Reciprocal developmental pathways for the generation of pathogenic effector T_H17 and regulatory T cells

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T_H) cells are traditionally thought to differentiate into T_H1 and T _H2 cell subsets. T_H1 cells are necessary to clear intracellular pathogens and T_H2 cells are important for clearing extracellular organisms^1,2. Recently, a subset of interleukin (IL)-17-producing T (T_H17) cells distinct from T_H1 or T_H2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury^3,5. In contrast, CD4 ⁺CD25⁺Foxp3⁺ regulatory T (T_reg) cells inhibit autoimmunity and protect against tissue injury⁶. Transforming growth factor-β (TGF-β) is a critical differentiation factor for the generation of T_reg cells⁷. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation^8,9, completely inhibits the generation of Foxp3⁺ T_reg cells induced by TGF-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of T_H17 cells. Instead, IL-6 and TGF-β together induce the differentiation of pathogenic T_H17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T_H17) T cells that induce autoimmunity and regulatory (Foxp3⁺) T cells that inhibit autoimmune tissue injury.