Th17: the third member of the effector T cell trilogy

Abstract

T helper responses have now grown to include three T cell subsets: Th1, Th2 and Th17. Th17 cells have recently emerged as a third independent T cell subset that may play an essential role in protection against certain extracellular pathogens. However, Th17 cells with specificity for self-antigens are highly pathogenic and lead to the development of inflammation and severe autoimmunity. A combination of TGF-beta plus IL-6 and the transcription factors STAT3 and RORgammat were recently described to be essential for initial differentiation of Th17 cells and IL-23 for the later stabilization of the Th17 cell subset. Here, we introduce another player IL-21 produced by Th17 themselves, which plays an important role in the amplification of Th17 cells. Thus, Th17 cells may undergo three distinct steps of development: differentiation, amplification and stabilization in which distinct cytokines play a role.

Figure 1 legend. Model of Th17 lineage development

The differentiation of Th17 cells is initiated by the activation of naïve T cells in the presence of IL-6 plus TGF-β. This leads to the expression of ROR-γt and production of IL-17. IL-6, produced by the innate immune system, is critical during this phase but when this cytokine is not present and T-reg cells are eliminated, IL-21 produced by NK cells together with TGF-β can initiate an alternate pathway of Th17 differentiation. Upon differentiation, IL-21 is also massively induced by the developing Th17 cells and act in autocrine fashion on Th17 cells to amplify this population. Then, IL-23 stabilizes previously differentiated Th17 cells and enables further expansion of the Th17 lineage with sustained production of its hallmark cytokines.