Constrained TCRγδ-associated Syk activity engages PI3K to facilitate thymic development of IL-17A–secreting γδ T cells

Abstract

Murine γδ¹⁷ cells, which are T cells that bear the γδ T cell receptor (TCRγδ) and secrete interleukin-17A (IL-17A), are generated in the thymus and are critical for various immune responses. Although strong TCRγδ signals are required for the development of interferon-γ (IFN-γ)-secreting γδ cells (γδ^IFN cells), the generation of γδ¹⁷ cells requires weaker TCRγδ signaling. Here, we demonstrated that constrained activation of the kinase Syk downstream of TCRγδ was required for the thymic development of γδ¹⁷ cells. Increasing or decreasing Syk activity by stimulating TCRγδ or inhibiting Syk, respectively, substantially reduced γδ¹⁷ cell numbers. This delimited Syk activity optimally engaged the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, which maintained the expression of master regulators of the IL-17 program, RORγt and c-Maf. Inhibition of PI3K not only abrogated γδ¹⁷ cell development but also augmented the development of a distinct, previously undescribed subset of γδ T cells. These CD8⁺Ly6a⁺ γδ T cells had a type-I IFN gene expression signature and expanded in response to stimulation with IFN-β. Collectively, these studies elucidate how weaker TCRγδ signaling engages distinct signaling pathways to specify the γδ¹⁷ cell fate and identifies a role for type-I IFNs in γδ T cell development.