A cardinal feature of the adaptive immune response is its ability to generate long-lived populations of memory T lymphocytes. Memory T cells that recognize donor allo-antigens jeopardize the survival of life- saving organ transplants. Therefore, exploring the biology of memory T cells is essential for developing better anti-rejection therapies. In the previous funding cycle (2001 - 2006), we investigated the mechanisms that govern the maintenance and recall of memory T cells in mouse models of heart, skin, and islet transplantation. A principal finding was that memory T cells generated in response to allo-stimulation migrate widely to non-lymphoid tissues where they are maintained long-term and are activated upon encountering donor antigens. Unlike naive T cells, whose migration and activation were largely restricted to secondary lymphoid tissues, allo-reactive memory T cells homed directly to the graft and mediated its rejection. Therefore, the goal of this application is to investigate the mechanisms that govern the migration of memory T cells to a transplanted organ.
The specific aims are: (1) To investigate the mechanisms which govern the migration of allo-reactive memory T cells to vascularized cardiac allografts during acute inflammation - we will examine the roles of the chemokine receptor CXCR3 and the adhesion molecule a4|31 integrin (VLA-4) expressed on memory T cells. (2) To investigate the mechanisms which govern the migration of allo-reactive memory T cells to vascularized cardiac allografts during chronic inflammation - we will examine the roles of the chemokine receptor CCR7 and the adhesion molecule L-selectin (CD62L) expressed on memory T cells. Although both CD4 and CD8 memory T cells mediate allograft rejection, we will concentrate on studying the CD8 memory population. Congenic markers will be used to track adoptively transferred CD8 memory T cells. Gene knockout mice and monoclonal antibodies will be used to examine the roles of chemokine receptors and adhesion molecules.
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