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T cells selectively filter oscillatory signals on the minutes timescale

T cells experience complex temporal patterns of stimulus via receptor–ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been ex...

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Autores principales: O’Donoghue, Geoff P., Bugaj, Lukasz J., Anderson, Warren, Daniels, Kyle G., Rawlings, David J., Lim, Wendell A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936380/
https://www.ncbi.nlm.nih.gov/pubmed/33627405
http://dx.doi.org/10.1073/pnas.2019285118
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author O’Donoghue, Geoff P.
Bugaj, Lukasz J.
Anderson, Warren
Daniels, Kyle G.
Rawlings, David J.
Lim, Wendell A.
author_facet O’Donoghue, Geoff P.
Bugaj, Lukasz J.
Anderson, Warren
Daniels, Kyle G.
Rawlings, David J.
Lim, Wendell A.
author_sort O’Donoghue, Geoff P.
collection PubMed
description T cells experience complex temporal patterns of stimulus via receptor–ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with different frequencies or temporal stimulation patterns is relatively unexplored. We engineered T cells to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR). We discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light. Systematically scanning signal oscillation period from 1 to 150 min revealed that expression of CD69, a T cell activation marker, reached a local minimum at a period of ∼25 min (corresponding to 5 to 15 min pulse widths). A combination of inhibitors and genetic knockouts suggest that this frequency filtering mechanism lies downstream of the Erk signaling branch of the T cell response network and may involve a negative feedback loop that diminishes Erk activity. The timescale of CD69 filtering corresponds with the duration of T cell encounters with self-peptide–presenting APCs observed via intravital imaging in mice, indicating a potential functional role for temporal filtering in vivo. This study illustrates that the T cell signaling machinery is tuned to temporally filter and interpret time-variant input signals in discriminatory ways.
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spelling pubmed-79363802021-03-11 T cells selectively filter oscillatory signals on the minutes timescale O’Donoghue, Geoff P. Bugaj, Lukasz J. Anderson, Warren Daniels, Kyle G. Rawlings, David J. Lim, Wendell A. Proc Natl Acad Sci U S A Biological Sciences T cells experience complex temporal patterns of stimulus via receptor–ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with different frequencies or temporal stimulation patterns is relatively unexplored. We engineered T cells to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR). We discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light. Systematically scanning signal oscillation period from 1 to 150 min revealed that expression of CD69, a T cell activation marker, reached a local minimum at a period of ∼25 min (corresponding to 5 to 15 min pulse widths). A combination of inhibitors and genetic knockouts suggest that this frequency filtering mechanism lies downstream of the Erk signaling branch of the T cell response network and may involve a negative feedback loop that diminishes Erk activity. The timescale of CD69 filtering corresponds with the duration of T cell encounters with self-peptide–presenting APCs observed via intravital imaging in mice, indicating a potential functional role for temporal filtering in vivo. This study illustrates that the T cell signaling machinery is tuned to temporally filter and interpret time-variant input signals in discriminatory ways. National Academy of Sciences 2021-03-02 2021-02-24 /pmc/articles/PMC7936380/ /pubmed/33627405 http://dx.doi.org/10.1073/pnas.2019285118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
O’Donoghue, Geoff P.
Bugaj, Lukasz J.
Anderson, Warren
Daniels, Kyle G.
Rawlings, David J.
Lim, Wendell A.
T cells selectively filter oscillatory signals on the minutes timescale
title T cells selectively filter oscillatory signals on the minutes timescale
title_full T cells selectively filter oscillatory signals on the minutes timescale
title_fullStr T cells selectively filter oscillatory signals on the minutes timescale
title_full_unstemmed T cells selectively filter oscillatory signals on the minutes timescale
title_short T cells selectively filter oscillatory signals on the minutes timescale
title_sort t cells selectively filter oscillatory signals on the minutes timescale
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936380/
https://www.ncbi.nlm.nih.gov/pubmed/33627405
http://dx.doi.org/10.1073/pnas.2019285118
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