The principal aim of this Program Project Grant is to define the cellular and molecular interactions involved in the development and function of T lymphocytes. Since T cells play a crucial role in directing the immune response to malignancies, it is of fundamental importance to achieve a clear understanding of T cell immunobiology. Each of the three individual projects on the grant is concerned with the life history of T cells, beginning with the initial formation of T cells in the thymus. With the aid of intact mice, thymic organ cultures and an in vitro system involving the use of dispersed populations of thymic stromal cells, concerted efforts will be made to achieve an understanding of how positive and negative selection in the thymus generates a T cell repertoire which is self tolerant to major histocompatibility complex (MHC) molecules yet is poised to respond to foreign antigens complexed to these """"""""self"""""""" MHC molecules. Various aspects of thymic selection will be studied, including the particular self ligands (self peptide/MHC complexes) controlling selection, the T cell molecules used in selection (e.g. TCR, CD4, CD8 and possibly CD40L), the changes produced in cell- surface phenotype and cellular proliferation. These studies will involve the use of both normal mice and various types of transgenic mice, including TCR, MHC and CD8 transgenic mice. In addition to T cell differentiation in the thymus, information will be sought on the functions and properties of extrathymic T cells. Topics to be addressed here will include the turnover and surface markers of T cell subsets, the role of CD8 molecules in determining the avidity of T cell interaction with other cells, the role of certain T accessory molecules, notably CD40L, in controlling T cell response to superantigens vs conventional antigens, and the generation of cytotoxic T cells specific for a potential tumor-specific antigen (human p53 antigen). Addressing each of these various topics will depend on close collaborative interactions among the three principal investigators.
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