Differentiation and function of Th17 T cells
Introduction
Although the importance of the IL-17 cytokine family and in particular of IL-17A and IL-17F has been known for several years [1], 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 protected from autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis [4]. However, although IL-23 seems to be involved in Th17-mediated immune pathology, it is not required for the differentiation of Th17 from naïve CD4 T cells. A breakthrough for the field came with the description of transforming growth factor β (TGF-β) and interleukin-6 (IL-6) as the factors responsible for differentiation of this subset from naïve 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-β in the absence of IL-6 [6••, 7••]. The characterization of Th17 as a fourth major CD4 T-cell subset and the elucidation of the crucial factors involved in its differentiation offer a host of new insights into the differentiation and functional 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, and their probable physiological role in autoimmunity and host defense.
Section snippets
Differentiation of Th17 T cells
IL-17-producing T cells entered the limelight with the description of their involvement in autoimmune inflammation [4]. 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 naïve T-cell precursors, and the number of IL-17-producing T cells detected following stimulation of T cells in
The Treg/Th17 dichotomy
Foxp3-expressing CD25+CD4+ Treg that have suppressive function can be generated by culture of naïve T cells with TGF-β [17, 18, 19], although TGF-β is not required for intrathymic development of Treg [20]. Differentiation of Treg from naïve 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 mutually exclusive [6••, 7••]. Pasare and Medzhitov [21] reported that the suppressive function of Treg is
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 spontaneously develop arthritis and have high numbers of IL-17-expressing T cells in inflamed joints [24]; the augmented joint pathology
Th17 and autoimmunity
The crucial role of TGF-β in the formation of Th17 T cells was highlighted by the finding that mice overexpressing TGF-β under control of the IL-2 promoter generated more Th17 cells and had exacerbated EAE pathology [6••]. However, the final proof that TGF-β-mediated signals are obligatory for the development of EAE was obtained using mice that had defective TGF-β signaling (CD4dnTGFβRII) in their T cells [29•]. These data also provide unequivocal evidence that, in the absence of Th17, no
Th17 and host defense
Th17 T cells have become notorious for their involvement 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) [40], thereby bridging innate and adaptive immunity. It has been suggested that this might constitute an early defense mechanism against severe trauma that would result in tissue necrosis or
Conclusions
The new CD4 T-cell subset of Th17 T cells is proving to fill many gaps in our understanding of how immune responses are regulated. Identification of the crucial differentiation factors has highlighted an interesting collaboration of pro-inflammatory mediators such as IL-6, TNF and IL-1 with TGF-β that has contradictory pro- or anti-inflammatory roles depending on the location and timing of the immune response. The role of Th17 T cells in host defense against pathogens is only beginning to
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to acknowledge our funding from the Medical Research Council UK.
References (49)
- et al.
Interleukin-17 family members and inflammation
Immunity
(2004) - et al.
TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells
Immunity
(2006) - et al.
A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis
J Exp Med
(2006) - et al.
Enhanced Th2-like responses in IL-1 type 1 receptor-deficient mice
Eur J Immunol
(1998) - et al.
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) - et al.
Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis
Eur J Immunol
(2006) - et al.
Interleukin 18-independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation
Nat Immunol
(2006) - et al.
Interleukin-17
Int Rev Immunol
(1998) - et al.
Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance
J Clin Invest
(2006) - et al.
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages
Nat Immunol
(2005)
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
Nat Immunol
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
J Exp Med
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
Nature
Transforming growth factor-beta induces development of the T(H)17 lineage
Nature
Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17
J Biol Chem
Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation
J Exp Med
The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells
Cell
Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice
J Immunol
Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells
Proc Natl Acad Sci USA
Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells
Nat Immunol
Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system
Nat Immunol
Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3
J Exp Med
Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7
J Immunol
Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter
Proc Natl Acad Sci USA
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