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T cell lymphopenia is a condition which arises from defects in T cell development and/or peripheral homeostatic mechanisms. Importantly, lymphopenia is often associated with T cell-mediated pathology in animal models and in patients with autoimmune disease. In this thesis, using an ENU mutagenesis approach, we identified sphinx mice which presented severe lymphopenia due to a missense mutation in Gimap5. Characterization of Gimap5 sph/sph mice revealed that Gimap5 is necessary for the development of NK and CD8+ T cells, and is required for the maintenance of peripheral CD4+ T and B cell populations. Moreover, Gimap5-deficient mice developed spontaneous colitis which resulted in early mortality. Gimap5 sph/sph CD4+ T cells presented progressive lymphopenia-induced proliferation (LIP), became Th1/Th17 polarized, and mediated the development of colitis. Furthermore, Gimap5 sph/sph FoxP3+ regulatory T cells became selectively reduced in the mesenteric lymph nodes and adoptive transfer of wild type regulatory T cells prevented colitis in Gimap5-deficient mice. Importantly, the expression of Foxo transcription factors, which play a critical role in T quiescence and Treg function, was progressively lost in the absence of Gimap5 suggesting a link between Gimap5 deficiency and loss of immunological tolerance. Using OT-II RAG-/-TCR transgenic model, we showed that treatment with cognate antigen under tolerizing conditions failed to induce a Treg population and resulted in the acquisition of LIP phenotype by Gimap5-deficient CD4+ T cells. Given that Gimap5 is expressed in lysosomes, we investigated whether Gimap5 is …