Selective T cell receptor Vbeta gene usage by alloreactive T cells responding to defined HLA-DR alleles

Previous studies have provided strong evidence for restricted Vbeta gene usage in response to DR synthetic peptides presented in context by self MHC molecules, i.e., via the indirect pathway of allorecognition. Although numerous studies have suggested a role for the T cell receptor (TCR) beta chain in the direct pathway of allorecognition, it is not clear whether a particular HLA allele elicits a consistent pattern of restricted Vbeta gene usage by resting T cells from different individuals. To address this problem, HLA class II homozygous cell lines that do not express class I antigens were used to study the role of the TCR Vbeta elements in direct recognition of specific DR alleles. Analysis of TCR V gene usage revealed that each DR allele tested elicited the same pattern of preferential Vbeta gene usage in all individuals studied. For example, the DRB1*0101 allele was preferentially recognized by T cells expressing Vbeta2, Vbeta13.1, Vbeta18, and Vbeta20, and the DRB1*1301 caused expansion of Vbeta4-, Vbeta6-, Vbeta8-, and Vbeta18-bearing T cells. Similarly, analysis of TCR V gene usage in response to defined DR alleles expressed on homozygous cell lines that express class I was also made possible by using anti-class I antibodies to block class I recognition and focus the response on the DR molecule. The results showed that the DRB1*1501 allele expressed on two distinct homozygous lines elicited the preferential expansion of Vbeta2, Vbeta8, and Vbeta13.2 T cells. Similarly, the DRB1*0301 allele expressed on normal, Epstein-Barr virus-transformed, or transfected fibroblasts was found to elicit the same pattern of Vbeta expansion and to selectively stimulate T cells bearing Vbeta2, Vbeta16, and Vbeta17 elements. In contrast to this highly reproducible pattern of Vbeta gene usage elicited by specific DR alleles, extensive heterogeneity in the CDR3 region was found and no preferential Jbeta or Valpha gene usage was observed in response to any of the DR alleles tested. The data suggest that, similar to the situation with the indirect pathway, TCR Vbeta elements are involved in the direct pathway of allorecognition. Although some overlap may exist, different sets of Vbeta elements may be preferentially used for each of these pathways. Inasmuch as HLA-identical siblings, but not HLA-identical unrelated individuals, express a very similar TCR repertoire, our data suggest that additional factors are involved in shaping the repertoire. Preferential activation of T-cell subsets by specific DR alleles may play an important role in primary alloresponses, e.g., in mixed lymphocyte reactions, and organ transplantation. Elucidation of the Vbeta specificity of each DR allele may have an impact on therapeutic strategies aimed at blocking specific alloresponse and prolonging graft survival in transplant recipients while avoiding the hazardous sequelae of nonspecific immunosuppression.