BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.
During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy), or can be deleted from the repertoire by cell death. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)-CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis), but the mechanisms ensuring this 'negative selection' are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim (also known as Bcl2l11) are refractory to apoptosis induced by TCR-CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.
Bouillet
Philippe
P
The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital, Victoria 3050, Australia.
Purton
Jared F
JF
Godfrey
Dale I
DI
Zhang
Li-Chen
LC
Coultas
Leigh
L
Puthalakath
Hamsa
H
Pellegrini
Marc
M
Cory
Suzanne
S
Adams
Jerry M
JM
Strasser
Andreas
A
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D019891:Leukopoiesis; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D021381:Protein Transport; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology; D013210:Staphylococcus / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology*; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; D002352:Carrier Proteins; D004768:Enterotoxins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018089:Superantigens; D051020:bcl-X Protein; C031818:enterotoxin B, staphylococcal