ArticlePloS one2010
A novel TCR transgenic model reveals that negative selection involves an immediate, Bim-dependent pathway and a delayed, Bim-independent pathway.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Dysfunctional CD4 T cells in an oncovirus-specific TCR-transgenic in vivo model.Nature communications · 2025Article
- Integrative scATAC-seq and scRNA-seq analyses map thymic iNKT cell development and identify Cbfβ for its commitment.Cell discovery · 2023Article
- T Cells and Regulated Cell Death: Kill or Be Killed.International review of cell and molecular biology · 2019Review
- Indirect presentation in the thymus limits naive and regulatory T-cell differentiation by promoting deletion of self-reactive thymocytes.Immunology · 2018Article
- Dying to protect: cell death and the control of T-cell homeostasis.Immunological reviews · 2017Review
- Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire.Journal of immunology (Baltimore, Md. : 1950) · 2017Article
- The 3'-Jα Region of the TCRα Locus Bears Gene Regulatory Activity in Thymic and Peripheral T Cells.PloS one · 2015Article
- T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity.eLife · 2014Article
- NF-κB control of T cell development.Nature immunology · 2014Review
- Complete TCR-α gene locus control region activity in T cells derived in vitro from embryonic stem cells.Journal of immunology (Baltimore, Md. : 1950) · 2013Article
- Murine thymic selection quantified using a unique method to capture deleted T cells.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB.The Journal of experimental medicine · 2013Article
- The transcriptional repressor NKAP is required for the development of iNKT cells.Nature communications · 2013Article
- T-cell tolerance: central and peripheral.Cold Spring Harbor perspectives in biology · 2012Article
- Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.Nature immunology · 2012Article
- T-cell receptor affinity in thymic development.Immunology · 2012Review
- Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Bcl-2-regulated cell death signalling in the prevention of autoimmunity.Cell death & disease · 2010Review
- Functional development of the T cell receptor for antigen.Progress in molecular biology and translational science · 2010Article
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4 authors.
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Abstract
A complete understanding of negative selection has been elusive due to the rapid apoptosis and clearance of thymocytes in vivo. We report a TCR transgenic model in which expression of the TCR during differentiation occurs only after V(D)J-like recombination. TCR expression from this transgene closely mimics expression of the endogenous TCRalpha locus allowing for development that is similar to wild type thymocytes. This model allowed us to characterize the phenotypic changes that occurred after TCR-mediated signaling in self-reactive thymocytes prior to their deletion in a highly physiological setting. Self-reactive thymocytes were identified as being immature, activated and CD4(lo)CD8(lo). These cells had upregulated markers of negative selection and were apoptotic. Elimination of Bim reduced the apoptosis of self-reactive thymocytes, but it did not rescue their differentiation and the cells remained at the immature CD4(lo)CD8(lo) stage of development. These cells upregulate Nur77 and do not contribute to the peripheral T cell repertoire in vivo. Remarkably, development past the CD4(lo)CD8(lo) stage was possible once the cells were removed from the negatively selecting thymic environment. In vitro development of these cells occurred despite their maintenance of high intracellular levels of Nur77. Therefore, in vivo, negatively selected Bim-deficient thymocytes are eliminated after prolonged developmental arrest via a Bim-independent pathway that is dependent on the thymic microenvironment. These data newly reveal a layering of immediate, Bim-dependent, and delayed Bim-independent pathways that both contribute to elimination of self-reactive thymocytes in vivo.
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