Differentiation and function of Th17 T cells

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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.

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.

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