The interaction of the T cell receptor (TCR) with its specific ligand, the peptide-MHC complex, is only one of the events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize cell surface antigens (co-receptors) and their soluble or cell associated ligands (counter-receptors) which play critical roles in cell-cell interaction and in the interaction of T cells with their environment. Our studies have focused on two distinct areas: 1) Although the interaction of the B7 family of costimulatory molecules with CD28 on T cells has been shown to play a critical role in providing T cell costimulation for induction of maximal T cell activation, accumulating evidence has suggested the existence of non-B7 mediated costimulation. We have characterized this alternative pathway of costimulation and demonstrated that B cells which have been activated via the CD40 antigen on their cell surface express potent B7/CD28 independent costimulatory activity which was capable of augmenting the activation of CD4+ T cells from CD28 deficient mice. To further characterize the molecules which mediate this alternative costimulatory pathway, we have developed monoclonal antibodies (mAbs) which are capable of blocking its delivery and shown that the TSA-1/sca2 antigen, a member of the Ly-6 gene family, on the activated B cells plays a key role in the delivery of the alternative costimulatory signal. 2) Integrins represent a candidate group of cell surface receptors which may control the homing and population of the thymus by T cell precursors and the subsequent migration of developing thymocytes through the thymic architecture. We have shown that blockade of the interaction of the integrin, alpha4beta1, with its ligands fibronectin (FN) and VCAM-1 inhibits the development of the earliest thymic precursor into immature CD4+ CD8+ (DP) thymocytes. Furthermore, analyses of the expression of VCAM-1 in the thymus revealed its selective localization on cortical thymic epithelial cells, while fibronectin was localized primarily in the thymic medulla. Thus, the selective localization of VCAM-1 to the cortex and FN to the medulla may play an important role in regulating the participation of each ligand in thymocyte development. Lastly, the possible role of integrins in the process of positive selection in the thymus was suggested by the demonstration that engagement of alpha4beta1 on DP thymocytes significantly potentiated anti-CD3 mediated reversal of glucocorticoid induced thymocyte apoptosis.
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