γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

gamma delta 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 gamma delta T (gamma delta T17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for gamma delta TCR signal transduction and development of gamma delta T17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of alpha beta T cells, failed to functionally substitute for Syk in the development of gamma delta T17. Syk induced the activation of the PI3K/Akt pathway upon gamma delta TCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of gamma delta T17, without impaired development of IFN-gamma-producing gamma delta T cells. Moreover, gamma delta 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 gamma delta T cell differentiation.