Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection.
Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1003102 |
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| author | Iren Bains Hisse M van Santen Benedict Seddon Andrew J Yates |
| author_facet | Iren Bains Hisse M van Santen Benedict Seddon Andrew J Yates |
| author_sort | Iren Bains |
| collection | DOAJ |
| description | Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T(conv) and T(reg) are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T(conv) and T(reg) development. |
| format | Article |
| id | doaj-art-15ddf4fa2f904eb799ec8433efb133b7 |
| institution | Kabale University |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-15ddf4fa2f904eb799ec8433efb133b72025-08-20T03:46:12ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582013-01-0197e100310210.1371/journal.pcbi.1003102Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection.Iren BainsHisse M van SantenBenedict SeddonAndrew J YatesConventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T(conv) and T(reg) are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T(conv) and T(reg) development.https://doi.org/10.1371/journal.pcbi.1003102 |
| spellingShingle | Iren Bains Hisse M van Santen Benedict Seddon Andrew J Yates Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. PLoS Computational Biology |
| title | Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. |
| title_full | Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. |
| title_fullStr | Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. |
| title_full_unstemmed | Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. |
| title_short | Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. |
| title_sort | models of self peptide sampling by developing t cells identify candidate mechanisms of thymic selection |
| url | https://doi.org/10.1371/journal.pcbi.1003102 |
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