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&ggr;&dgr;T cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development… Click to show full abstract
&ggr;&dgr;T cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17–producing &ggr;&dgr;T (&ggr;&dgr;T17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for &ggr;&dgr;TCR signal transduction and development of &ggr;&dgr;T17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of &agr;&bgr;T cells, failed to functionally substitute for Syk in the development of &ggr;&dgr;T17. Syk induced the activation of the PI3K/Akt pathway upon &ggr;&dgr;TCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of &ggr;&dgr;T17, without impaired development of IFN-&ggr;–producing &ggr;&dgr;T cells. Moreover, &ggr;&dgr;T17-dependent skin inflammation was ameliorated in mice deficient in RhoH, an adaptor known to recruit Syk. Thus, we deciphered lineage-specific TCR signaling and identified the Syk/PI3K pathway as a critical determinant of proinflammatory &ggr;&dgr;T cell differentiation.