, IL-13, IL-17, IL-15 and
other growth factors . Noteworthy, this profile is not
present in patients with established RA . A recent
prospective 2-year study has also stressed this notion as
well as the role of IL-17 in the pathogenesis of RA .
Interestingly, the synovial membrane mRNA levels of
IL-1β, TNF-α, IL-17, and IL-10 are predictive of
damage progression  and correlate well with the
expression of IL-23p19 mRNA and IL-23 in IL-17-
stimulated RA synovial fibroblasts .
6. Concluding remarks
Recent studies have demonstrated that the classical
Th1/Th2 CD4+Tcell effector model needs reinterpreta-
tion. It is now known that the IL-17-producer T cell,
heretofore thought of as a Th1 subset, is a distinct Tcell
lineage on its own right. This newly discovered T cell,
Human IL-17 and IL-17R key features
Cell and tissue
Cell and tissue
A35 1556p12 Th17, neutrophils,
IL-17RA866 22q11.1 IL-17A/F Lungs, kidneys,
mesothelial cells, B
and T cells
44 153 6p12Th17, basophils, cord
blood derived mast
cells, liver, lung, ovary
intestine, spinal cord
B 41 1805q32-34IL-17RB
499 3p21.1 IL-17B/E Kidney, pancreas,
liver, brain and
muscle, heart, small
C 40197 16p24Human testes, thymus,
D 52 202 13q12.11Skeletal muscle,
neuronal cells, adipose
tissue, heart, lung,
pancreas, low levels in
resting CD4+T cells
and CD19+B cells
Brain, lung, testis,
adrenal gland, spinal
cord, trachea, prostate
E (IL-25) 34161 14q11.2IL-17RE
667 3p25.3?Brain, prostate,
aTwo isoforms (long and short).
173J. Furuzawa-Carballeda et al. / Autoimmunity Reviews 6 (2007) 169–175
termed Th17, has a defined cytokine profile, it has its
own set of lineage-specific developmental genes and is
the main pro-inflammatory CD4+effector T cell in-
volved in murine models of CIA and EAE. Th17 cells
are feasible candidates to fill the void left by the para-
doxical development of autoimmune diseases in animals
lacking the IFN-γ gene, so far interpreted on Procrustes'
Bed. The role of the Th17 cell subset in human auto-
immune diseases is not as black and white, but old and
recent reports point at the IL-17/IL-23 axis of inflam-
mation as a promising Ariadnian thread to guide re-
search in human RA. Born as a robust child, the Th17
differentiation pathway nicely confirms the classical
Darwinian dictum that the effects of certain genes de-
pend on the environment. Time will tell if the novel Th1/
Th2/Th17 paradigm indeed changes our rules and stan-
dards for scientific practice.
• Th17 cell is a recently discovered CD4+effector T
cell lineage, distinct from Th1, Th2 and Tregcells. Its
master regulator is the orphan nuclear receptor
• IL-17 is a marker molecule for Th17 cells rather than
a unique cytokine of this helper cell lineage.
• The Th17 cytokine effector molecules are IL-17 A/F,
TNF-α, IL-6 and GM-CSF.
• Murine Th17 cells play a major role in the
pathogenesis of the human equivalent of multiple
sclerosis and rheumatoid arthritis.
• Rheumatoid arthritis and multiple sclerosis are
emerging as models of IL-17-driven autoimmune
• Time will tell if the new Th1/Th2/Th17 paradigm of
CD4+effector cells settles enough to truly transform
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synovial fibroblasts via NF-κB- and P13-kinase/AK1-dependent
pathways. Arthritis Res Ther 2004;6:120–8.
 Ryu S, Lee JH, Kim SI. IL-17 increased the production of
vascular endothelial growth factor in rheumatoid arthritis
synoviocytes. Clin Rheumatol 2005;25:16–20.
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IL-17 derived from juxta-articular and synovium contributes to
joint degradation in rheumatoid arthritis. Arthritis Res 2001;3:
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CWGM. Interleukin 17 synergises with tumor necrosis factor α
to induce cartilage destruction in vitro. Ann Rheum Dis 2002;61:
synovial fluid cytokine profile of T cell and stromal cell origin.
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predictive of joint damage progression in rheumatoid arthritis.
A two-year prospective study (the DAMAGE study cohort).
Arthritis Rheum 2006;54:1122–31.
Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomized
Chaperonin 10 (heat shock protein 10, XToll) has anti-inflammatory properties related to the inhibition of Toll-like
receptor signaling pathways. The aim of this study, Vanags D. et. al. (Lancet 2006;368:855-63) was to establish
whether chaperonin 10 is safe and effective in the treatment of rheumatoid arthritis. In a randomized, double-blind,
multicentre study, 23 patients with moderate to severe active rheumatoid arthritis receiving disease-modifying
antirheumatic drugs were allocated to three treatment groups receiving intravenous chaperonin 10 twice weekly for
12 weeks at doses of 5 mg (n = 8), 7.5 mg (8), or 10 mg (7). The primary outcomes were change in disease activity
score (DAS28) and improvement of core disease measures from baseline to weeks 12. Primary endpoint measures
improved from day 14 in all groups and continued to improve to day 84. By end of study, a 20% improvement of
core disease measures was seen in six (86%, 95% CI 43-100) patients given the highest dose of chaperonin 10.
Clinical remission was achieved in three (13%) of 23 patients. The most common adverse events were
exacerbation of rheumatoid arthritis and upper respiratory tract infection. Thus, chaperonin 10 seems to be well
tolerated and efficacious in treatment of the symptoms of rheumatoid, at least in the short term.
175 J. Furuzawa-Carballeda et al. / Autoimmunity Reviews 6 (2007) 169–175