The long term objective of this proposal is to understand the physiological role of accessory molecules in modulating T cell responses. This proposal focusses on the T cell ligand for the CD40 molecule expressed on the surface of B cells. Interactions between these molecules have been shown to have important effects on B cells, including augmentation of proliferation, survival and differentiation. The consequences of these interactions for T cell responses is less clear. Preliminary data suggest that CD40L expression is an obligatory requirement for T hybridoma response to endogenous superantigens. Using chimeric fusion proteins of CD40 and CD40L, as well as monoclonal antibodies generated to these molecules, we propose to study the regulation of the expression of CD40L on T cells and to define the types of T cell responses which are influenced by this ligand pair. A second major goal of this proposal is to define the mechanism(s) by which interactions between CD40L and CD40 affect T cell responses. Experiments propose to test three general hypotheses, including a) an effect on B cell antigen presentation, b) a costimulatory effect on T cells ad c) a role in the presentation or processing of endogenous superantigens. Finally, information will be sought on the possible role of CD40L in thymic selectin with particular attention focussed on an analysis of the expression of CD40 and CD40L in the thymus and on negative selection of thymocytes reactive to endogenous superantigens. It has become increasingly clear during the past years that accessory molecules play key roles in regulating, modifying and augmenting T cell responses. Defining the molecules and the interactions involved in regulating the mature T cell responses as well as the selection of the repertoire is very likely to lead to new treatments of human disease based on a manipulation of these molecules.
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