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.
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Acknowledgements
We are grateful to H. von Boehmer and W. Heath for HY-TCR and OT-II TCR transgenic mice. We thank A. Naughton and C. Tilbrook for animal care, A. Harris, J. Miller, D. Huang and L. O'Reilly for discussions and critical comments on the manuscript, and G. Smyth and R. Thomson for statistical advice. This work was supported by fellowships and grants from the National Health and Medical Research Council (Canberra), the Dr Josef Steiner Cancer Research Foundation (Bern), the Leukemia and Lymphoma Society of America, the Anti-Cancer Council of Victoria and the NIH.
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Bouillet, P., Purton, J., Godfrey, D. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002). https://doi.org/10.1038/415922a
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DOI: https://doi.org/10.1038/415922a
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