The molecular interaction of class II molecule, antigen and T cell receptor is central to the immune response. The polymorphic residues of the class II molecule not only control the bindings of specific antigens but also select the repertoire of T cell receptors available to recognize the class II/antigen complex. Thus, class II diversity is important in the survival of a species which must coexist with diverse and versatile pathogens. The remarkable polymorphism within the HLA-DRw52 family of DRB1 alleles is characterized by subtle, stepwise changes outlining an evolutionary pathway. One hypothesis is that this family of DRB1 alleles and their associated HLA haplotypes, present at a high frequency in the American black population, have evolved to provide a selective advantage to these individuals who derive from a region plagued by multiple pathogens. The goal of this study is to define how these DRB1 microvariants affect immune recognition and to probe how selection may have influenced DR polymorphism. To do this, a panel of DR transfectants expressing naturally occurring and mutated DRB1 genes will be generated (AIM1). These transfectants will be used to examine the impact of variations in specific regions of the DR beta chain on function. The mutants will also provide a means of assessing the effect of point mutation/gene conversion on the DR molecule as it evolves. Existing alloproliferation T cell clones will be used to survey the effect of DR polymorphism on immune recognition (AIM2). T cell clones specific for an immunodominant T cell epitope of the malaria parasite will be generated (AIM3). This model system will not only allow us to analyze the effect of DR polymorphism on immune recognition in a defined antigen system (AIM4) but will also allow us to analyze the influence of DR polymorphism on peptide binding (AIM5). Finally, the interaction between DR polymorphism and pathogen diversity will be studied (AIM6). These studies will provide basic information about the effect of subtle amino acid substitutions in various regions of the DR molecule on immune recognition and will begin to examine the role that pathogens may have played in positive selection of DR polymorphism and, ultimately, in shaping the human immune response repertoire.
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