Fundamental to long lasting immunity to infections is the process of immunologic surveillance of tissue that is largely mediated by memory T lymphocytes. At basis of this process is the continuous recirculation of lymphocytes from blood to lymph which is achieved by their adhesion to, and transmigration across vascular endothelium of both lymphoid and nonlymphoid tissue. yet little is known regarding the parameters that regulate the migration of memory T cells. It is thought that the route of immunization influences development of functionally distinct subsets of memory T cells which preferentially recirculate to lymphoid tissue draining the site(s) of initial antigen exposure. Such tissue-specific migration is regulated by homing receptors and their ligand that are expressed on vascular endothelium. Identifying parameters that control memory T cell migration into tissue are critical both for understanding regulation of memory and for strategies to potentiate memory and achieve tissue-specific priming in the design of effective vaccines. In order to identify adhesion molecules that contribute to normal memory cell trafficking, the proposed study will analyze the homing of T cell populations that are exclusively comprised of memory CD4 or CD8 cells. We will investigate the roles of several adhesion molecules including selectins (L-, E-, and P-), several integrins (alpha4beta1, alpha4beta7, and LFA-1) and their counter receptors (ICAM-1, VCAM01), as well as CD44 in this process. We will use antibodies to the selectins or the respective Ig chimeras to block homing and function of memory cells in normal mice in vivo and will examine memory T cell homing and function in selectin KO mice. We will perform a similar analysis of integrin function and the adhesion molecule CD44 in memory T cell migration using antibodies to block the homing and function of memory CD4 and CD8 T cell populations, and the homing of memory B cells, both in responses to experimental antigens and in affording protection, and the homing of memory B cells, both in responses to experimental antigens and in affording protection to influenza as a disease model. Because the route of priming may play a critical role in determining migratory patterns of memory cells and the development of CD4 subsets with different cytokine secretion patterns, we will directly compare responses of CD4 cells generated by parenteral vs oral immunization and will examine selectin land integrin function in their homing. Unlike previous studies, we will not rely solely on phenotypic markers to identify memory cells or in vitro adhesion assays, but will in addition evaluate CD4 and CD8 memory in secondary antigen=-specific responses. The proposed study represents a comprehensive analysis of the biologic role of adhesion molecules in memory cell migration, which together with the studies proposed in projects 1, 2, and 4 to define parameters that regulate memory in the CD4, CD8 and B cell populations will provide valuable insights into methodology for achieving optimal memory responses.

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University of California San Diego
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