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

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

Automated summary

The study demonstrates that constrained Syk activity optimally engages the PI3K-Akt signaling pathway to promote the development of gamma delta(17) cells and maintain the expression of the IL-17 program. Inhibition of PI3K not only hinders the development of gamma delta(17) cells, but also increases the development of a new subset of gamma delta T cells with a type-I IFN gene expression signature.