RasGRP1 signaling is required for Vγ2+ thymocyte c-Maf expression and γδT17 lineage programming

The γδ TCR instructively directs both lineage specification and effector programming of developing γδ T cells. However, the way in which different TCR signal strengths and other auxiliary signals coordinate downstream of the γδ TCR to regulate γδ T-cell development remains unclear. In this study we defined the role of Ras guanyl-releasing protein 1 (RasGRP1) in the development and effector programming of γδ T cells. While RasGRP1 was not necessary for bulk γδ T-cell generation, we found it was required for efficient generation of Vγ4+ thymocytes and lineage-committed CD73+ γδ T cells in the thymus and periphery. Despite a decrease in immature CD73+ γδ thymocytes, there was an expansion of the perinatally derived CD8+IFNγ+ γδ T-cell population in the absence of RasGRP1. IL-17-producing γδ T cells were significantly reduced in RasGRP1 knockout mice, with a specific loss of Vγ2+ γδ T cells that corresponded to a loss of c-Maf expression as early as the DN1d thymocyte stage. Critically, these cells undergoing γδT17 programming in adults could express c-Maf in response to CCR9 stimulation, with RasGRP1 but not MEK activity being required for CCR9-induced c-Maf expression. Thus, RasGRP1 activation serves as an important signaling hub in the effector programming of γδ T cells, which integrates signals from both non-TCR and TCR inputs to direct differentiation.