Positive and negative selection of T cells in T-cellreceptor transgenic mice expressing a bcl-2 transgene.

To explore the role of bcl-2 in T-celldevelopment, a bcl-2 transgene was introduced into mice expressing a T-cellreceptor (TCR) transgene encoding reactivity for the mouse male antigen HYpresented by the H-2Db class I antigen of the major histocompatibility complex(MHC). Normal thymic development is contingent on the ability of immaturethymocytes to interact with self-MHC molecules presented by thymic stroma(positive selection). Thus, thymocyte numbers are low in female anti-HY TCRtransgenic mice with a nonselecting (H-2Dd) background. Expression of bcl-2inhibited the death of nonselectable thymocytes since, strikingly, female H-2Ddbcl-2/TCR transgenic mice developed normal numbers of CD4+CD8+ thymocytes,although these did not mature further into functional T cells. Hence, TCR-MHCinteraction may induce positive selection through two signals, one which savescells from death by increasing Bcl-2 synthesis and another which promotesmaturation. Male H-2Db anti-HY TCR transgenic mice normally have a very smallthymus, due to deletion of the self-reactive T cells. Expression of bcl-2reduced the efficiency of deletion, since bcl-2/TCR transgenic male miceaccumulated 4- to 6-fold more thymocytes than did TCR transgenic malelittermates. Anti-HY TCR-expressing cells were also more numerous in theperipheral lymphoid tissues, but these cells expressed abnormally low levels ofCD8 co-receptor and were not responsive to the HY antigen. Thus, although bcl-2expression hampers the deletion of immature self-reactive cells in the thymus,self-tolerance is maintained.