Transforming growth factor-β induces development of the TH17 lineage

Abstract

A new lineage of effector CD4⁺ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (T_H17) lineage, was recently described based on developmental and functional features distinct from those of classical T_H1 and T_H2 lineages^1,2. Like T_H1 and T_H2, T_H17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens³, such as extracellular bacteria⁴. Aberrant T_H17 responses have been implicated in a growing list of autoimmune disorders^5,6,7. T_H17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rβ1, that pairs with unique, inducible components, IL-23R and IL-12Rβ2, to confer receptor responsiveness⁹. Here we identify transforming growth factor-β (TGF-β) as a cytokine critical for commitment to T_H17 development. TGF-β acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-β on naive T cells is antagonized by interferon-γ and IL-4, thus providing a mechanism for divergence of the T_H1, T_H2 and T_H17 lineages.