Role of RasGRP1 in T cell development and function

The unique feature of the thymus is to establish the discrimination between self and non-self and providing immunity to foreign peptides, particularly those derived from pathogens, that are presented by self-major histocompatibility complex (MHC) molecules. The development and activation of T lymphocytes require many critical decisions that profoundly affect their differentiation and ability to mount an effective immune response. A central mediator of this developmental program is the small GTPase Ras, emitting cytoplasmic signals through downstream MAPK pathways and eventually affecting gene expression. TCR signal transduction orchestrates the activation of Ras by integrating at least two Ras-guanyl nucleotide exchange factors, RasGRP1 and Sos. RasGRP1 is especially critical for the survival and differentiation of developing thymocytes whereas negative selection of thymocytes bearing an autoreactive TCR appears to be RasGRP1 independent. In this thesis, by using RasGRP1 null mutant mice, we characterized the role of RasGRP1 in conventional and regulatory T cell (Treg) development, as well as the consequential effects that result from its deficiency in peripheral tolerance, T cell activation, proliferation and immune response against infections. Investigations on RasGRP1-/- mice expressing a transgenic (Tg) MHC class Il-restricted TCR revealed that RasGRP1 transmits differentiation signaling critically required for conventional CD4 T cell development. As a result of the impaired developmental program, RasGRP1-/- mice spontaneously acquire an acutely activated and proliferating CD4 T cell population that exhibits characteristics of T cell exhaustion. Interestingly, studies using MHC class I-restricted TCR Tg mice lacking RasGRP1 suggest that RasGRP1 is essential for lowering activation threshold and achieving optimal cytokine receptor expression on conventional CD8 T cells upon activation. We also investigated the consequence of RasGRP1 deficiency on the development and function of regulatory T cells. We found that RasGRP1 differentially affected the development and function of CD4 and CD8 regulatory T cells. Overall, our studies provide novel insights to the significance of RasGRP1 signaling pathway in T cell development and function, along with how its deficiency affects the development and function of regulatory T cells.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat