INFLUENCE OF THE T-CELL RECEPTOR ALPHA-CHAIN ON T-CELL REACTIVITY ANDTOLERANCE TO MIS-1 IN T-CELL RECEPTOR BETA-CHAIN TRANSGENIC MICE

Previous analyses of a TCR Vbeta8.1 transgenic mouse revealed multiple mechanisms of tolerance to the retroviral superantigen, Mls-1. Wherea s some T cells were clonally deleted in the thymus, others became aner gic in the periphery, or remained unaffected by the expression of Mls- 1. In addition, a strong correlation between TCR alpha-chain usage and Mls-1 reactivity of individual transgenic Vbeta8.1+ T cell hybridomas was established. Based on these observations, we speculated that the different mechanisms of tolerance were a consequence of the alpha-chai n-mediated differences in Mls-1 reactivity. In the current studies, we make use of a Valpha2-specific mAb to directly examine the role of th e alpha-chain on tolerance in this transgenic model. We show, first, t hat Valpha2+CD4+ T cells, as a group, are relatively less Mls-1-reacti ve, and are elevated twofold in the periphery of Mls-1+ compared with Mls-1- Vbeta8.1 transgenic mice. This elevated expression is also seen in the Valpha2+CD4+ population of mature thymocytes, but not in immat ure thymocytes. Second, Mls-1-induced neonatal tolerance in Mls-1-nega tive mice caused an increase of Valpha2+CD4+ T cells, comparable with the frequency of expression in transgenic mice that endogenously expre ssed Mls-1. Third, we have demonstrated a general correlation between the age-dependent increase in Mls-1-expression and the levels of Valph a2+CD4+ T cells during the first 4 wk of life. Taken together, these d ata suggest that the over-expression of Valpha2+CD4+ T cells in Mls-1 mice is a consequence of mechanisms of tolerance, predominantly media ted by preferential lack of clonal deletion in the thymus. These data support the idea that clonal deletion is a competitive process and the influence of the TCR alpha-chain on the strength of Mls-1 reactivity of individual Vbeta8.1+ transgenic T cells controls their susceptibili ty to clonal deletion.