BCL-X-L-REGULATED APOPTOSIS IN T-CELL DEVELOPMENT

Thymocyte differentiation progresses through well-defined stages in wh ich apoptosis is central to the selection of a functional TCR repertoi re, In the present study, we explored the developmental effects of BCL -X-L, a repressor of apoptosis. We found that endogenous BCL-X-L is do wn-regulated by both positive and negative selection signals at the CD 4(+) CD8(+) stage of thymocyte development, We examined the role of BC L-X-L regulatable apoptosis in T cell development in the context of an alpha beta TCR transgene, Rag-1 deficiency and the scid model, We fou nd that BCL-X-L expression promoted accumulation of CD8 single-positiv e thymocytes even in MHC class Ii-restricted TCR transgenic mice, Howe ver, the apoptotic resistance conferred by BCL-X-L could not fully sub stitute for TCR-mediated positive selection signals nor did it prevent negative selection. Overexpression of BCL-X-L promoted partial matura tion of CD4(-)CD8(-) thymocytes to CD4(+)CD8(+) cells in a Rag-deficie nt, but not a scid background, Thus, TCR-mediated signals mediate the regulation of endogenous BCL-X-L during thymocyte development, indicat ing that the principal protection of double-positive thymocytes by BCL -X-L occurs prior to selection, The impact of BCL-X-L on the CD8 but n ot CD4 lineage supports the asymmetric model of lineage commitment, Mo reover, several critical control points in T cell development could be distinguished as BCL-X-L responsive or unresponsive.