BCL-XL-regulated apoptosis in T cell development.
Thymocyte differentiation progresses through well-defined stages in which apoptosis is central to the selection of a functional TCR repertoire. In the present study, we explored the developmental effects of BCL-XL, a repressor of apoptosis. We found that endogenous BCL-XL is down-regulated by both positive and negative selection signals at the CD4+ CD8+ stage of thymocyte development. We examined the role of BCL-XL regulatable apoptosis in T cell development in the context of an alpha beta TCR transgene, Rag-1 deficiency and the scid model. We found that BCL-XL expression promoted accumulation of CD8 single-positive thymocytes even in MHC class II-restricted TCR transgenic mice. However, the apoptotic resistance conferred by BCL-XL could not fully substitute for TCR-mediated positive selection signals nor did it prevent negative selection. Overexpression of BCL-XL promoted partial maturation of CD4-CD8- thymocytes to CD4+CD8+ cells in a Rag-deficient, but not a scid background. Thus, TCR-mediated signals mediate the regulation of endogenous BCL-XL during thymocyte development, indicating that the principal protection of double-positive thymocytes by BCL-XL occurs prior to selection. The impact of BCL-XL on the CD8 but not CD4 lineage supports the asymmetric model of lineage commitment. Moreover, several critical control points in T cell development could be distinguished as BCL-XL responsive or unresponsive.
Chao
D T
DT
Howard Hughes Medical Institute, Department of Medicine and Pathology, Washington University School of Medicine, St Louis, MO 63110, USA.
Korsmeyer
S J
SJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D016654:Genes, RAG-1 / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D000949:Histocompatibility Antigens Class II; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051020:bcl-X Protein