Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

T cells, an important component of the adaptive immune system, are derived from stem cells that undergo differentiation in an organ called the thymus. T cells can be broadly separated into two distinct lineages, αβ T cells and γδ T cells, based upon the class of T cell receptor (TCR) they express. These lineages arise from a bi-potent progenitor. While much is known regarding the signaling pathways required for development of αβ T cells, the role of these same signaling pathways in γδ T cell development is unclear. Furthermore, unlike most αβ T cells, γδ T cells possess the ability to rapidly produce cytokines. Signaling through the Ras pathway has been demonstrated to regulate the development of γδ-thymocytes. However, it is unclear which family of Ras activators, the Ras guanyl nucleotide releasing protein (RasGRP) or the Son of Sevenless (Sos) family is required for Ras activation in the context of gd-thymocyte development. Published data from us and others and our preliminary data suggest that RasGRP1 deficiency plays a critical role in γδ thymocyte development. We propose to test the hypothesis that RasGRP1 is a critical regulator of γδ thymocyte development and functional lineage specification. Furthermore, we will determine the mechanism underlying RasGRP1 regulation of gd-T cell development. This information will prove critical to further our long-term goal of understanding the molecular regulation of cell fate decisions.