The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation

Abstract

T helper 17 (T(h)17) cells represent a new subset of CD4+ effector T cells which have been described in both mice and humans. However, some differences seem to exist between murine and human T(h)17 cells with regard to their features, origin and role in immunopathology. Murine T(h)17 cells share their developmental origin with Foxp3+ Treg cells, indeed naive T-cell precursors can be differentiated to regulatory T (Treg) cells by transforming growth factor-beta (TGF-beta) alone, whereas the contemporaneous presence of TGF-beta and IL-6 gives origin to T(h)17 cells. Human T(h)17 cells which consistently express the CC chemokine receptor 6 and the equivalent of the murine NK1.1, CD161, appear to exclusively originate in response to IL-1beta and IL-23 from a small subset of CD161+CD4+ T-cell precursors detectable in the thymus and in umbilical cord blood. These cells constitutively express the T(h)17-driving transcription factor retinoic acid-related orphan receptor (ROR)gamma t and the IL-23R and can also give origin to T(h)1 cells or T(h)2 cells under the appropriate polarizing conditions. By contrast, human CD161-naive T cells only give rise to T(h)1 and T(h)2 cells, but not T(h)17 cells. TGF-beta may not exert a direct critical role in human T(h)17 cell differentiation, but indirectly favours their development by inhibiting the development of T(h)1 cells, which are much more susceptible than T(h)17 cells to its suppressive activity on cell proliferation. Moreover, while murine T(h)17 are pathogenic in some murine models of autoimmunity where T(h)1 cells seem to play a protective role, both T(h)17 and T(h)1 certainly contribute to the pathogenesis of human autoimmune and other chronic inflammatory disorders.