All complex immune responses are simplified by the well-established, but poorly understood phenomenon of immunodominance that allows immune responses to certain peptide epitopes to prevail over others. The overall goal of the proposed work is to exploit the well-developed minor histocompatibility antigen system to understand the principles of immunodominance and the level of alloantigenic complexity in which immunodominance operates in a transplantation setting. Our studies show that one particular minor H antigen, H60, is remarkably immunodominant because mice have an unusually high frequency of precursor CD8 T cells directed against H60 minor H peptide. While most minor H Ags are alloantigenic because of polymorphisms within an allelic self peptide, H60 is unusual in that responder mice fail to transcribe the El60 gene. We therefore hypothesize that H60 immunodominance results because its T cell repertoire in not attenuated by negative selection. We will transgenically introduce allelic H60 self analogues into mice and determine whether they attenuate H60 immunodominance. H13 is alloantigenic because of a single conservative (Val+ Ile) amino acid change in a core nonamer self peptide, which results in a discrete single carbon extension of a T-cell receptor contact methyl residue. The H13 minor H antigen is subordinate to most known minor H Ags. We hypothesize that its self-allele attenuates the immunodominance potential of H13 by efficient negative selection of its CD8 T cell repertoire. We will test this hypothesis by producing mice lacking their normal self H13 allele, and determine whether H13 is now immunodominant. Because of the phenomenon of immunodominance, it has never been possible to determine the actual alloantigenic complexity encountered during transplant rejection. Our hypothesis is that the genome is replete with minor H antigens that are difficult to detect because of their subordinance. To shed light on the 'real' antigenic complexity of tissue transplantation, we will exploit newly rederived H3 congenic and subcongenic strains, genomic and gene expression databases to determine how many H loci reside in the H3 complex. Taken together, the studies will clarify how a single epitope successfully immunodominates over all others; in doing so, the studies should provide considerable insight into key unsolved issues pertinent not only to transplant immunobiology, but more generally, to cancer and pathogen vaccine design.
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