RasGRP1 Signalling Programs Developing γδ-Thymocytes towards the γδT17 Lineage Through Control of c-Maf Expression

Abstract

The {gamma}{delta} TCR instructively directs both lineage specification and effector programming of developing {gamma}{delta} T cells. However, the manner in which different TCR signal strengths and other auxiliary signals coordinate downstream of the {gamma}{delta} TCR to regulate {gamma}{delta} T cell development remains unclear. In this study we characterized the role of Ras guanyl-releasing protein 1 (RasGRP1) in the development and effector programming of {gamma}{delta} T cells. While RasGRP1 was not necessary for bulk {gamma}{delta} T cell generation, we found it required for efficient generation of V{gamma}4+ thymocytes, and lineage-committed CD73+ {gamma}{delta} T cells in the thymus and periphery. Despite a decrease in immature CD73+ {gamma}{delta} thymocytes, we report an expansion of the perinatal wave of CD8+IFN{gamma}+ {gamma}{delta} T cell population in the absence of RasGRP1. IL-17 producing {gamma}{delta} T cells were significantly reduced in RasGRP1 KO mice, with a specific loss of V{gamma}2+ {gamma}{delta} T cells that corresponds to a loss of c-Maf expression as early as the DN1d thymocyte stage. Critically, these adult-programmed {gamma}{delta}T17s could express c-Maf in response to CCR9 stimulation, with RasGRP1 being required for CCR9-induced c-Maf expression. Thus, RasGRP1 activation serves as an important signalling hub in the effector programming of {gamma}{delta} T cells, which integrates signals from both non-TCR and TCR inputs to direct differentiation.