Th17 cells: from precursors to players in inflammation and infection

Abstract

Upon activation, naive CD4(+) T cells differentiate into different lineages of effector T(h) subsets. Each subset is characterized by its unique cytokine profile and biological functions. T(h)17, a newly described T(h) subset that produces IL-17, IL-17F and IL-22 in preference to other cytokines, has been shown to play an important role in clearing specific pathogens and in inducing autoimmune tissue inflammations. Over the last 2-3 years, significant progress has been made to understand the development and biological functions of T(h)17 subset. Transforming growth factor beta (TGF) together with IL-6 or IL-21 initiates the differentiation while IL-23 stabilizes the generation of T(h)17 cells. The transcription factors of T(h)17 cells [retinoid-related orphan receptor (ROR) gammat, ROR-alpha and signal transducer and activator of transcription-3] have been described recently. Since TGF-beta is essential for the generation of both T(h)17 and regulatory T (T(reg)) cells from naive T cells, which suggests a developmental link between T(h)17 and T(reg) cells. Functions of these two subsets of T cells are, however, opposite to each other; T(h)17 cells are highly pathogenic during the inflammatory process while T(reg) cells are crucial for inhibiting tissue inflammation and maintaining self-tolerance. Here, we review the recent information on differentiation and effector functions of T(h)17 cells during inflammatory conditions.

Fig. 1.

T_h subsets. Antigen and specific cytokine signals induce the differentiation of naive T cells into various subsets of T_h (T_h1, T_h2 and T_h17). While these subsets produce specific patterns of cytokines that induce immunity, T_reg cells, naturally occurring Foxp3⁺T_reg cells and induced Foxp3⁺ T_reg cells secrete anti-inflammatory mediators such as IL-10 and TGF-β that maintain immune tolerance and immune homeostasis.

Fig. 2.

Reciprocal generation of T_reg and T_h17 cells. Activation of naive T cells in the presence of IL-23 did not induce the generation of T_reg or T_h17 cells. Supplementation of TGF-β in the culture induced the generation of Foxp3⁺ T_reg cells while the addition of IL-6 not only inhibited the induction of TGF-β-induced Foxp3 but also concomitantly induced the generation of T_h17 cells.

Fig. 3.

Steps in the generation of T_h17 cells. The activation of naive T cells in the presence of TGF-β and IL-6 initiates the T_h17 differentiation pathway. T_h17 cells produce IL-21, which further amplifies T_h17 generation in an autocrine manner. IL-21 also induces the IL-23R on differentiated T_h17 cells to make them responsive to IL-23 signaling. IL-23 stabilizes the T_h17 phenotype by secreting IL-17A, IL-17F and IL-22 and helping T_h17 cells to acquire effector functions. STAT-3 plays an important role in T_h17 differentiation, amplification and stabilization as IL-6, IL-21 and IL-23 signals through STAT-3.