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However, the way in which different TCR signal strengths and other auxiliary signals coordinate downstream of the \u03b3\u03b4 TCR to regulate \u03b3\u03b4 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 \u03b3\u03b4 T cells. While RasGRP1 was not necessary for bulk \u03b3\u03b4 T-cell generation, we found it was required for efficient generation of V\u03b34+ thymocytes and lineage-committed CD73+ \u03b3\u03b4 T cells in the thymus and periphery. Despite a decrease in immature CD73+ \u03b3\u03b4 thymocytes, there was an expansion of the perinatally derived CD8+IFN\u03b3+ \u03b3\u03b4 T-cell population in the absence of RasGRP1. IL-17\u2013producing \u03b3\u03b4 T cells were significantly reduced in RasGRP1 knockout mice, with a specific loss of V\u03b32+ \u03b3\u03b4 T cells that corresponded to a loss of c-Maf expression as early as the DN1d thymocyte stage. Critically, these cells undergoing \u03b3\u03b4T17 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 \u03b3\u03b4 T cells, which integrates signals from both non-TCR and TCR inputs to direct differentiation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf230","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T17:27:23Z","timestamp":1756747643000},"page":"3413-3424","source":"Crossref","is-referenced-by-count":1,"title":["RasGRP1 signaling is required for V\u03b32+ thymocyte c-Maf expression and \u03b3\u03b4T17 lineage programming"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2764-2028","authenticated-orcid":false,"given":"Kevin","family":"Joannou","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, 6-25 Heritage Medical Research Centre, University of Alberta , Edmonton, Alberta,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic P","family":"Golec","sequence":"additional","affiliation":[{"name":"Cell Signaling and Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abul K","family":"Azad","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, 6-25 Heritage Medical Research Centre, University of Alberta , Edmonton, Alberta,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura M","family":"Henao Caviedes","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, 6-25 Heritage Medical Research Centre, University of Alberta , Edmonton, Alberta,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia F","family":"May","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, 6-25 Heritage Medical Research Centre, University of Alberta , Edmonton, Alberta,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ress G","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, 6-25 Heritage Medical Research Centre, University of Alberta , Edmonton, Alberta,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0122-3746","authenticated-orcid":false,"given":"Troy A","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, 6-25 Heritage Medical Research Centre, University of Alberta , Edmonton, 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