BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes
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), 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.
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Pro-apoptotic BH3-only proteins are activated transcriptionally or post-translationally as specific organelles or cellular compartments experience perturbations of homeostasis, operating as cellular transducers of stress signaling.
“These pro-apoptotic members of the BCL2 protein family (which contain a single BH3 domain) are activated transcriptionally or post-translationally as specific organelles or cellular compartments experience perturbations of homeostasis, de facto operating as cellular transducers of stress signaling [60–63].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [61]
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- Authors
- Bouillet, P., Purton, J. F., Godfrey, D. I., Zhang, L.-C., Coultas, L., Puthalakath, H., Pellegrini, M., Cory, S., Adams, J. M., & Strasser, A.
- Affiliations
- The Royal Melbourne Hospital (AU)
- Monash University (AU)
- Corresponding author
- Strasser, Andreas
- ORCID
- Venue
- Nature
- Published
- 2002-02-21
- Volume
- 415
- Issue
- 6874
- Pages
- 922-926
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2079650395
- Cited by
- 782
- References
- 30
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 12 · 2022: 15 · 2021: 14 · 2020: 17 · 2019: 11 · 2018: 20 · 2017: 22 · 2016: 28 · 2015: 19 · 2014: 42 · 2013: 35 · 2012: 42
- FWCI
- 23.60
- Type
- journal article
- Language
- en
- Update notices
- erratum (2002-07-04)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- building information modeling, Bcl-2 family proteins, apoptosis, thymocyte negative selection, autoreactive T cells, T cell receptor signaling, Bcl-xL, TCR/CD3 complex, lymphocyte development, autoimmune disease, BCL2L11
- MeSH terms
- Bcl-2-Like Protein 11, Amino Acid Sequence, Animals, Carrier Proteins, Cells, Cultured, Enterotoxins, Female, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Proto-Oncogene Proteins, Staphylococcus, T-Lymphocytes, Thymus Gland, CD4 Antigens, CD8 Antigens, Apoptosis, Receptor-CD3 Complex, Antigen, T-Cell, Self Tolerance, Superantigens, Proto-Oncogene Proteins c-bcl-2, Leukopoiesis, Protein Transport, Apoptosis Regulatory Proteins, bcl-X Protein, Mice
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