REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES

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T lymphocytes play an integral role in both cellular and humoral immune responses, carrying out direct effector functions such as cytolysis as well as mediating regulatory functions via secreted lymphokines. The particular functions of T cells are determined by differentiation events that occur independently of the acquisition of the specific receptor for antigen (TCR). The TCR accounts for the specificity of T cell responses. However, several other T cell surface molecules, defined by monoclonal antibodies (mAb), also affect the response of the T cell. These include CD4, CD8, and LFA-1 expressed by human T cells (and the corresponding structures, L3T4, Lyt-2,3, and LFA-1 on murine T cells and CD3 and CD2 (for which murine counterparts have not been identified with certainty). The responses of T cells also are influenced by interleukin 2 (IL-2) which induces T cell proliferation but which also causes cloned murine HTL to become unresponsive to antigen. The proposed studies are concerned with events associated with T cell activation, events associated with development of unresponsiveness of T cells to antigenic stimulation, and development of better approaches to regulate immune responses in vivo. Specifically, we intend to derive mAb reactive with cell surface structures that are important in T cell activation including the murine homologues of human CD3 and the CD2 molecular complex; to determine linkage of T cell surface structures with particular functions by constructing "cytolytic- helper" T cell hybrids using drug-marked cloned murine CTL and HTL as fusion partners; to determine the basis for unresponsiveness induced in cloned murine HTL by exposure to IL- 2 or by exposure to high levels of antigen; to distinguish between cellular events initiated through the TCR (leading to lymphokine production) and those initiated through the IL-2 receptor (leading to proliferation), and to compare the IL-2- dependent and IL-2-independent pathways of proliferation in CTL with the autocrine pathway found in HTL; to determine the properties of "accessory cells" that permit continued replication of cloned murine T cells; to develop additional anti-TCR mAb in order to determine the role of T cell idiotype in immune regulation; to determine the optimal method to achieve immunosuppression in vivo using mAb directed against T cell surface structures; and to determine the functional significance of mAb isotype in allograft enhancement.