Immunity 24, 677–688, June 2006 ª2006 Elsevier Inc. DOI 10.1016/j.immuni.2006.06.002
ReviewTh17: An Effector CD4 T Cell Lineage
with Regulatory T Cell Ties
Casey T. Weaver,1,2,* Laurie E. Harrington,1
Paul R. Mangan,2Maya Gavrieli,3,4
and Kenneth M. Murphy3,4
1Department of Pathology
2Department of Microbiology
University of Alabama at Birmingham
Birmingham, Alabama 35294
3Department of Pathology and Center for Immunology
4Howard Hughes Medical Institute
Washington University School of Medicine
St. Louis, Missouri 63110
The naive CD4 T cell is a multipotential precursor with
defined antigen recognition specificity but substantial
ulatory lineages, contingent upon signals from cells of
the innate immune system. The range of identified ef-
fector CD4 T cell lineages has recently expanded with
description of an IL-17-producing subset, called Th17,
which develops via cytokine signals distinct from,
and antagonized by, products of the Th1 and Th2 line-
ages. Remarkably, Th17 development depends on the
pleiotropic cytokine TGF-b, which is also linked to reg-
ulatory T cell development and function, providing
a unique mechanism for matching CD4 T cell effector
and regulatory lineage specification. Here, we review
Th17 lineage development, emphasizing similarities
and differences with established effector and regula-
esis, and host defense.
The directed development of CD4 effector T cells by
cytokines elicited from pathogen-activated cells of the
innate immune system is a hallmark of adaptive immu-
nity. Until recently, the known universe of adaptive CD4
T cell responses has been encompassed by the Th1-
Th2 paradigm (Mosmann and Coffman, 1989; Murphy
and Reiner, 2002). Development of T helper 1 (Th1) cells,
lar pathogens, is coupled to the sequential actions of in-
terferon-g (IFN-g) and interleukin-12 (IL-12) (Hsieh et al.,
1993; Scharton and Scott, 1993). The development of
asites, is coupled to IL-4 (Min et al., 2004; Shinkai et al.,
2002). The divergence of Th1 and Th2 differentiation is
largely due tocrossregulatory effects ofthese polarizing
cytokines, providing a mechanism whereby first-line in-
nate immune defenses guide appropriate effector T cell
responses that, in turn, orchestrate the host response
to efficiently clear pathogens and establish long-lived
memory for enhanced recall responses. The benefits of
adaptive CD4 T cell responses, however, come at
acost. Inappropriate orpoorly controlledeffector Tcells
can cause host pathology and are particularly deleteri-
ous when directed against self or ubiquitous environ-
mental or commensal floral antigens, which, unlike
most pathogens, cannot be effectively cleared. In this
inflammatory disorders such as autoimmunity and al-
lergy, or atopy. Effector T cell responses are therefore
normally under stringent regulatory control.
Although a key mechanism whereby dysregulated
effector responses are avoided is through intrathymic
tally or physically sequestered from developing thymo-
cytes and because the recombinatorial capacity of anti-
gen-recognition receptors in lymphocytes is so robust.
Hence, evolutionary pressure tomatch the development
regulatory T cell programs has probably been critical to
subsets of regulatory T cells, or Tregs, have been de-
scribed, albeit with incompletely defined lineage rela-
tionships and functions at present (Figure 1). At least
one class of Tregs, so-called natural Tregs (nTregs), is
the product of a developmental lineage distinct from
Th1 and Th2 lineages and therefore represents the
first well-defined expansion of the CD4 T cell functional
represents the only additional effector CD4 T cell arm to
be described since the original discovery of Th1 and
Th2 two decades ago. Th17 cells are characterized by
the production of a distinct profile of effector cytokines,
including IL-17 (or IL-17A), IL-17F, and IL-6, and have
probably evolved to enhance host clearance of a range
of pathogens distinct from those targeted by Th1 and
Th2. Th17 cells develop via a pathway separate from
Th1 and Th2, but with several notable parallels to the
Th1 lineage that have led to some confusion over the
role of the Th1 cells in autoimmunity. The development
of Th17 effectors also shares with some Tregs a require-
ment for TGF-b, establishing an important link between
Th17 and Treg development. As a basis for understand-
ing recent advances in Th17 development and function,
we first highlight features of Th1, Th2, and Treg develop-
ment and function for comparison.
Th1 and Th2 Development: Mechanisms for Lineage
Since the advent of T cell receptor (TCR) transgenic
mouse models, it has been established that naive T cells
functional effectors, e.g., Th1 and Th2, contingent upon
early signals received in concert with antigen (Hsieh
et al., 1992; Seder etal., 1992). There has been extensive
investigation of the factors and signaling pathways that
distinguish differentiation of Th1 and Th2 cells (see Mur-
phy and Reiner, 2002 for review), and although there is
now general consensus on many features that control
these developmental programs, certain details remain
contentious (Berenson et al., 2004). An important facet
with many developmental strategies, is the presence of
reiterative feedback mechanisms that propagate early
lineage decisions once initiated. Th1 differentiation is
initiated by coordinate signaling through the TCR and
STAT1-associated cytokine receptors. Both type I and
receptors (Hibbert et al., 2003; Lucas et al., 2003; Pflanz
et al., 2002), as can the IL-12 family member IL-27
(Hunter, 2005). Receptors for each of these cytokines
are expressed on naive T cell precursors and are acti-
vated by products of pathogen-stimulated cells of the
innate immune system. NK cells are a major source of
IFN-g, whereas plasmacytoid dendritic cells (DCs) are
the primary source of IFN-a. STAT1 signaling down-
to be a ‘‘master regulator’’ of Th1 differentiation (Mullen
tion factor Hlx is selectively expressed by Th1 cells by
virtue of its being a target of T-bet (Mullen et al., 2002)
(Zheng et al., 2004). T-bet potentiates expression of the
Ifng gene and upregulates the inducible chain of the
ated factors. Induction of a competent IL-12 receptor on
developing Th1 cells licenses IL-12 signaling through
STAT4, which further potentiates IFN-g production and
induces expression of IL-18Ra, thereby conferring re-
sponsiveness to IL-18 by mature Th1 cells. The IL-12-
driven component of Th1 development results in mature
dependent or -independent (IL-12 plus IL-18) pathways
(Robinson et al., 1997; Yang et al., 1999). Thus, the later
ture Th1 cells to produce IFN-g in an antigen-indepen-
dent mode, not unlike cells of the innate immune system
such as NK cells.
Although aT-bet-dependent pathway to Th1 develop-
ment has been well described, alternative pathways ap-
pear to exist. For example, the innate phase of the IFN-g
response during Listeria monocytogenes (LM) infection
is unaffected in the absence of T-bet (Way and Wilson,
2004). The adaptive immune response to LM showed
only a modest reduction in the numbers of Th1 cells or
IFN-g secretion by CD4 T cells, suggesting that alterna-
tive pathways can independently contribute to Th1 de-
velopment. Whether these include known pathways,
such as IL-12 and IL-18, or unknown pathways is un-
clear. Nevertheless, there may be greater plasticity in
Th2 differentiation is initiated by TCR signaling in con-
cert with IL-4 receptor signaling via STAT6. Signals that
emanate from the TCR and IL-4 receptors act coopera-
tively to upregulate low expression of GATA-3, a master
regulator of Th2 differentiation (Ouyang et al., 1998,
2000; Zheng and Flavell, 1997). GATA-3 autoactivates
its own expression and drives epigenetic changes in
the Th2 cytokine cluster (Il4, Il5, and Il13 genes) while
suppressing factors critical to the Th1 pathway, such
as STAT4 and the IL-12Rb2 chain. In addition, IL-4 sig-
naling prevents the colocalization of the TCR with IFN-g
receptors at the immunologic synapse of naive T cells
activated by APCs, suggesting another way in which IL-4
may inhibit Th1 development (Maldonado et al., 2004).
Thus, early IL-4 signaling rapidly initiates positive and
negative feedback loops that operate at a number of
levels to reinforce early commitment to Th2 develop-
ment while blocking Th1 development.
Figure 1. Diversification of CD4 T Cell Lineages
Although functional CD4 T cell development has been dominated by the Th1-Th2 paradigm for nearly two decades, the number of defined
lineages has now increased.The cytokines associated with arrows indicate dominant cytokines involved in specification of each of the indicated
lineages. The cytokines listed below each cell type indicate key effector or regulatory cytokines produced by differentiated cells of that lineage
or, in the case of nTreg, a contact-dependent mechanism of suppression. Tn: naive, postthymic CD4 T cell precursors; Tp: thymic precursors.
Dotted lines represent less well-defined lineage relationships.
(2004). Treatment with a neutralizing anti-murine interleukin-17 anti-
body after the onset of collagen-induced arthritis reduces joint in-
flammation, cartilage destruction, and bone erosion. Arthritis
Rheum. 50, 650–659.
Lucas, S., Ghilardi, N., Li, J., and de Sauvage, F.J. (2003). IL-27 reg-
ulates IL-12 responsiveness of naive CD4+ T cells through Stat1-
dependent and -independent mechanisms. Proc. Natl. Acad. Sci.
USA 100, 15047–15052.
Maldonado, R.A., Irvine, D.J., Schreiber, R., and Glimcher, L.H.
(2004). A role for the immunological synapse in lineage commitment
of CD4 lymphocytes. Nature 431, 527–532.
Malek, T.R., Yu, A., Vincek, V., Scibelli, P., and Kong, L. (2002). CD4
regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient
mice. Implications for the nonredundant function of IL-2. Immunity
Mangan, P.R., Harrington, L.E., O’Quinn, D.B., Helms, W.S., Bullard,
D.C., Elson, C.O., Hatton, R.D., Wahl, S.M., Schoeb, T.R., and
Weaver, C.T. (2006). Transforming growth factor-beta induces
development of the T(H)17 lineage. Nature 441, 231–234.
beta1 maintains suppressor function and Foxp3 expression in
CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067.
Matthys, P., Vermeire, K., Mitera, T., Heremans, H., Huang, S., and
Billiau, A. (1998). Anti-IL-12 antibody prevents the development
and progression of collagen-induced arthritis in IFN-gamma recep-
tor-deficient mice. Eur. J. Immunol. 28, 2143–2151.
Matthys, P., Vermeire, K., Mitera, T., Heremans, H., Huang, S.,
Schols, D., De Wolf-Peeters, C., and Billiau, A. (1999). Enhanced
autoimmune arthritis in IFN-gamma receptor-deficient mice is
conditioned by mycobacteria in Freund’s adjuvant and by increased
expansion of Mac-1+ myeloid cells. J. Immunol. 163, 3503–3510.
the IL-23-IL-17 immune pathway. Trends Immunol. 27, 17–23.
Min, B., Prout, M., Hu-Li, J., Zhu, J., Jankovic, D., Morgan, E.S., Ur-
ban, J.F., Jr., Dvorak, A.M., Finkelman, F.D., LeGros, G., and Paul,
W.E. (2004). Basophils produce IL-4 and accumulate in tissues after
infection with a Th2-inducing parasite. J. Exp. Med. 200, 507–517.
Mosmann, T.R., and Coffman, R.L. (1989). Th1 and Th2 cells: Differ-
ent patterns of lymphokine secretion leads to different functional
properties. Annu. Rev. Immunol. 7, 145–173.
Mullen, A.C., High, F.A.,Hutchins, A.S., Lee,H.W., Villarino, A.V., Liv-
ingston, D.M., Kung, A.L., Cereb, N., Yao, T.P., Yang, S.Y., and
Reiner, S.L. (2001). Role of T-bet in commitment of TH1 cells before
IL-12-dependent selection. Science 292, 1907–1910.
Mullen, A.C., Hutchins, A.S., High, F.A., Lee, H.W., Sykes, K.J., Cho-
dosh, L.A., and Reiner, S.L. (2002). Hlx is induced by and genetically
interacts with T-bet to promote heritable T(H)1 gene induction. Nat.
Immunol. 3, 652–658.
Murphy, C.A., Langrish, C.L., Chen, Y., Blumenschein, W., McClana-
han, T., Kastelein, R.A., Sedgwick, J.D., and Cua, D.J. (2003). Diver-
gent pro- and antiinflammatory roles for IL-23 and IL-12 in joint au-
toimmune inflammation. J. Exp. Med. 198, 1951–1957.
Murphy, K.M., and Reiner, S.L. (2002). The lineage decisions of
helper T cells. Nat. Rev. Immunol. 2, 933–944.
Sekikawa, K., Asano, M., and Iwakura, Y. (2002). Antigen-specific
T cell sensitization is impaired in IL-17-deficient mice, causing sup-
pression of allergic cellular and humoral responses. Immunity 17,
Nakae, S., Nambu, A., Sudo, K., and Iwakura, Y. (2003). Suppression
of immune induction of collagen-induced arthritis in IL-17-deficient
mice. J. Immunol. 171, 6173–6177.
Nakamura,K.,Kitani, A., andStrober, W.(2001). Cell contact-depen-
dent immunosuppression by CD4(+)CD25(+) regulatory T cells is
mediated by cell surface-bound transforming growth factor beta.
J. Exp. Med. 194, 629–644.
Nakamura, K., Kitani, A., Fuss, I., Pedersen, A., Harada, N., Nawata,
H., and Strober, W. (2004). TGF-beta 1 plays an important role in the
mechanism of CD4+CD25+ regulatory T cell activity in both humans
and mice. J. Immunol. 172, 834–842.
Oppmann, B., Lesley, R., Blom, B., Timans, J.C., Xu, Y., Hunte, B.,
Vega, F., Yu, N., Wang, J., Singh, K., et al. (2000). Novel p19 protein
engages IL-12p40 to form a cytokine, IL-23, with biological activities
similar as well as distinct from IL-12. Immunity 13, 715–725.
Ouyang, W., Ranganath, S.H., Weindel, K., Bhattacharya, D., Mur-
phy, T.L., Sha, W.C., and Murphy, K.M. (1998). Inhibition of Th1
development mediated by GATA-3 through an IL-4-independent
mechanism. Immunity 9, 745–755.
Ouyang, W., Lohning, M., Gao, Z., Assenmacher, M., Ranganath, S.,
Radbruch, A., and Murphy, K.M. (2000). Stat6-independent GATA-3
autoactivation directs IL-4-independent Th2 development and com-
mitment. Immunity 12, 27–37.
Park, H., Li, Z., Yang, X.O., Chang, S.H., Nurieva, R., Wang, Y.H.,
Wang, Y., Hood, L., Zhu, Z., Tian, Q., and Dong, C. (2005). A distinct
lineage of CD4 T cells regulates tissue inflammation by producing
interleukin 17. Nat. Immunol. 6, 1133–1141.
Pasare, C., and Medzhitov, R. (2003). Toll pathway-dependent
blockade of CD4+CD25+ T cell-mediated suppression by dendritic
cells. Science 299, 1033–1036.
Peng, Y., Laouar, Y., Li, M.O., Green, E.A., and Flavell, R.A. (2004).
TGF-betaregulatesin vivo expansion
CD4+CD25+ regulatory T cells responsible for protection against
diabetes. Proc. Natl. Acad. Sci. USA 101, 4572–4577.
Pflanz, S., Timans, J.C., Cheung, J., Rosales, R., Kanzler, H., Gilbert,
J., Hibbert, L., Churakova, T., Travis, M., Vaisberg, E., et al. (2002).
IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein,
induces proliferation of naive CD4(+) T cells. Immunity 16, 779–790.
Robinson, D., Shibuya, K., Mui, A., Zonin, F., Murphy, E., Sana, T.,
Hartley, S.B., Menon, S., Kastelein, R., Bazan, F., and O’Garra, A.
(1997). IGIF does not drive Th1 development but synergizes with
IL-12 for interferon-gamma production and activates IRAK and
NFkappaB. Immunity 7, 571–581.
Sakaguchi, S. (2000). Regulatory T cells: Key controllers of immuno-
logic self-tolerance. Cell 101, 455–458.
Sakaguchi, S. (2004). Naturally arising CD4+ regulatory T cells for
immunologic self-tolerance and negative control of immune
responses. Annu. Rev. Immunol. 22, 531–562.
Scharton, T.M., and Scott, P. (1993). Natural killer cells are a source
of interferon gamma that drives differentiation of CD4+ T cell sub-
sets and induces early resistance to Leishmania major in mice.
J. Exp. Med. 178, 567–577.
Schramm, C., Huber, S., Protschka, M., Czochra, P., Burg, J.,
Schmitt, E., Lohse, A.W., Galle, P.R., and Blessing, M. (2004).
TGFbeta regulates the CD4+CD25+ T-cell pool and the expression
of Foxp3 in vivo. Int. Immunol. 16, 1241–1249.
Seder, R.A., Paul, W.E., Davis, M.M., and Fazekas de St Groth, B.
(1992). The presence of interleukin 4 during in vitro priming deter-
mines the lymphokine-producing potential of CD4+ T cells from
T cell receptor transgenic mice. J. Exp. Med. 176, 1091–1098.
Segal, B.M., Dwyer, B.K., and Shevach, E.M. (1998). An interleukin
(IL)-10/IL-12 immunoregulatory circuit controls susceptibility to
autoimmune disease. J. Exp. Med. 187, 537–546.
Shinkai, K., Mohrs, M., and Locksley, R.M. (2002). Helper T cells reg-
ulate type-2 innate immunity in vivo. Nature 420, 825–829.
Spilianakis, C.G., Lalioti, M.D., Town, T., Lee, G.R., and Flavell, R.A.
(2005). Interchromosomal associations between alternatively ex-
pressed loci. Nature 435, 637–645.
Stark, M.A., Huo, Y., Burcin, T.L., Morris, M.A., Olson, T.S., and Ley,
K. (2005). Phagocytosis of apoptotic neutrophils regulates granulo-
poiesis via IL-23 and IL-17. Immunity 22, 285–294.
Stavnezer, J. (1996). Immunoglobulin class switching. Curr. Opin.
Immunol. 8, 199–205.
Szabo, S.J., Kim, S.T., Costa, G.L., Zhang, X., Fathman, C.G., and
Glimcher, L.H. (2000). A novel transcription factor, T-bet, directs
Th1 lineage commitment. Cell 100, 655–669.
Ulloa,L.,Doody, J., andMassague,J.(1999).Inhibitionof transform-
ing growth factor-beta/SMAD signalling by the interferon-gamma/
STAT pathway. Nature 397, 710–713.
Veldhoen,M.,Hocking, R.J.,Atkins,C.J.,Locksley, R.M.,andStock-
inger, B. (2006). TGFbeta in the context of an inflammatory cytokine
milieu supports de novo differentiation of IL-17-producing T cells.
Immunity 24, 179–189.
von Boehmer, H., Aifantis, I., Gounari, F., Azogui, O., Haughn, L.,
Apostolou, I., Jaeckel, E., Grassi, F., and Klein, L. (2003). Thymic
selection revisited: how essential is it? Immunol. Rev. 191, 62–78.
Wahl, S.M. (1994). Transforming growth factor beta: the good, the
bad, and the ugly. J. Exp. Med. 180, 1587–1590.
Wakkach, A., Fournier, N., Brun, V., Breittmayer, J.-P., Cottrez, F.,
and Groux, H. (2003). Characterization of denritic cells that induce
tolerance and T regulatory 1 cell differentiation in vivo. Immunity
Walker, L.S., Chodos, A., Eggena, M., Dooms, H., and Abbas, A.K.
(2003a). Antigen-dependent proliferation of CD4+ CD25+ regulatory
T cells in vivo. J. Exp. Med. 198, 249–258.
Walker, M.R., Kasprowicz, D.J., Gersuk, V.H., Benard, A., Van Land-
eghen, M., Buckner, J.H., and Ziegler, S.F. (2003b). Induction of
FoxP3 and acquisition of T regulatory activity by stimulated human
CD4+CD25- T cells. J. Clin. Invest. 112, 1437–1443.
Wan, Y.Y., and Flavell, R.A. (2005). Identifying Foxp3-expressing
suppressor T cells with a bicistronic reporter. Proc. Natl. Acad.
Sci. USA 102, 5126–5131.
Way, S.S., and Wilson, C.B. (2004). Cutting edge: immunity and IFN-
gamma production during Listeria monocytogenes infection in the
absence of T-bet. J. Immunol. 173, 5918–5922.
Willenborg, D.O., Fordham, S., Bernard, C.C., Cowden, W.B., and
Ramshaw, I.A. (1996). IFN-gamma plays a critical down-regulatory
role in the induction and effector phase of myelin oligodendrocyte
glycoprotein-induced autoimmune encephalomyelitis. J. Immunol.
Wolf, M., Schimpl, A., and Hunig, T. (2001). Control of T cell hyperac-
tivation in IL-2-deficient mice by CD4(+)CD25(-) and CD4(+)CD25(+)
T cells: evidence for two distinct regulatory mechanisms. Eur. J. Im-
munol. 31, 1637–1645.
Yamazaki, S., Iyoda, T., Tarbell, K., Olson, K., Velinzon, K., Inaba, K.,
and Steinman, R.M. (2003). Direct expansion of functional CD25+
CD4+ regulatory T cells by antigen-processing dendritic cells.
J. Exp. Med. 198, 235–247.
Yang, J., Murphy, T.L., Ouyang, W., and Murphy, K.M. (1999). Induc-
tion of interferon-gamma production in Th1 CD4+ T cells: evidence
for two distinct pathways for promoter activation. Eur. J. Immunol.
and Rostami, A. (2003). Induction of experimental autoimmune
encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12
responsiveness is not required in the pathogenesis of inflammatory
demyelination in the central nervous system. J. Immunol. 170, 2153–
Zheng, W., and Flavell, R.A. (1997). The transcription factor GATA-3
is necessary and sufficient for Th2 cytokine gene expression in CD4
T cells. Cell 89, 587–596.
IFN-gamma expression. J. Immunol. 172, 114–122.