The histone H2A deubiquitinase MYSM1 regulates CCR9 expression on CD4⁺ T cells and thymocytes

2013-11-08Directed cellular migration, also known as homing, is the hallmark of an efficient and effective immune system. Not only is cellular migration a necessary requirement to attain developmental maturity for multiple immunological lineages, it is a fundamental functional mechanism that ensures coordinated and specific immune responses. Dysregulated immunological homing can result in a myriad of consequences including autoimmune disorders or the inability to proper engage and clear pathogenic organisms. To facilitate successful migration, cells are dependent on a series of specific ligand- receptor interactions that are unique for individual anatomical compartments. ❧ Chemotactic cytokines, a particular group of soluble signaling molecules that induce a migratory response by binding to cellular G protein-coupled receptors, are indispensable in cellular migration. The chemokine CCL25 and its receptor, CCR9, are integral for the development of thymocytes as well as inflammatory cell responses in the small intestine and colon. Expression of CCR9 by thymic settling progenitor cells has been shown to be critical for transmigration through the thymic endothelium. Mice that lack CCR9 expression display defects in thymic colonization. Moreover, the ability of mature lymphocytes to migrate to the small intestine is contingent on the expression of CCR9. Recently, the novel histone H2A deubiquitinase MYSM1 has been implicated as a regulator of T cell development and function. Using a MYSM1-deficient mouse model, I report in this dissertation that MYSM1 is required for optimal expression of CCR9 on CD4⁺ T helper cells as well as developing thymocytes. ❧ Examination of CCR9 on CD4⁺ and CD8⁺ T cells in MYSM1 KO mice revealed elevated levels of expression in a number of peripheral lymphoid organs. MYSM1 KO mice exhibited increased accumulation of T lymphocytes in the gut-associated lymphoid tissues and the intestinal lamina propria. In the intestinal context, CCR9 expression is induced through uptake of the vitamin A metabolite, retinoic acid (RA). Stimulation of naïve MYSM1 KO CD4⁺ T cells with RA resulted in elevated levels of CCR9 expression compared to similarly treated WT cells. Moreover, RA-stimulated MYSM1 KO T cells displayed greater chemotactic sensitivity to CCL25 in vitro and homed more efficiently to the small intestine in vivo. I also show that MYSM1 interacts with the Ccr9 locus and implicate MYSM1 in the regulation of several CCR9-related transcription factors. ❧ Next, I investigated MYSM1’s role in CCR9 regulation during thymocyte development. CCR9 expression is necessary for optimal thymic colonization and cellular localization during thymopoiesis. Surprisingly MYSM1-deficient bone marrow-derived progenitors possess diminished levels of CCR9 expression and are inhibited from properly settling the thymus. Expression of CCR9 on MYSM1-deficient thymocytes is decreased as well, resulting in diminished chemotactic sensitivity toward CCL25. MYSM1-deficient thymocytes also exhibit significantly altered levels of proliferation and apoptosis that likely contribute to contracted thymocyte populations observed in MYSM1 KO mice. Collectively, these results suggest that MYSM1 is a novel regulator of CCR9 expression and likely plays a role in the optimal development and function of T lymphocytes