The Colitogenic Capacity of Gut Homing Recent Thymic Emigrants

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DESCRIPTION (provided by applicant): The youngest peripheral T cells are called recent thymic emigrants or RTEs, lymphocytes that constitute the entire T cell pool in neonates and are crucial in adults for maintaining T cell diversity and reconstituting the na¿ve T cell pool following lymphoablative viral infection or therapy. Using a mouse model system in which RTEs can be distinguished from the bulk of peripheral T cells, we have shown that stimulated RTEs exhibit diminished proliferation, decreased cytokine production, and altered surface phenotype compared to similarly treated mature T cells. This distinct functional profile lasts well after RTEs have entered the mature peripheral T cell pool. We suspect that this 2-3 week transitional period of T cell development allows young T cells to scan the lymphoid periphery for self-antigens that are not expressed in the thymus and to become tolerized to them. Preliminary data indicate that RTEs express high levels of gut homing receptors and may first traffic to the gut after leaving the thymus. We hypothesize that RTEs efficiently enter the gut lymphoid tissue and are retained there by interaction with gut-derived antigens to which they become tolerized, thereby diminishing RTE colitogenic potential. Proposed experiments encompass the following specific aims: Specific Aim 1: To determine whether RTEs preferentially home to the gut. These experiments will compare the expression of functional gut homing receptors on RTEs and mature na¿ve peripheral T cells and the distribution of these cells in the gut-associated lymphoid tissue. Specific Aim 2: To assess whether RTE gut homing is dependent on gut antigens. These experiments will determine whether RTE localization to and retention in the gut-associated lymphoid tissue is disturbed in antibiotic treated mice or in mice expressing in gut epithelial cells or commensal bacteria an antigen specifically recognized by T cells. Specific Aim 3: To investigate whether gut homing RTEs become tolerized to gut antigens. These experiments will compare the colitogenic potential of RTEs and mature T cells and determine whether blockade of RTE gut homing or elimination of the gut microbiota are associated with greater RTE colitogenic potential. Further experiments will compare the ability of RTEs and mature T cells to induce colitis when encountering specific antigen in the gut epithelial cells or lumen. PUBLIC HEALTH RELEVANCE: The steady export of newly generated T cells (or recent thymic emigrants) is required to maintain the diversity of the T cell compartment throughout life. Recent thymic emigrants in both mice and humans have dampened immune function, a property we hypothesize makes them sensitive to tolerance induction. We will test this hypothesis in a mouse model of colitis, a chronic inflammatory disease triggered in part by T cell recognition of gut antigens. Understanding the immune dysregulation that drives colitis has the ultimate objective of augmenting the spectrum of agents available to treat this disease.