Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease

Abstract

T helper (Th) cell have a central role in modulating immune responses. While Th1 and Th2 cells have long been known to regulate cellular and humoral immunity, Th17 cells have been identified only recently as a Th lineage that regulates inflammation via production of distinct cytokines such as interleukin (IL)-17. There is growing evidence that Th17 cells are pathological in many human diseases, leading to intense interest in defining their origins, functions and developing strategies to block their pathological effects. The cytokines that regulate Th17 differentiation have been the focus of much debate, due primarily to inconsistent findings from studies in humans. Evidence from human disease suggests that their in vivo development is driven by specialized antigen-presenting cells. Knowledge of how Th17 cells interact with other immune cells is limited, but recent data suggest that Th17 cells may not be subject to strict cellular regulation by T regulatory cells. Notably, Th17 cells and T regulatory cells appear to share common developmental pathways and both cell types retain significant plasticity. Herein, we will discuss the molecular and cellular regulation of Th17 cells with an emphasis on studies in humans.

Fig. 1

Molecular antagonism in the differentiation of human T helper type 17 (Th17) cells. Interleukin (IL)-6, IL-21 and IL-1β act via signal transducer and activator of transcription 3 (STAT3) to up-regulate retinoic-acid related orphan receptor C isoform 2 (RORC2) expression and induce Th17 differentiation. Both IL-4 and interferon (IFN)-γ suppress RORC2 by up-regulating GATA binding protein 3 (GATA-3) and transcription factor T-bet (T-bet), respectively, thereby inhibiting Th17 differentiation. Ectopic expression of RORC2 or ROR-α induces expression of IL-17. In addition, over-expression of RORC2 induces expression of IL-26, IL-22, CCR6, CCR4, IL-23R and CD161. The development of regulatory T cells (T_regs) and Th17 cells is linked because expression of forkhead box P3 (FoxP3) suppresses T-bet, RORα and RORC2, thereby inhibiting Th1 and Th17 differentiation. Although transforming growth factor (TGF)-β can regulate expression of RORC2, because TGF-β also decreases IL-17 expression via induction of FoxP3, its role in the development of human Th17 cells remains to be clarified.

Fig. 2

Modulation of Th17 cells by other immune cells. Antigen-presenting cells (APCs) and other T helper (Th) subsets regulate the differentiation and function of Th17 cells via production of cytokines. While regulatory T cells (T_regs) cells are known to inhibit Th1 cells differentiation and function, their role in regulating Th17 cells is poorly understood, particularly in humans.

Fig. 3

Putative pathways of CD4⁺ T cells plasticity. T helper type 1 (Th1), Th17 and regulatory T cells (T_regs) cells have unique cytokine, chemokine receptor and transcription factor expression profiles. Th1/Th17 and T_reg/Th17 cell intermediates display intermediate phenotypes and may represent distinct lineages with specialized functions or may be in the process of converting from one cell type to another.