Spleen tyrosine kinase mediates the γδTCR signaling required for γδT cell commitment and γδT17 differentiation

The gamma delta T cells that produce IL-17 (gamma delta T17 cells) play a key role in various pathophysiologic processes in host defense and homeostasis. The development of gamma delta T cells in the thymus requires gamma delta T cell receptor (gamma delta TCR) signaling mediated by the spleen tyrosine kinase (Syk) family proteins, Syk and Zap70. Here, we show a critical role of Syk in the early phase of gamma delta T cell development using mice deficient for Syk specifically in lymphoid lineage cells (Syk-conditional knockout (cKO) mice). The development of gamma delta T cells in the Syk-cKO mice was arrested at the precursor stage where the expression of Rag genes and alpha beta T-lineage-associated genes were retained, indicating that Syk is required for gamma delta T-cell lineage commitment. Loss of Syk in gamma delta T cells weakened TCR signal-induced phosphorylation of Erk and Akt, which is mandatory for the thymic development of gamma delta T17 cells. Syk-cKO mice exhibited a loss of gamma delta T17 cells in the thymus as well as throughout the body, and thereby are protected from gamma delta T17-dependent psoriasis-like skin inflammation. Collectively, our results indicate that Syk is a key player in the lineage commitment of gamma delta T cells and the priming of gamma delta T17 cell differentiation.

Automated summary

We demonstrate that Syk plays a critical role in the early development of γδT cells, as well as in the differentiation of γδT17 cells. Loss of Syk leads to arrested development of γδT cells and a subsequent loss of γδT17 cells, resulting in protection against γδT17-dependent psoriasis-like skin inflammation in mice.