TRANSMEMBRANE SIGNALING BY CD4 IN T-HELPER CELLS

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Interaction of CD4+ T helper lymphocytes (Th) with specific antigen- presenting cells (APC) results in secretion of cytokines and proliferation. In addition to their autocrine effects, many cytokines also effect the growth and maturation of antibody-producing B lymphocytes and cytotoxic T lymphocytes. Th cells, thus, play a central regulatory role in the hosts immune response to antigen. The antigen-specific T cell receptor (TCR) dictates recognition of antigenic peptides, but non- specific accessory proteins also facilitate binding to the APC. The CD4 molecule participates in Th-APC adhesion by its interaction with monomorphic determinants on class II proteins borne by the APC. Recent work has shown that several T cell accessory proteins are normally in a relatively "inactive" state, but become activated to bind their ligands via TCR engagement. Preliminary results suggest that this is also the case for CD4-class II binding. One aim of this proposal is to employ purified class II proteins to further elucidate the events controlling TCR-activated binding between CD4 class II proteins. Several transmembrane signalling events are initiated upon Th cell activation by specific APC; these include activation of tyrosine kinases and the phosphatidylinositol pathway, which results in increased concentrations of intracellular free Ca2+ and activated protein kinase C. The CD4 molecule plays a direct part in Th cell transmembrane signalling, as evidenced by its intracellular association with the tyrosine kinase p56lck. Experiments will, therefore, be performed to identify those signalling events which are specifically involved in the activation of CD4 to bind class II protein, and those resulting from binding, which may contribute to the functional response. The final aim proposes experiments to determine the qualitative and quantitative effect of additional accessory interactions, such as those mediated by LFA1 and the VLA receptors, to TCR- and CD4-dependent binding and signalling events. The proposed experiments should, therefore, contribute to our understanding of the molecular mechanisms by which T lymphocytes recognize and initiate a functional response to antigen borne by APC.