CD45 functions as a signaling gatekeeper in T cells
Name
nihms-1065097.pdf
Description
Accepted version
Size
1.84 MB
Format
Adobe PDF
Checksum (MD5)
9148560479bd3015455a5391ee2b1e80
Author(s)
Courtney, Adam H
Shvets, Alexey A
Lu, Wen
Griffante, Gloria
Mollenauer, Marianne
Horkova, Veronika
Lo, Wan-Lin
Yu, Steven
Stepanek, Ondrej
Chakraborty, Arup K
Date Issued
2019
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Version
Author's final manuscript
Abstract
Copyright © 2019 The Authors T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activation, TCR-associated ξ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ξ-chain phosphorylation and was necessary for a regulatable pool of active Lck, thereby interconnecting the activating and suppressive roles of CD45 that tune antigen discrimination. CD45 suppressed signaling events that were antigen independent or induced by low-affinity antigen but not those initiated by high-affinity antigen. Together, our findings reveal that CD45 acts as a signaling “gatekeeper,” enabling graded signaling outputs while filtering weak or spurious signaling events.
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
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
10.1126/SCISIGNAL.AAW8151
https://doi.org/10.1126/SCISIGNAL.AAW8151
