The long term goals of this proposal are to understand the specific interactions between the T cell antigen receptor and its peptide/MHC ligand on the antigen presenting cell (APC) surface that would allow manipulation of the immune response to minor histocompatibility (miH) gene products. T-cell/APC interactions are mediated by the unique peptide/MHC ligand. Exact knowledge of the antigenic miH peptides and their donor proteins are thus the key to design of altered ligands and to understanding their role in the immune response to complex mammalian tissues. Until recently it was virtually impossible to define the antigenic peptides involved in T cell responses except for simple model antigens. We developed novel methods that have permitted us to identify the unique peptides recognized by individual T cells specific for complex cellular immunogens by expression cloning the gene of the donor antigenic protein. We apply these methods here to isolate cDNA clones of miH antigens in well characterized mouse models. The nucleotide sequence, expression and functional characteristics of the miH cDNAs will allow test of several unresolved hypotheses on the origin, genetics and mechanism of immune responses to miH antigens by determining, (a) the concordance, if any, between the previous functionally defined and actual chromosomal locations of miH loci, (b) the identity of the donor miH protein and the definition and abundance of its naturally processed peptide product, (c) the molecular basis of antigenic polymorphism at the miH loci, (d) whether all or a subset of tissues express the miH peptide/MHC ligands, and finally, (e) the immunodominance of individual miH as a function of their complexity and relative levels of expression. The answers to these questions will lead to new models and insights into the origin and role of immunodominant antigenic peptides in the context of complex cellular antigens. They will also provide key reagents for manipulation of the antigen-specific immune responses during chronic transplant rejection and graft versus host disease reactions.
