It is well known that particular major histocompatibility complex (MHC) alleles promote the appearance of many autoimmune diseases. It is also known that certain MHC alleles protect against such illnesses, even in the presence of the disease-promoting allele. Studies over the last 20 years have suggested many explanations for the inhibitory effects of some MHC alleles, with explanations ranging from the fact that the protective alleles may delete or dilute out the potentially damaging T cells to the notion that the protective alleles induce regulatory T cells which prevent attack on the tissue target of autoimmunity. Any of these explanations suggest that MHC heterozygosity affects the T cell receptor repertoire and function of the T cells in the animal. Surprisingly little is known about the effects of MHC heterozygosity versus homozygosity on T cells. It might be predicted that MHC heterozygous animals would contain T cells bearing almost all T cell receptors that are present in either parent, with some T cell receptors missing in the heterozygote because of clonal deletion in the thymus of the F1. Nevertheless, the guess would be that the T cell receptor repertoire of heterozygous animals would be much greater than that of either parent. Experiments suggest that this is not the case, many T cell receptor sequences that are present in the parents are missing from their heterozygous progeny. The experiments here will extend these findings and investigate why such sequences are missing from the heterozygote. The results of these experiments will inform knowledge of the consequences, for the T cell receptor repertoire, of MHC heterozygosity versus homozygosity. The results may also suggest ideas about how some MHC alleles are protective against autoimmune diseases.
T cells bear receptors (TCRs) that allow them to recognize infections. TCRs react with their targets via the MHCs in their hosts. Almost all humans have two versions of MHC, this proposal will find out how the possession of two MHCs versus one, affects TCRs and T cell function.
