POSITIVE AND NEGATIVE SELECTION OF T-CELLS IN T-CELL RECEPTOR TRANSGENIC MICE EXPRESSING A BCL-2 TRANSGENE

To explore the role of bcl-2 in T-cell development, a bcl-2 transgene was introduced into mice expressing a T-cell receptor (TCR) transgene encoding reactivity for the mouse male antigen HY presented by the H-2 D(b) class I antigen of the major histocompatibility complex (MHC). No rmal thymic development is contingent on the ability of immature thymo cytes to interact with self-MHC molecules presented by thymic stroma ( positive selection). Thus, thymocyte numbers are low in female anti-HY TCR transgenic mice with a nonselecting (H-2D(d)) background. Express ion of bcl-2 inhibited the death of nonselectable thymocytes since, st rikingly, female H-2D(d) bcl-2/TCR transgenic mice developed normal nu mbers of CD4(+)CD8(+) thymocytes, although these did not mature furthe r into functional T cells. Hence, TCR-MHC interaction may induce posit ive selection through two signals, one which saves cells from death by increasing Bcl-2 synthesis and another which promotes maturation. Mal e H-2D(b) anti-HY TCR trans genic mice normally have a very small thym us, due to deletion of the self-reactive T cells. Expression of bcl-2 reduced the efficiency of deletion, since bcl-2/TCR transgenic male mi ce accumulated 4- to 6-fold more thymocytes than did TCR transgenic ma le littermates. Anti-HY TCR-expressing cells were also more numerous i n the peripheral lymphoid tissues, but these cells expressed abnormall y low levels of CDS coreceptor and were not responsive to the HY antig en. Thus, although bcl-2 expression hampers the deletion of immature s elf-reactive cells in the thymus, self-tolerance is maintained.