Reciprocal developmental pathways for the generation of pathogenic effector TH17 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(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms(1,2). Recently, a subset of interleukin ( IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 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 injury(6). Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T-reg cells(7). 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-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3(+)) T cells that inhibit autoimmune tissue injury.