The unique feature of antigen presenting MHC molecules is their genetic polymorphism. Unlike other eukaryotic genes, MHC genes have no """"""""wild-type"""""""", but an even distribution of many alleles.The variation functions to diversify T cell responses between individuals, increasing the probability that populations survive the unpredictable predation of pathogens. MHC polymorphism is highly developed in humans, especially for class I (HLA-A,B,C) which presents viral, tumor and self antigens to CD8+ cytotoxic T cells. Thus resistances and susceptibilities to infectious diseases, cancers and autoimmune diseases are conferred by particular class I alleles. HLA-A,B,C diffferences can be instrumental in rejection of transplanted tissues, particularly bone marrow. Previous research has focussed on the HLA-A and B genes of caucasian populations and has been guided by the picture painted by the serological assay used in transplantation matching. Exploratory studies show this picture is biased and requires major overhaul, for class I polymorphism in other ethnic groups is different. The differences appear focussed on HLA-B and further studies to describe the polymorphism of this locus and its plasticity are proposed in Aim 1. The function of HLA-C is poorly understood, in part because of its low expression at the cell surface. This appears due to poor assembly and binding of peptides, properties which may be advantageous in responding to viral infections.
In Aim 2, HLA-C polymorphism will be molecularly defined and the source of its unique assembly properties identified by site-directed mutagenesis. Recent experiments have demonstrated the expression of free HLA-A,B heavy chains on activated, but not resting, human T cells. These potential alloantigens are hypothesized to arise from class I molecules that are empty, or have weakly bound peptide, fonned as a consequence of limiting peptide supply. This model will be tested in Aim 3, as will the effects of added peptide and beta2-microglobulin on the formation of free heavy chains. The changes in class 1, and induction of class II, suggest major changes of antigen presentation in activated human T cells which may regulate the immune response. Overall this investigation will provide unique insights into human immune responsiveness and its variation in different populations. It will also lay the foundation for absolute definition of class I HLA type, thereby facilitating development of accurate typing and more incisive analysis of human immunology, human genetics and of tissue match in transplantation.
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