Recognition of foreign antigens by T lymphocytes depends upon the inter- membrane complexes formed by MHC molecules, processed peptide antigens, T cell receptors and either CD4 or CD8 molecules. MHC molecules thus play a critical role in most, if not all, specific immune phenomena, including protective responses against pathogens or parasites and detrimental responses against self components leading to autoimmune diseases. Tremendous polymorphism in human MHC molecules provides beneficial individuality to the immune system but also creates strong allo-antigens that provoke the T cell responses which cause rejection of transplanted tissues. The overall goals of this application are to understand in detail the physiologically important interactions that occur between human cells I MHC molecules, antigenic peptides, the CD8 glycoprotein and the T cell receptor. Of particular importance is the contribution of polymorphic variation to these processes, the nature of the target structures seen by alloreactive T cells and the role of bound peptide to their formation. Five inter-related specific aims are proposed which will exploit the complementary expense of two laboratories. Studies will focus on three class I HLA molecules--HLA-A2.1-Aw68.1 and B27.1-for which crystallographic structures are either known or in progress. Panels of alloreactive and antigen-specific CTL against these molecules will be established as will procedures for routine preparation of engineered water-soluble protein. The role of serologically defined """"""""public epitopes"""""""" in the alloreactive response is to be assessed as will the properties of an HLA-A related locus which has recently become a pseudogene. Site-directed mutagenesis will investigate the contribution of beta2-microglobulin to the adhesive interaction between CD8 and class I molecules and transfection studies are aimed on testing whether interaction of CD8 and the T cell receptor to the same class I molecule is critical for T cell activation. Finally, an investigation of the potentially unique chemistry of HLA-B27 is aimed at understanding the striking association of this molecule with ankylosing spondylitis and other arthritic diseases. The results of this investigation should contribute to fundamental understanding of the mechanism of T cell activation in the human system: the targets stimulating tissue graft rejection will be more sharply defined and the molecular basis for class I HLA associated disease better understood. This knowledge may contribute to the design of antigen- specific therapeutic intervention in transplant rejection and autoimmune diseases.
Showing the most recent 10 out of 81 publications
