CD45 functions as a signaling gatekeeper in T cells

Adam H. Courtney, Alexey A. Shvets, Wen Lu, Gloria Griffante, Marianne Mollenauer, Veronika Horkova, Wan Lin Lo, Steven Yu, Ondrej Stepanek, Arup K. Chakraborty, Arthur Weiss

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereaaw8151
JournalScience Signaling
Volume12
Issue number604
DOIs
StatePublished - 22 Oct 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2019 The Authors

Funding

We thank the Shokat laboratory at UCSF for providing the 3-IB-PP1 compound, the Palmer laboratory at the University of Basel, and the NIH tetramer core for providing pMHC. We thank B. Au-Yeung and E. Jutkiewicz for providing feedback on the manuscript. Microscopy was conducted at the UCSF Nikon Imaging Center, and cell sorting was carried out using the flow cytometry core at UCSF. We thank A. Roque for assisting with animal husbandry. A.H.C. was supported by a Robertson Foundation/Cancer Research Institute fellowship. G.G. was supported by the doctoral training program GRK1660 from the German Research Foundation (DFG). This work was supported, in part, by the Howard Hughes Medical Institute, the NIH, NIAID PO1 AI091580 (A.W. and A.K.C.), and the Czech Science Foundation, 16-09208Y (O.S.).

FundersFunder number
Robertson Foundation/Cancer Research InstituteGRK1660
National Institutes of Health
Howard Hughes Medical Institute
National Institute of Allergy and Infectious DiseasesP01AI091580
University of California, San Francisco
Universität Basel
Deutsche Forschungsgemeinschaft
Grantová Agentura České Republiky16-09208Y

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