MECHANISMS OF CELLULAR IMMUNE RESPONSES

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Our studies of human T cell recognition emphasize two fundamental areas: 1) identifying and characterizing the functions of cell surface molecules which facilitate T cell recognition; and 2) analysis of heterogeneity among subsets of human T cells and of the functional capacities of those subsets. Major new findings relate to T cell interaction with extracellular matrix (ECM) components. Resting T cells express on their surface three members of the VLA (beta1) integrin family and can adhere to ECM via three distinct VLA-mediated pathways: VLA-4/fibronectin, VLA-5/fibronectin, VLA-6/laminin. Binding via these pathways is regulated by two distinct and complementary mechanisms: 1) Expression of the VLA receptors is regulated with T cell differentiation; 2) the functional capacity of the receptors is rapidly regulated. Since we find that these receptors also facilitate activation of the T cells in vitro, they may be important not only in T cell adhesion/migration, but also in T cell activation. The mechanisms for regulation of adhesion are under investigation; one possibility being explored is that rapid activation-induced shedding of cell surface molecules modulates T cell adhesion. Concurrent studies have extended our understanding of the importance of pathways involving other accessory molecules in facilitating T cell activation. Systematic analyses of T cell LFA-1 interaction with biochemically purified ligand ICAM-1 emphasize the potent role of this molecular interaction as a costimulus for T cell activation. Furthermore, analysis of the costimulatory role of monocytes in T-cell receptor-mediated activation demonstrate important contributions not only of LFA-I/ICAM-1 but also CD2/LFA-3 and other molecules currently under investigation. New subsets of T cells have been defined with a mAb specific for the CD45RB antigen. This marker allows discrimination of two subsets of memory T cells, whose functional capacities are under investigation. Systematic quantitative analysis of expression of many molecules on the surface of T cells from normals and AIDS patients continue to reveal new heterogeneity of T cell subsets, whose physiological relevance is now being investigated.