CONSEQUENCES OF A T CELL RECEPTOR B CHAIN GENE DELETION

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We have identified an unusual allele of the T cell receptor Beta chain locus in New Zealand White (NZW) mice. This allele is distinguished by the deletion of 8.8 kb of DNA containing CBeta1, DBeta2, and the entire JBeta2 cluster. Thus, all NZW T cell receptor Beta chains are derived from a single set of Beta chain gene segments (DBeta1, JBeta1 and CBeta2). Interestingly, this deletion of T cell receptor Beta gene segments is present in a strain known to contribute to lupus-like autoimmune diseases. This grant proposes to fully characterize this unusual Beta chain allele and to examine the consequences of its expression. It is first planned to clone and sequence the germline Beta chain gene complex from NZW mice. This may elucidate the mechanism by which this allele was generated. Mice congenic for the NZW Beta chain genes will be bred on the C57BL/6 and BALB/c backgrounds. Once these congenic strains are available, experiments examining the repertoire of T cell specificities in these mice will be performed. The response to alloantigens (mutant H-2Kb gene products), and conventional antigens (peptides of ovalbumin) will be investigated. These studies should allow us to examine the contribution of DBeta2 and JBeta2 gene segments to the T cell repertoire. Since NZW mice contribute to the development of lupus-like autoimmunity in NZB x NZW F1 animals, a straightforward genetic analysis [(NZB x NZW) F1 x NZB backcross] will be undertaken to determine whether or not the NZW Beta chain genes are involved in the pathogenesis of the F1 autoimmune disease. If the NZW Beta chain genes are linked to development of lupus-like disease, experiments are planned to elucidate the role of NZW Beta chain genes in the disease process. Mapping experiments are also planned to examine the contribution of other NZW loci to NZB/NZW disease. Finally, we will examine the DNA from patients with systemic lupus erythematosus (SLE) to determine whether T cell receptor gene polymorphisms are present in these individuals.