BCL-2 IS UP-REGULATED AT THE CD4(+)CD8(+) STAGE DURING POSITIVE SELECTION AND PROMOTES THYMOCYTE DIFFERENTIATION AT SEVERAL CONTROL POINTS

In vivo thymocyte maturation models were used to investigate the differentiation role of Bcl-2. In alpha/beta T cell receptor (TCR) class II-restricted transgenic mice, Bcl-2 was upregulated at the CD4(+)CD8(+) stage during positive selection. The lck(pr)-bcl2 transgene was bred onto MHC classes I--/- and II-/-, MHC(-/-), and alpha/beta TCR backgrounds to determine whether Bcl-2 promoted thymocyte maturation in the absence of coreceptor-MHC interaction. Bcl-2 rescued CD8(+) thymocytes in class I--/- and alpha/beta TCR mice; however, they were not exported to the periphery. Bcl-2 had no effect an CD4 lineage maturation in class II-/- mice. No single-positive thymocytes accumulate in MHC(-/-) mice despite overexpressed Bcl-2. Thus, Bcl-2 enables selection of certain TCRs on class II molecules and their differentiation along the CD8 pathway; however, Bcl-2 did not substitute for positive selection. In RAG-1(-/-) mice, Bcl-2 promoted differentiation to the CD4(+)CD8(+) stage. Bcl-2 can promote thymocyte maturation at several control points.