BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes

Philippe Bouillet, Jared F. Purton, Dale I. Godfrey, Li-Chen Zhang, Leigh Coultas, Hamsa Puthalakath, Marc Pellegrini, Suzanne Cory, Jerry M. Adams and Andreas Strasser ()
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Philippe Bouillet: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Jared F. Purton: Monash University Medical School
Dale I. Godfrey: Monash University Medical School
Li-Chen Zhang: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Leigh Coultas: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Hamsa Puthalakath: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Marc Pellegrini: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Suzanne Cory: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Jerry M. Adams: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research, Melbourne, P.O. The Royal Melbourne Hospital

Nature, 2002, vol. 415, issue 6874, 922-926

Abstract: Abstract 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)1, or can be deleted from the repertoire by cell death1. 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)2,3,4, but the mechanisms ensuring this ‘negative selection’ are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim5,6 (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.

Date: 2002
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DOI: 10.1038/415922a

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