Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1783661182615289856 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7936380 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT odonoghuegeoffp tcellsselectivelyfilteroscillatorysignalsontheminutestimescale AT bugajlukaszj tcellsselectivelyfilteroscillatorysignalsontheminutestimescale AT andersonwarren tcellsselectivelyfilteroscillatorysignalsontheminutestimescale AT danielskyleg tcellsselectivelyfilteroscillatorysignalsontheminutestimescale AT rawlingsdavidj tcellsselectivelyfilteroscillatorysignalsontheminutestimescale AT limwendella tcellsselectivelyfilteroscillatorysignalsontheminutestimescale |