How the T cell signaling network processes information to discriminate between self and agonist ligands
© 2020 National Academy of Sciences. All rights reserved. T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/135224 |
| _version_ | 1826204669834166272 |
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| author | Ganti, Raman S Lo, Wan-Lin McAffee, Darren B Groves, Jay T Weiss, Arthur Chakraborty, Arup K |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Ganti, Raman S Lo, Wan-Lin McAffee, Darren B Groves, Jay T Weiss, Arthur Chakraborty, Arup K |
| author_sort | Ganti, Raman S |
| collection | MIT |
| description | © 2020 National Academy of Sciences. All rights reserved. T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback. |
| first_indexed | 2024-09-23T12:59:10Z |
| format | Article |
| id | mit-1721.1/135224 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:59:10Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1352242024-03-20T19:56:40Z How the T cell signaling network processes information to discriminate between self and agonist ligands Ganti, Raman S Lo, Wan-Lin McAffee, Darren B Groves, Jay T Weiss, Arthur Chakraborty, Arup K Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Physics Ragon Institute of MGH, MIT and Harvard Massachusetts Institute of Technology. Department of Chemistry © 2020 National Academy of Sciences. All rights reserved. T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback. 2021-10-27T20:22:33Z 2021-10-27T20:22:33Z 2020 2021-06-08T17:25:36Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135224 en 10.1073/PNAS.2008303117 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Ganti, Raman S Lo, Wan-Lin McAffee, Darren B Groves, Jay T Weiss, Arthur Chakraborty, Arup K How the T cell signaling network processes information to discriminate between self and agonist ligands |
| title | How the T cell signaling network processes information to discriminate between self and agonist ligands |
| title_full | How the T cell signaling network processes information to discriminate between self and agonist ligands |
| title_fullStr | How the T cell signaling network processes information to discriminate between self and agonist ligands |
| title_full_unstemmed | How the T cell signaling network processes information to discriminate between self and agonist ligands |
| title_short | How the T cell signaling network processes information to discriminate between self and agonist ligands |
| title_sort | how the t cell signaling network processes information to discriminate between self and agonist ligands |
| url | https://hdl.handle.net/1721.1/135224 |
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