The specific pattern of lymphocyte migration and localization is important for the induction and expression of normal immune responses. The ability of circulating cells to home to lymph nodes (LN) is regulated by the expression of a surface receptor that mediates lymphocyte recognition of specialized high endothelial venules (HEV) within LN. Preliminary results have shown that, after in vitro activation by specific antigen, murine T lymphocytes cease expression of this homing receptor, as demonstrated by the lack of binding of a monoclonal antibody (MEL-14) specific for this protein. These cells also undergo changes in surface glycosylation which results in strong staining by the lectin PNA. T cell clones share this MEL-14- PNA++ phenotype, and also do not home to peripheral lymphoid tissue. The objective of this research plan is to test the hypothesis that activation of T lymphocytes by specific antigen results in a striking alteration in the ways in which these cells migrate and localize within host tissues. This proposes a pathway of T cell differentiation that is defined by changes in cell migration and localization rather than by changes in functional activity. MEL-14, PNA and T cell markers will be used for flow cytometric analysis of activated lymphocytes to determine which cells undergo changes in migratory phenotype following activation in vitro. The role of organ-specific lymphocyte homing receptors in regulating the localization and in vivo activity of cloned antigen-specific T cells will also be examined. It will then be determined whether T lymphocytes activated in vivo by a skin allograft, soluble antigen injection, and contact sensitization also pass through a MEL-14- PNA++ stage, and whether these changes are a function of the type of antigenic stimulus. In addition, the reversibility of these changes in migratory behavior will be studied in order to determine whether these activated cells subsequently return to the pool of recirculating small, lymphocytes. These experiments may define a novel aspect of antigen-driven T cell differentiation in which cells activated in situ undergo changes in surface protein expression, become nonrecirculating, and remain localized at the site of activation. By understanding what controls T cell localization, both within lymphoid tissues and in the periphery, one may be able to influence the migration of effector cells to, for example, a renal allograft, and to design practical strategies for using T cells clones in the therapy of human disease.
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