THE BALANCE BETWEEN DELETION AND ACTIVATION OF CD4(-CELL RECEPTOR-ANTIGEN INTERACTIONS AND IS AFFECTED BY CYCLOSPORINE-A()8(+) THYMOCYTES IS CONTROLLED BY T)

The sensitivity of immature thymocytes to antigen-induced deletion has been shown to correlate with their differentiation status. By using a n in vitro approach we have investigated whether parameters of antigen ic stimulation may also affect the response of thymocytes. Two T cell receptor (TcR)-transgenic (Tg) mouse models have been compared, both o f which recognize the allo-antigen H-2K(b) but are functionally CD8''- dependent'' (KB5.C20-Tg) and ''-independent'' (BM3.3-Tg). Presentation of the antigen H-2K(b) on the surface of fibroblasts, to thymocytes i n vitro, resulted in the apoptosis of CD4(+)8(+) thymocytes. In contra st to in vivo deletion, in vitro deletion was much greater for KB5.C20 -Tg than for BM3.3-Tg. In the absence of engagement of CD8 (using an a ltered H-2K(b)-alpha 3 domain or CD8-specific antibodies), the H-2K(b) -induced deletion of CD4(+)8(+) thymocytes was decreased for KB5.C20-T g, but no change in the pattern of deletion for BM3.3-Tg occurred. CD4 (+)8(+) thymocytes which remained viable after in vitro exposure to an tigen, were shown to have been activated. Cyclosporin A (CsA), which h as been reported to inhibit activation-induced cell death, did not aff ect antigen-induced deletion of CD4(+)8(+) thymocytes from KB5.C20-Tg. More strikingly, deletion of CD4(+)8(+) thymocytes from BM3.3-Tg incr eased, whilst activation was partially inhibited by CsA. These results provide direct evidence that presentation of antigen to thymocytes ca n result in deletion or activation, depending on not only the differen tiation status of the cell, but also parameters of TcR-antigen interac tion. Additionally, the effects of CsA suggest that activation can pre vent the induction of deletion.