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 , 4 , 5 . In contrast, CD4 + CD25 + Foxp3 + regulatory T (T reg ) cells inhibit autoimmunity and protect against tissue injury 6 . Transforming growth factor-β (TGF-β) 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-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of T H 17 cells. Instead, IL-6 and TGF-β 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.