Elimination of Self-Reactive T Cells in the Thymus: A Timeline for Negative Selection
Open accessAbstract
The elimination of autoreactive T cells occurs via thymocyte apoptosis and removal by thymic phagocytes, but the sequence of events in vivo, and the relationship between thymocyte death and phagocytic clearance, are unknown. Here we address these questions by following a synchronized cohort of thymocytes undergoing negative selection within a three-dimensional thymic tissue environment, from the initial encounter with a negative selecting ligand to thymocyte death and clearance. Encounter with cognate peptide-MHC complexes results in rapid calcium flux and migratory arrest in auto-reactive thymocytes over a broad range of peptide concentrations, followed by a lag period in which gene expression changes occurred, but there was little sign of thymocyte death. Caspase 3 activation and thymocyte loss were first detectable at 2 and 3 hours, respectively, and entry of individual thymocytes into the death program occurred asynchronously over the next 10 hours. Two-photon time-lapse imaging revealed that thymocyte death and phagocytosis occurred simultaneously, often with thymocytes engulfed prior to changes in chromatin and membrane permeability. Our data provide a timeline for negative selection and reveal close coupling between cell death and clearance in the thymus.
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The rapid microglia-mediated removal of dying neurons in the subventricular zone and apoptotic thymocytes during T-cell development is compatible with the observed scenario.
“This scenario is compatible with the rapid microglia-mediated removal of dying neurons in the subventricular zone25 as well as apoptotic thymocytes during T-cell development39.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [39]
Most newly generated neurons/T-cells undergo apoptotic cell death, and dying cells cannot be readily detected due to rapid removal by resident macrophages/microglia.
“While most of the newly generated neurons/T-cells undergo apoptotic cell death, the dying cells cannot be readily detected due to their rapid removal by resident macrophages/microglia25,39.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [39]
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Cites
T cell tolerance by clonal elimination in the thymus
Kappler, J. W., Roehm, N. W., & Marrack, P. (1987) · Cell · doi:10.1016/0092-8674(87)90568-x · Cited by 2,226 · see citing works
Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes
Kisielow, P., Blüthmann, H., Staerz, U., Steinmetz, M., & von Boehmer, H. (1988) · Nature · doi:10.1038/333742a0 · Cited by 1,793 · see citing works
Induction by Antigen of Intrathymic Apoptosis of CD4 + CD8 + TCR lo Thymocytes in Vivo
MURPHY, K. M. M., Heimberger, A. B., & Loh, D. Y. (1990) · Science · doi:10.1126/science.2125367 · Cited by 1,735 · see citing works
T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases
Mempel, T. R., Henrickson, S. E., & von Andrian, U. H. (2004) · Nature · doi:10.1038/nature02238 · Cited by 1,720 · see citing works
Positive and negative selection of T cells
Starr, T. K., Jameson, S. C., & Hogquist, K. A. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141107 · Cited by 1,601 · see citing works
T-cell apoptosis detected in situ during positive and negative selection in the thymus
Surh, C. D., & Sprent, J. (1994) · Nature · doi:10.1038/372100a0 · Cited by 1,082 · see citing works
The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant
Goldstein, J. C., Waterhouse, N. J., Juin, P. P., Evan, G. I., & Green, D. R. (2000) · Nature Cell Biology · doi:10.1038/35004029 · Cited by 1,073 · see citing works
Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis
Spencer, S. L., Gaudet, S., Albeck, J. G., Burke, J. M., & Sorger, P. K. (2009) · Nature · doi:10.1038/nature08012 · Cited by 1,023 · see citing works
Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen
Pircher, H., Bürki, K., Lang, R., Hengartner, H., & Zinkernagel, R. M. (1989) · Nature · doi:10.1038/342559a0 · Cited by 1,019 · see citing works
Cell death modalities: classification and pathophysiological implications
Galluzzi, L., Maiuri, M. C., Vitale, I., Zischka, H., Castedo, M., Zitvogel, L., & Kroemer, G. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402148 · Cited by 832 · see citing works
Faust, N., Varas, F., Kelly, L. M., Heck, S., & Graf, T. (2000) · Blood · doi:10.1182/blood.v96.2.719 · Cited by 751 · see citing works
Antigen presentation in the thymus for positive selection and central tolerance induction
Klein, L., Hinterberger, M., Wirnsberger, G., & Kyewski, B. (2009) · Nature reviews. Immunology · doi:10.1038/nri2669 · Cited by 588 · see citing works
Mathis, D. J., & Benoist, C. O. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141532 · Cited by 566 · see citing works
Beginnings of a Good Apoptotic Meal: The Find-Me and Eat-Me Signaling Pathways
Ravichandran, K. S. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.004 · Cited by 559 · see citing works
Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums
Ravichandran, K. S. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20101157 · Cited by 547 · see citing works
Mempel, T. R., Pittet, M. J., Khazaie, K., Weninger, W., Weissleder, R., von Boehmer, H., & von Andrian, U. H. (2006) · Immunity · doi:10.1016/j.immuni.2006.04.015 · Cited by 489 · see citing works
Henrickson, S. E., Mempel, T. R., Mazo, I. B., Liu, B., Artyomov, M. N., Zheng, H., Peixoto, A., Flynn, M. P., Senman, B. C., Junt, T., et al. (2008) · Nature Immunology · doi:10.1038/ni1559 · Cited by 390 · see citing works
T-cell activation by dendritic cells in the lymph node: lessons from the movies
Bousso, P. (2008) · Nature reviews. Immunology · doi:10.1038/nri2379 · Cited by 363 · see citing works
Selection of Self-Reactive T Cells in the Thymus
Stritesky, G. L., Jameson, S. C., & Hogquist, K. A. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075035 · Cited by 329 · see citing works
McCaughtry, T. M., Wilken, M. S., & Hogquist, K. A. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070601 · Cited by 278 · see citing works
Swat, W., Ignatowicz, L., von Boehmer, H., et al. (1991) · Nature · doi:10.1038/351150a0 · Cited by 246 · see citing works
Cutting Edge: Developmental Switches in Chemokine Responses During T Cell Maturation
Campbell, J. J., Pan, J., & Butcher, E. C. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.5.2353 · Cited by 244 · see citing works
Bhakta, N. R., Oh, D. Y., & Lewis, R. S. (2005) · Nature Immunology · doi:10.1038/ni1161 · Cited by 236 · see citing works
Morphological and cytochemical determination of cell death by apoptosis
Taatjes, D. J., Sobel, B. E., & Budd, R. C. (2007) · Histochemistry and Cell Biology · doi:10.1007/s00418-007-0356-9 · Cited by 235 · see citing works
Programmed death of autoreactive thymocytes
MacDonald, H. R., & Lees, R. K. (1990) · Nature · doi:10.1038/343642a0 · Cited by 224 · see citing works
Derbinski, J., Pinto, S., Rösch, S., Hexel, K., & Kyewski, B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707486105 · Cited by 203 · see citing works
Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla
McCaughtry, T. M., Baldwin, T. A., Wilken, M. S., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20080866 · Cited by 190 · see citing works
In vivo and in vitro clonal deletion of double-positive thymocytes.
Vasquez, N. J., Kaye, J. G., & Hedrick, S. Μ. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.175.5.1307 · Cited by 166 · see citing works
The impact of negative selection on thymocyte migration in the medulla
Borgne, M. L., Ladi, E., Dzhagalov, I. L., Herzmark, P., Liao, Y. F., Chakraborty, A. K., & Robey, E. A. (2009) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 152 · see citing works
Self-citationMamalaki, C., Norton, T., Tanaka, Y., Townsend, A., Chandler, P., Simpson, E., & Kioussis, D. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.23.11342 · Cited by 151 · see citing works
Enouz, S., Carrié, L., Merkler, D., Bevan, M. J., & Zehn, D. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20120905 · Cited by 142 · see citing works
Thymocyte Apoptosis Induced by T Cell Activation Is Mediated by Glucocorticoids In Vivo
Brewer, J. A., Kanagawa, O., Sleckman, B. P., & Muglia, L. J. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.4.1837 · Cited by 133 · see citing works
Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus
Ueda, Y., Katagiri, K., Tomiyama, T., et al. (2012) · Nature Communications · doi:10.1038/ncomms2105 · Cited by 124 · see citing works
Volkmann, A. (1997) · Immunology Letters · doi:10.1016/s0165-2478(97)87179-9 · Cited by 109 · see citing works
Ehrlich, L. I. R., Oh, D. Y., Weissman, I. L., & Lewis, R. S. (2009) · Immunity · doi:10.1016/j.immuni.2009.09.020 · Cited by 108 · see citing works
Volkmann, A., Żal, T., & Stockinger, B. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.2.693 · Cited by 94 · see citing works
Martin, S. F., & Bevan, M. J. (1997) · European Journal of Immunology · doi:10.1002/eji.1830271037 · Cited by 93 · see citing works
Apoptotic Cells Are Cleared by Directional Migration and elmo1- Dependent Macrophage Engulfment
van Ham, T. J., Kokel, D., & Peterson, R. T. (2012) · Current Biology · doi:10.1016/j.cub.2012.03.027 · Cited by 72 · see citing works
Canté-Barrett, K., Gallo, E. M., Winslow, M. M., & Crabtree, G. R. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.4.2299 · Cited by 68 · see citing works
Guerri, L., Péguillet, I., Geraldo, Y., Nabti, S., Prémel, V., & Lantz, O. J. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202883 · Cited by 47 · see citing works
Suen, A. Y. W., & Baldwin, T. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1114834109 · Cited by 46 · see citing works
The End and After: How Dying Cells Impact the Living Organism
Green, D. R. (2011) · Immunity · doi:10.1016/j.immuni.2011.10.003 · Cited by 45 · see citing works
Two‐Photon Imaging of the Immune System
Dzhagalov, I. L., Melichar, H. J., Ross, J. O., et al. (2012) · Current Protocols in Cytometry · doi:10.1002/0471142956.cy1226s60 · Cited by 45 · see citing works
Self-citationRole of TCR specificity in CD4 versus CD8 lineage commitment.
Kersh, G. J., & Hedrick, S. Μ. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.3.1057 · Cited by 38 · see citing works
Direct Visualization of thymocyte apoptosis in neglect, acute and steady-state negative selection
Wack, A., Ladyman, H. M., Williams, O., et al. (1996) · International Immunology · doi:10.1093/intimm/8.10.1537 · Cited by 38 · see citing works
Dampening of death pathways by schnurri-2 is essential for T-cell development
Staton, T. L., Lazarevic, V., Jones, D. C., Lanser, A. J., Takagi, T., Ishii, S., & Glimcher, L. H. (2011) · Nature · doi:10.1038/nature09848 · Cited by 36 · see citing works
Zhan, Y., Purton, J. F., Godfrey, D. I., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237316100 · Cited by 31 · see citing works
CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision
Yin, X., Ladi, E., Chan, S. W., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7358 · Cited by 27 · see citing works
Antigen-Induced Coreceptor Down-Regulation on Thymocytes Is Not a Result of Apoptosis
McGargill, M. A., & Hogquist, K. A. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.3.1237 · Cited by 23 · see citing works
Susceptibility and Resistance to Antigen-Induced Apoptosis in the Thymus of Transgenic Mice
Tarazona, R., Williams, O., Moskophidis, D., et al. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.11.5397 · Cited by 19 · see citing works
The impact of negative selection on thymocyte migration in the medulla
Borgne, M. L., Ladi, E., Dzhagalov, I. L., Herzmark, P., Liao, Y. F., Chakraborty, A. K., & Robey, E. A. (2009) · Nature Immunology · doi:10.1038/ni.1761 · Cited by 3 · see citing works
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Epigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460 · see citing works
Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation
Klein, L., Robey, E. A., & Hsieh, C.-S. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-018-0083-6 · Cited by 214 · see citing works
Self-citation
- Authors
- Dzhagalov, I. L., Chen, K. G., Herzmark, P., & Robey, E. A.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Robey, Ellen A.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-05-21
- Volume
- 11
- Issue
- 5
- Pages
- e1001566
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC3660248
- OpenAlex
- W2014575353
- Cited by
- 82
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 4 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 4
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research Institute
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI064227, R01AI064227)
- National Center for Research Resources (S10RR026821)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- negative selection, thymocyte apoptosis, autoreactive T cells, peptide-MHC complex, calcium flux, caspase-3 activation, phagocytosis, thymic tissue, autoimmunity tolerance
- MeSH terms
- Animals, Mice, Inbred Strains, Phagocytosis, T-Lymphocytes, Thymus Gland, Cell Death, Apoptosis, Mice, Caspase 3
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