DEVELOPMENT AND FUNCTION OF INTESTINAL T-CELLS

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The gastrointestinal tract serves as a portal of entry for many bacterial, parasitic, fungal, and viral pathogens, and is a significant site of infection in healthy and immunocompromised hosts. An elaborate specific immune system consisting of both humoral and cellular components is used by the host to maintain the integrity of the small intestine against microbial invasion. The humoral arm of the specific mucosal immune response is dominated by secretion of IgA antibodies, but much of the functional potential of the cellular arm of specific mucosal immunity is poorly understood. We will use experimental reovirus infection in mice to dissect the function of intestinal T cells during a mucosal immune response. This proposal describes a plan to accomplish 3 specific aims that are developed from observations made and reported in the previous funding period. The central hypothesis of this proposal is that enteric infection elicits distinct populations of intestinal T-cells that regulate the development of local and systemic immune responses. In aim 1, we will test the hypothesis that the route of infection affects the development of T-helper cell responses by examining IgG subclass and cytokine responses in mice orally or systemically infected with reovirus, and compare these responses to mice infected with enteric bacteria and non-enteric virus. In aim 2, we will test the hypothesis that CD8+ T cells regulate the mucosal immune response to reovirus infection. We will continue to characterize immune responses to enteric virus infection in CD8-deficient mice, and examine the ability of adoptively transferred CD8+ T-cells to regulate mucosal immune responses in CD8-deficient mice. In aim 3, we will test the hypothesis that the route of infection affects the repertoire of T cell receptors (TCR) expressed on cytotoxic T lymphocytes (CTL). We will by analyze TCR expression on CTL that are generated following oral or systemic infection using Vbeta and CDR3 analysis. This work will contribute to understanding mucosal immunity in pathogenesis, particularly with regards to T cell function in the gut. Understanding the development and function of intestinal T-cells and cellular immunity in the gut will provide information that can be used for the rational design of oral vaccines that can target appropriate responses by immunologic effectors in the intestine, particularly against intracellular pathogens.