In this proposal we will focus on two major aims concerning the biology of T lymphocyte mediated immune responses. The long term objective of the first aim is to understand the physical structure of the antigen receptor expressed on T lymphocytes (T cell receptor-TCR), particularly as it relates to the functional recognition of foreign antigens, and the functional recognition of major histocompatibility complex (MHC) molecules. Specifically, we propose to carry out a comprehensive analysis of a series of T cell clones specific for an antigen, pigeon cytochrome c, in association with an MHC molecule encoded by the E alpha k and E beta k genes. Comparisons will be made between the derived amino acid sequences involved in beta chains of the receptor heterodimer and a detailed analysis of the antigen and MHC sequences involved in forming the antigenic determinant. This information will be further analyzed by three dimensional modelling studies starting with coordinants of immunoglobulin structures previously determined. The long term goal of the second aim is to understand the processes of development and selection that are important for the maturation of class I and class II MHC-specific T lymphocytes.
The aim i s to understand the role of various structures of the immune system in selecting against self reactive T lymphocytes, and selecting for T cells that recognize self-encoded MHC molecules in association with antigen. We are approaching these questions in two complementary ways. The first approach is to analyse the receptors expressed by two different (MHC disparate) mice in response to the same antigen/MHC determinant. Experiments performed thus far indicate that MHC differences highly influence the repertoire of T cells, and further studies are focusing on mechanisms of selection that determine the particular alpha and beta chains expressed in population of antigen- responsive T cells. Since previous experiments have indicated a distinction between class I MHC-specific T cell maturation and class II MHC-specific T cell maturation, we will compare results obtained in each system. The second approach is to study T cell maturation and function under conditions in which the normal development of the immue system is perturbed, and we have proposed to accomplish this in two different ways. First, transgenic mice will be produced that possess rearranged alpha and beta chains encoding a TCR of known specificity. Experiments will be directed at determining the maturation process and fate of transgenic T cells in different anatomical locations and in mice of different MHC class I and class II backgrounds. Second, class I and class II molecules have different expression patterns, even within the epithelium of the thymus. Transgenic mice will be produced that express a class II gene under control of class I gene regulatory elements, and conversely mice will be produced that express a class I gene under control of Class II gene regulatory elements. These experiments will determine whether there are distinct mechanisms of selection for class I and class II specific T cells.
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