Th17 cells: effector T cells with inflammatory properties

Abstract

Upon activation, naïve CD4(+) T cells differentiate into effector T cells with specific effector functions and cytokine profiles. The Th1/Th2 paradigm has recently been reevaluated to include a third population of T helper cells, producing IL-17 and designated Th17. The differentiation of Th17 cells requires the coordinate and specific action of the proinflammatory cytokine IL-6 and the immunosuppressive cytokine TGF-beta. In addition, the IL-12 family member IL-23 is involved in the maintenance of these cells. Analogous to other T helper cell subsets, Th17 commitment is initiated by sequential involvement of STAT molecules, i.e. STAT3 downstream of cytokine receptors, and specific transcription factors, i.e. ROR-gammat. Recent data also support the existence of a complex network of cytokines regulating Th17 cells. Clearly, the specific effector functions of Th17 cells expand beyond previously described effects of Th1 and Th2 immunity, with specific roles in host defense against certain pathogens and in organ-specific autoimmunity. The potential dynamics of Th17 cell populations and their interplay with other inflammatory cells in the induction of tissue inflammation in host defense and organ-specific autoimmunity are discussed.

Figure 1. Differentiation and effector cytokines of T helper cell subsets

Th1, Th17, and Th2 cells constitute different T helper cell subsets with different cytokine signatures. The induction of the various T helper cell subsets requires different cytokine stimuli to induce distinct transcriptional programs. Other cytokines are necessary to stabilize the transcriptional phenotype (For details see text). Cross-inhibition of Th17 cell development by Th1 and Th2 associated cytokines has been shown in vitro and in vivo.

Figure 2. Development of tissue inflammation driven by Th17 cells

Antigen specific T cells are primed in secondary lymphoid tissue and driven into the Th17 developmental pathway in the presence of IL-6 and TGF-β. Sources of TGF-β are other T cells like Foxp3-expressing regulatory T cells (Treg) or Th3 cells. Similarly, antigen specific T cells are committed to the Th1 subset in the presence of IFN-γ and IL-12. Activated Th17 cells are among the first to infiltrate the target organ. By induction of chemokines, secondary waves of inflammatory cells like mononuclear cells and Th1 cells are attracted into the inflamed tissue. Both IL-17 produced by Th17 cells and IFN-γ produced by Th1 cells may act on myeloid cells to induce their effector functions that eventually lead to tissue damage. Whereas Th17 cells are prone to apoptosis, Th1 cells might finally be suppressed by T-reg cells that accumulate in the target organ and thus induce the resolution of inflammation.