Differentiation and function of Th17 T cells
Brigitta Stockinger and Marc Veldhoen
IL-17-producing T cells have recently been classified as a new
effector T-cell subset, termed Th17, which is distinct from Th1,
Th2 and Treg subsets. There has been much progress in the
past year, leading to identification of the molecular
mechanisms that drive differentiation of Th17 T cells. This has
helped to clarify many aspects of their role in host defense as
well as in autoimmunity. Nevertheless, many intriguing
questions remain to be answered regarding the regulation of
Th17-mediated responses as well as their interactions with the
other T-cell subsets. Furthermore, the role of pathogens and
pathogen-derived molecules in influencing effector T-cell
polarization needs to be re-evaluated in the light of the
differentiation conditions that favor Th17 T-cell responses.
Division of Molecular Immunology, The MRC National Institute for
Medical Research, The Ridgeway, Mill Hill, London NW7 1AA,
Corresponding author: Stockinger, Brigitta (firstname.lastname@example.org)
Current Opinion in Immunology 2007, 19:281–286
This review comes from a themed issue on
Edited by Ulrich von Andrian and Federica Sallusto
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Although the importance of the IL-17 cytokine family
and in particular of IL-17A and IL-17F has been known
for several years , it was only recently that it became
clear that IL-17-producing T cells constitute a separate
T-cell subset, termed Th17, distinct from Th1 and Th2
cells [2,3]. Th17 T cells had been linked with the pro-
inflammatory cytokine IL-23, because IL-23-deficient
(p19?/?) mice contain very few Th17 cells and are pro-
tected from autoimmune diseases such as experimental
autoimmune encephalomyelitis (EAE) and collagen-
induced arthritis . However, although IL-23 seems
to be involved in Th17-mediated immune pathology, it
is not required for the differentiation of Th17 from naı ¨ve
CD4 T cells. A breakthrough for the field came with the
description of transforming growth factor b (TGF-b) and
interleukin-6 (IL-6) as the factors responsible for differ-
entiation of this subset from naı ¨ve T cells [5??]. Two
further reports confirmed these findings and suggested an
intriguing link to regulatory T cells (Treg) that can be
generated in vitro by stimulation with TGF-b in the
absence of IL-6 [6??,7??]. The characterization of Th17
the crucial factors involved in its differentiation offer a
host of new insights into the differentiation and func-
tional activities of this important new T-cell subset.
In this review, we discuss the conditions that lead to
differentiation of Th17 T cells, their relationship to Treg,
Differentiation of Th17 T cells
IL-17-producing T cells entered the limelight with the
description of their involvement in autoimmune inflam-
mation . The pro-inflammatory cytokine IL-23
appeared to take a prominent role in this process, as
IL-23-deficient p19?/?mice were reported to be resistant
to induction of EAE and to lack IL-17-producing T cells.
However, IL-23 did not seem sufficient to generate Th17
from naı ¨ve T-cell precursors, and the number of IL-17-
producing T cells detected following stimulation of T
cells in vitro with IL-23 remained very low with the few
cells detected having arisen from pre-existing activated T
cells [8,9]. In fact, once the crucial factors required for the
de novo differentiation of Th17 T cells were known, it
became clear that IL-23 is entirely dispensable for this
process and that Th17 will develop unperturbed in the
presence of IL-23-blocking anti-p40 antibodies on
the condition that the essential factors IL-6 and TGF-b
are present [5??]. Th17 T cells do not express the Th1 or
Th2 lineage-defining transcription factors Tbet or
GATA3, respectively [2,3,5??], which further underlines
their separate origin. The recent identification of the
orphan nuclear receptor RORgt as the key transcription
factor that specifies the Th17 lineage [10??] was the final
step in establishing this T-cell population as a unique and
distinct CD4 T-cell subpopulation (Figure 1).
Despite the description of the differentiation pathway of
Th17 cells, there is still considerable confusion in the
literature regarding experimental protocols. One note of
caution concerns the interpretation of experimental find-
it is often stated that Th17 can be generated using either
IL-23 or TGF-b and IL-6. This is incorrect, as IL-23 will
only allow the outgrowth of already differentiated Th17
. Such cells will contaminate T-cell populations that
are not rigorously sorted on the basis of markers for naı ¨ve
T cells. Naı ¨ve T cells, by contrast, will only differentiate
to Th17 in the presence of TGF-b and IL-6. A similar
misinterpretation concernsthe secretion of IL-6 byTh17.
Current Opinion in Immunology 2007, 19:281–286
The only T-cell subset capable of producing IL-6 is Th2.
Th17 make no IL-6, but this cytokine can be mistakenly
attributed to Th17, again because of insufficient purifi-
cation. Magnetic cell sorting (MACS) purification leaves
see by fluorescence activated cell sorter (FACS) analysis,
this nevertheless represents a substantial contamination
with IL-6 because dendritic cells produce high levels of
this cytokine, and the presence of IL-17 further increases
IL-6 production .
IL-1 and TNF were ascribed supporting roles in promot-
ing Th17 differentiation, but neither of these cytokines,
alone or in combination, was sufficient for this differen-
tiation step. Because activation of dendritic cells will
elicit IL-6, IL-1 and TNF simultaneously, the presence
of dendritic cells is sufficient to guarantee optimal sup-
port for Th17 differentiation in vitro; however, optimal
Th17 differentiation in a stringently dendritic cell free
culture system (using FACS sorted cells) depends on the
addition of all three cytokines together with TGF-b [5??].
This seems in contrast with a recent report that showed
abrogation of Th17 induction and EAE in mice deficient
for IL-1 receptor . However, absence of IL-1 receptor
might affect IL-6 responses by antigen-presenting cells
 and furthermoreskewsT-cellresponses towards Th2
, both of which are expected to compromise Th17
Socs3 was found to be a negative regulator of Th17
generation affecting Stat3 phosphorylation (probably in
response to IL-6 rather than to IL-23), and Soc3-deficient
mice show enhanced Th17 generation . More
recently, IL-27, a cytokine that belongs to the IL-6
family, was shown to antagonize Th17 development in
a signal transducers and activators of transcription 1
(Stat1)-dependent manner [15?,16?].
The Treg/Th17 dichotomy
Foxp3-expressing CD25+CD4+Treg that have suppres-
sive function can be generated by culture of naı ¨ve T cells
with TGF-b [17–19], although TGF-b is not required for
intrathymic development of Treg . Differentiation of
Treg from naı ¨ve precursors is strongly inhibited by Toll-
like receptor (TLR) stimulation through IL-1 and IL-6,
and differentiation of Treg versus Th17 was found to be
Effector differentiation of CD4 T-cell subsets. Following activation, naı ¨ve CD4 T cells differentiate towards Th1 in the presence of IL-12, which
upregulates IFNg via Stat4, leading to IFNg-mediated Stat1 activation and induction of the Th1 lineage determining transcription factor Tbet.
Th2 by contrast differentiates in response to IL-4, which activates Stat6, resulting in induction of GATA3. The Th17 T-cell subset develops in
response to IL-6 and TGFb, and this differentiation step is strongly inhibited by Th1 or Th2 cytokines. Signaling via IL-6 activates Stat3 and the
lineage-determining transcription factor RORgt. Signaling through TGFb receptor is also essential for Th17 development, as T cells defective in
TGFbRII signalling cannot differentiate to Th17. Additional cytokines modify the response of the three T-cell subsets. IL-18 strongly increases
IFNg secretion by Th1, IL-33 upregulates IL-5 and IL-13 in Th2, and IL-23 induces IL-22 secretion in Th17.
Current Opinion in Immunology 2007, 19:281–286 www.sciencedirect.com
mutually exclusive [6??,7??]. Pasare and Medzhitov 
reported that the suppressive function of Treg is reversed
by TLR activation of dendritic cells, resulting in restor-
ation of proliferation in co-cultures of naı ¨ve T cells and
Treg. Upon a closer examination we found, however, that
suppression of IL-2 and interferon g (IFNg) production
remains unchanged in these cultures [5??]. Thus,
the increased proliferative response probably reflects
the differentiation of IL-17-producing T cells under
these conditions rather than alleviation of Treg suppres-
sor function. Although there are reports that TGF-b
administration or transgenic expression expands Foxp3-
expressing Treg in vivo [22,23], it is difficult to envisage
this pathway to operate with the exclusion of Th17
generation. Any T-cell activation in vivo is unlikely to
proceed in the absence of innate stimuli that would divert
Treg generation to Th17 generation. In fact, mice over-
expressing TGF-b were used by Bettelli et al. [6??] to
demonstrate increased Th17 generation and EAE path-
ology. By contrast, it cannot be ruled out that TGF-b-
driven Th17 differentiation and autoimmune pathology
might cause even more damage if there was no expansion
of Treg by TGF-b in parallel. Thus, sharing one import-
ant factor involved in either differentiation or functional
activity does not make these two T-cell subpopulations
close relatives, but it remains to be seen whether their
joint usage of TGF-b has functional significance in vivo.
The role of IL-23 in Th17 development
Although IL-23 is not involved in Th17 differentiation, it
plays an important role in maintaining Th17 effector
function. Thus, infection with the intestinal pathogen
Citrobacter rodentium induced Th17 in both wild-type and
IL-23-deficient hosts, but IL-23-deficient hosts failed to
clear the infection [7??].
IL-1 receptor antagonist deficient (IL-1Ra?/?) mice spon-
taneously develop arthritis and have high numbers of
IL-17-expressing T cells in inflamed joints ; the aug-
mented joint pathology in these mice seems to correlate
relapsing EAE , suggesting that interference with
chronic inflammation might ameliorate autoimmune
symptoms. In light of the new findings concerning Th17
differentiation, the phenotype of p19?/?mice might need
to be re-evaluated. It is unlikely that the absence of IL-23
in these mice would compromise Th17 generation, but
intriguing roles for IL-23 could be in the preservation of
effector function as well as recruitment of Th17 to sites of
inflammation. IL-17 is not the only cytokine released by
Th17 T cells, and it was recently described that IL-22,
which until recently had been considered a Th1-related
[27?]. Interestingly, the presence of IL-23 upregulates
IL-22 production and enhances the expansion of IL-22-
producing cells. This highlights the fact that IL-23 might
modulate the effector function of Th17 cells. IL-22 is
crucial in the innate skin immunity and induces the
expression of antimicrobial peptides in keratinocytes .
Th17 and autoimmunity
The crucial role of TGF-b in the formation of Th17 T
cells was highlighted by the finding that mice overex-
pressing TGF-b under control of the IL-2 promoter
generated more Th17 cells and had exacerbated EAE
pathology [6??]. However, the final proof that TGF-b-
mediated signals are obligatory for the development of
EAE was obtained using mice that had defective TGF-b
signaling (CD4dnTGFbRII) in their T cells [29?]. These
data also provide unequivocal evidence that, in the
absence of Th17, no autoimmune pathology develops
TGF-b receptor II are reported to have over-exuberant
Th1 responses caused by lack of TGF-b-mediated nega-
tive feedback mechanisms . These features of auto-
immune-like activation are exacerbated in mice that
completely lack TGF-b RII in T cells [31,32], illustrating
that Th17 T cells, which are probably absent also from
these mice, are not responsible for all autoimmune syn-
dromes. The resistance of IL-6-deficient mice to EAE
and collagen-induced arthritis has been reported earlier
[33,34] and is in line with its essential function in Th17
IL-17 after the onset of collagen-induced arthritis ame-
liorates joint damage , and more recently experimen-
tal vaccination strategies resulting in an auto-vaccine
against IL-17, were shown to protect mice against myo-
carditis, EAE and arthritis [36–38]. Thesedata emphasize
the important effector function of IL-17.
IL-27, a negative regulator of Th17 differentiation, was
found to suppress severe inflammation in the nervous
system, as mice deficient in IL-27 were hyperresponsive
to myelin oligodendrocyte glycoprotein (MOG)-induced
EAE and developed severe symptoms of neuroinflamma-
tion following infection with Toxoplasma gondii [15?,16?].
During the acute stage of EAE, about 50% of the Th17 T
cells found in the spinal cord co-express IL-17 and IFNg
T cells. This suggests that effector Th17 T cells might
respond to IL-12 at certain stages of their differentiation.
finding that IL-18Ra-deficient mice are protected from
EAE, in contrast to IL-18-deficient mice, which are
susceptible. In this case it was engagement of the
IL-18R on antigen-presenting cells by an alternative, to
genicity — a phenomenon that seemed to be linked to
the amounts of IL-23 secreted by antigen-presenting cells
. Thus, it seems that the induction of Th17 responses
can be uncoupled from autoimmune pathogenesis. As we
Th17 functional differentiation Stockinger and Veldhoen 283
Current Opinion in Immunology 2007, 19:281–286
reported recently, zymosan stimulation preferentially
drives Th17 differentiation, but although co-injection of
MOG peptide will induce EAE the disease is self-limiting
and reversal of disease parameters is correlated with
reduced IL-23 production [29?]. This suggests that down-
stream positive as well as negative regulation of proin-
flammatory cytokines determine whether an autoimmune
latory events might be particularly promising for interven-
multiple sclerosis or rheumatoid arthritis.
Th17 and host defense
Th17 T cells have become notorious for their involve-
ment in a range of autoimmune diseases, but an exclusive
role as mediators of pathology is unlikely to be their
primary function. IL-17 stimulates the mobilization
and de novo generation of neutrophils by granulocyte-
colony stimulating factor (G-CSF) , thereby bridging
innate and adaptive immunity. It has been suggested that
this might constitute an early defense mechanism against
severetraumathat would resultin tissuenecrosis orsepsis
. IL-17 is also important in the host defense against
extracellular bacteria such as Klebsiella pneumoniae  or
Bacteroides fragilis  and against fungi such as Candida
albicans . The fact that other pathogens such as
Mycobacterium tuberculosis or Borrelia burgdorferi  as
well as the fungal cell wall component zymosan [29?]
stimulate IL-17 expression suggests an important role of
IL-17-producing T cells in a wide range of infections.
There is a clear link between immune responses to
certain pathogens and the development of autoimmunity.
Infection with B. burgdorferi,for instance, results in devel-
opment of arthritis — an event that can be blocked by
inhibition of IL-17 . Similarly, arthritis is induced in
genetically susceptible mice by exposure to zymosan or
purified b-glucans . These data suggest that certain
pathogen-derived molecules have differential effects on
antigen-presenting cells, which is likely to shape T-cell
differentiation. Zymosan is an example for such modu-
lation as it has been shown that dendritic cells exposed to
zymosan secrete IL-10  and reduced levels of IL-12
p35 [29?,49] and macrophages secrete TGF-b following
stimulation with zymosan . It will be important
to study the effect of pathogens or pathogen-derived
molecules on activation and cytokine secretion by anti-
gen-presenting cells, as these events will shape the devel-
opmental program of effector T-cell differentiation.
The new CD4 T-cell subset of Th17 T cells is proving to
fill many gaps in our understanding of how immune
entiation factors has highlighted an interesting collabor-
ation of pro-inflammatory mediators such as IL-6, TNF
and IL-1 with TGF-b that has contradictory pro- or anti-
the immune response. The role of Th17 T cells in host
defense against pathogens is only beginning to emerge, as
emphasis has mainly concentrated on their destructive
potential in autoimmune diseases to date. Nevertheless,
cells and pathogen-derived molecules, not only for
initiation of Th17 T cells but also for their potentially
pathogenic role in many autoimmune diseases, warrants
further investigation and could represent a unique chance
of intervention even after onset of disease symptoms.
We would like to acknowledge our funding from the Medical Research
References and recommended reading
Papers of particular interest, published within the period of review,
have been highlighted as:
? of special interest
?? of outstanding interest
1. Kolls JK, Linden A: Interleukin-17 family members and
inflammation. Immunity 2004, 21:467-476.
2. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL,
T cells develop via a lineage distinct from the T helper type 1
and 2 lineages. Nat Immunol 2005, 6:1123-1132.
3.Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y,
Hood L, Zhu Z, Tian Q et al.: A distinct lineage of CD4 T cells
regulates tissue inflammation by producing interleukin 17.
Nat Immunol 2005, 6:1133-1141.
4.Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B,
Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ: IL-23 drives
a pathogenic T cell population that induces autoimmune
inflammation. J Exp Med 2005, 201:233-240.
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B:
TGFb in the context of an inflammatory cytokine milieu
supports de novo differentiation of IL-17-producing T cells.
Immunity 2006, 24:179-189.
This article identifies the crucial factors necessary for differentiation of
Th17 T cells from naı ¨ve CD4 T-cell precursors, and rules out IL-23 as a
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M,
Weiner HL, Kuchroo VK: Reciprocal developmental pathways
for the generation of pathogenic effector TH17 and regulatory
T cells. Nature 2006, 441:235-238.
This article shows that in vitro Treg formation in the presence of TGF-b is
subverted to Th17 generation in the presence of IL-6. Transgenic over-
expression of TGF-b increases symptoms of EAE and numbers of Th17 T
Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC,
Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT:
Transforming growth factor-beta induces development of the
T(H)17 lineage. Nature 2006, 441:231-234.
presence of IL-6. It furthermore shows that IL-23 is necessary to maintain
Th17 effector function against an intestinal bacterial pathogen.
8.Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL:
Interleukin-23 promotes a distinct CD4 T cell activation
state characterized by the production of interleukin-17.
J Biol Chem 2003, 278:1910-1914.
9.Murphy CA, Langrish CL, Chen Y, Blumenschein W,
McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ: Divergent
pro- and antiinflammatory roles for IL-23 and IL-12 in joint
autoimmune inflammation. J Exp Med 2003, 198:1951-1957.
Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A,
Lafaille JJ, Cua DJ, Littman DR: The orphan nuclear receptor
Current Opinion in Immunology 2007, 19:281–286 www.sciencedirect.com
RORgt directs the differentiation program of proinflammatory
IL-17+T helper cells. Cell 2006, 126:1121-1133.
This article identifies the key transcription factor that defines the Th17
T-cell lineage to be the orphan nuclear receptor RORg.
11. SuttonC,BreretonC,Keogh B,MillsKH,LavelleEC:Acrucialrole
for interleukin (IL)-1 in the induction of IL-17-producing T cells
that mediate autoimmune encephalomyelitis. J Exp Med 2006,
12. Labow M, Shuster D, Zetterstrom M, Nunes P, Terry R,
Cullinan EB, Bartfai T, Solorzano C, Moldawer LL, Chizzonite R
et al.: Absence of IL-1 signaling and reduced inflammatory
response in IL-1 type I receptor-deficient mice.
J Immunol 1997, 159:2452-2461.
13. Satoskar AR, Okano M, Connaughton S, Raisanen-Sokolwski A,
David JR, Labow M: Enhanced Th2-like responses in IL-1 type 1
receptor-deficient mice. Eur J Immunol 1998, 28:2066-2074.
14. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C,
Yoshimura A, Hennighausen L, O’Shea JJ: Selective regulatory
function of Socs3 in the formation of IL-17-secreting T cells.
Proc Natl Acad Sci USA 2006, 103:8137-8142.
Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de
Sauvage FJ, Ghilardi N: Interleukin 27 limits autoimmune
encephalomyelitis by suppressing the development of
interleukin 17-producing T cells. Nat Immunol 2006, 7:929-936.
These two articles [15?,16?] highlight an important negative feedback
regulation of Th17 T cells by IL-27. IL-27 inhibits in vitro differentiation of
Th17 T cells, and its absence in IL-27-deficient mice exacerbates auto-
immune pathology in the nervous system.
Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM,
Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D et al.:
Interleukin 27 negatively regulates the development of
interleukin 17-producing T helper cells during chronic
inflammation of the central nervous system. Nat Immunol 2006,
See annotation to [15?].
17. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G,
Wahl SM: Conversion of peripheral CD4+CD25Snaive T cells to
CD4+CD25+regulatory T cells by TGF-b induction of
transcription factor Foxp3. J Exp Med 2003, 198:1875-1886.
18. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR,
Neurath MF: Cutting edge: TGF-b induces a regulatory
phenotype in CD4+CD25ST cells through Foxp3 induction and
down-regulation of Smad7. J Immunol 2004, 172:5149-5153.
19. Wan YY, Flavell RA: Identifying Foxp3-expressing suppressor T
cells with a bicistronic reporter. Proc Natl Acad Sci USA 2005,
20. Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA,
Powrie F: T cells that cannot respond to TGF-b escape
control by CD4+CD25+regulatory T cells. J Exp Med 2005,
21. Pasare C, Medzhitov R: Toll pathway-dependent blockade of
CD4+CD25+T cell-mediated suppression by dendritic cells.
Science 2003, 299:1033-1036.
22. Peng Y, Laouar Y, Li MO, Green EA, Flavell RA: TGF-b regulates
in vivo expansion of Foxp3-expressing CD4+CD25+regulatory
T cells responsible for protection against diabetes.
Proc Natl Acad Sci USA 2004, 101:4572-4577.
23. Schramm C, Huber S, Protschka M, Czochra P, Burg J, Schmitt E,
Lohse AW, Galle PR, Blessing M: TGFb regulates the
CD4+CD25+T-cell pool and the expression of Foxp3 in vivo.
Int Immunol 2004, 16:1241-1249.
24. Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y: IL-17
production from activated T cells is required for the
spontaneous development of destructive arthritis in mice
deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA
25. Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT,
Min SY, Ju JH, Park KS et al.: STAT3 and NF-kB signal pathway
is required for IL-23-mediated IL-17 production in
spontaneous arthritis animal model IL-1 receptor antagonist-
deficient mice. J Immunol 2006, 176:5652-5661.
26. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS,
McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L
et al.: Anti-IL-23 therapy inhibits multiple inflammatory
pathways and ameliorates autoimmune encephalomyelitis.
J Clin Invest 2006, 116:1317-1326.
Liang SC, Tan X-Y, Luxenberg DP, Karim R, Danussi-
Joannopoulos K, Collins M, Fouser LA: Interleukin (IL)-22 and
IL-17 are coexpressed by Th17 cells and cooperatively
This article identifies IL-22 as a Th17-derived cytokine that is important in
the innate response to skin infections. IL-22 production is upregulated by
IL-23, establishing yet another function for this cytokine in the control of
Th17 effector function.
28. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R: IL-22
increases the innate immunity of tissues. Immunity 2004,
Veldhoen M, Hocking RJ, Flavell RA, Stockinger B: Signals
mediated by transforming growth factor-b initiate
autoimmune encephalomyelitis, but chronic inflammation is
needed to sustain disease. Nat Immunol 2006, 7:1151-1156.
for autoimmune pathology. Certain pathogen-derived molecules such as
zymosan can activate Th17 and initiate EAE but cannot sustain ongoing
inflammation. As a consequence, autoimmune pathology is reversed.
30. Gorelik L, Flavell RA: Abrogation of TGFb signaling in T cells
leads to spontaneous T cell differentiation and autoimmune
disease. Immunity 2000, 12:171-181.
31. Marie JC, Liggitt D, Rudensky AY: Cellular mechanisms of fatal
early-onset autoimmunity in mice with the T cell-specific
targeting of transforming growth factor-b receptor.
Immunity 2006, 25:441-454.
32. Li MO, Sanjabi S, Flavell RA: Transforming growth factor-b
controls development, homeostasis, and tolerance of T cells
by regulatory T cell-dependent and -independent
mechanisms. Immunity 2006, 25:455-471.
33. Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S,
Kopf M, Katada Y, Tanaka T, Suemura M et al.: Interleukin 6plays
a key role in the development of antigen-induced arthritis.
Proc Natl Acad Sci USA 1998, 95:8222-8226.
mice are resistant to experimental autoimmune
encephalomyelitis: roles of IL-6 in the activation and
differentiation of autoreactive T cells. J Immunol 1998,
35. Lubberts E, Koenders MI, Oppers-Walgreen B, van den
Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB:
Treatment with a neutralizing anti-murine interleukin-17
antibody after the onset of collagen-induced arthritis reduces
joint inflammation, cartilage destruction, and bone erosion.
Arthritis Rheum 2004, 50:650-659.
36. Uyttenhove C, Van Snick J: Development of an anti-IL-17A
auto-vaccine that prevents experimental auto-immune
encephalomyelitis. Eur J Immunol 2006, 36:2868-2874.
37. Sonderegger I, Rohn TA, Kurrer MO, Iezzi G, Zou Y, Kastelein RA,
Bachmann MF, Kopf M: Neutralization of IL-17 by active
vaccination inhibits IL-23-dependent autoimmune
myocarditis. Eur J Immunol 2006, 36:2849-2856.
38. Rohn TA, Jennings GT, Hernandez M, Grest P, Beck M, Zou Y,
Kopf M, Bachmann MF: Vaccination against IL-17 suppresses
autoimmune arthritis and encephalomyelitis. Eur J Immunol
39. Gutcher I, Urich E, Wolter K, Prinz M, Becher B: Interleukin
18-independent engagement of interleukin 18 receptor-a is
required for autoimmune inflammation. Nat Immunol 2006,
40. Fossiez F, Banchereau J, Murray R, Van Kooten C, Garrone P,
Lebecque S: Interleukin-17. Int Rev Immunol 1998, 16:541-551.
41. McKenzie BS, Kastelein RA, Cua DJ: Understanding the
IL-23–IL-17 immune pathway. Trends Immunol 2006, 27:17-23.
Th17 functional differentiation Stockinger and Veldhoen285
Current Opinion in Immunology 2007, 19:281–286