How the T cell signaling network processes information to discriminate between self and agonist ligands
Name
26020.full.pdf
Description
Published version
Size
1.42 MB
Format
Adobe PDF
Checksum (MD5)
06512d86963e456c0ab3470171f378e1
Author(s)
Ganti, Raman S
Lo, Wan-Lin
McAffee, Darren B
Groves, Jay T
Weiss, Arthur
Chakraborty, Arup K
Date Issued
2020
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Version
Final published version
Abstract
© 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.
MIT Department
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
Terms of Use
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.
Persistent DSpace Link
DOI of Published Version
10.1073/PNAS.2008303117
https://doi.org/10.1073/PNAS.2008303117
