Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice.

Abstract

The survival of T lymphocytes is tightly controlled during development. Here, we show that Bcl-xL, a protein homologue of Bcl-2, is highly regulated in the thymus in a pattern different than that of Bcl-2. The maximum expression was in CD4+CD8+ thymocytes, a developmental stage where Bcl-2 is downregulated. To assess the role of Bcl-xL in thymocyte apoptosis, we generated mice overexpressing an E mu-bcl-x transgene within the T cell compartment. Constitutive expression of Bcl-xL resulted in accumulation of thymocytes and mature T cells in lymphoid organs. Thymocytes overexpressing Bcl-xL exhibited increased viability in vitro and were resistant to apoptosis induced by different signals, including glucocorticoid, gamma irradiation, calcium ionophore, and CD3 cross-linking. However, Bcl-xL was unable to block clonal deletion of thymocytes reactive with self-superantigens or H-Y antigen. These studies demonstrate that Bcl-2 and Bcl-xL, two functionally related proteins, are regulated independently during T cell development. In contrast to Bcl-2, which has been implicated in the maintenance of mature T cells, Bcl-xL appears to provide a survival signal for the maintenance of more immature CD4+CD8+ thymocytes before positive selection.

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

“…It has been reported that, in contrast to thymocytes and transformed T cells, normal mature T cells may be independent of Bcl-xL as a result of high Bcl-2 expression (Grillot et al, 1995). This was elegantly confirmed in a Bcl-xL conditional knockout mouse.…”

“…The knockout mouse model showed that, as with Bcl11b, deficiency of Bcl-xL led to massive apoptosis of hematopoietic cells, and impaired maturation and shortened lifespan of lymphocytes (Motoyama et al, 1995). In turn, overexpression of Bcl-xL within the Tcell lineage resulted in accumulation of thymocytes in lymphoid organs and increased resistance to apoptosis (Grillot et al, 1995). Moreover, overexpression of BclxL was detected in T-ALL and ATLL cell lines and samples, and its suppression by anti-sense approaches induced apoptosis and sensitized T-ALL cells to chemotherapeutic drugs (Mori et al, 2001;Broome et al, 2002).…”

Constitutive expression of BCL‐XL in the T lineage attenuates collagen‐induced arthritis in Bcl‐XL transgenic mice

“…However, there are subtle differences between these 2 lines of Bcl-x L transgenic mice. First, the Bcl-x L transgene used in transplantation and EAE studies was under the control of the E promoter/ enhancer (12), while the Bcl-x L transgene used in this study was under the control of the lck promoter (10). However, since both transgenes are targeted to the T lineage, it seems unlikely that phenotypic differences in these 2 lines are due to differences in promoter/ enhancer elements.…”

The role of apoptosis in the development and function of T lymphocytes

“…During T lymphocyte development, the expression of Bcl-x L is tightly regulated [20,21]. Bcl-x L is not expressed at DN or SP stage.…”