CD45 functions as a signaling gatekeeper in T cells

Courtney AH, Shvets AA, Lu W, Griffante G, Mollenauer M, Horkova V, Lo WL, Yu S, Stepanek O, Chakraborty AK, Weiss A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Science Signaling American Association for the Advancement of Science

Book Volume: 12

Journal Issue: 604

DOI: 10.1126/scisignal.aaw8151

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 ζ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ζ-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.

Involved external institutions

University of California San Francisco (UCSF) US United States (USA) (US) Howard Hughes Medical Institute US United States (USA) (US) Institute of Molecular Genetics of the ASCR / Ústav molekulární genetiky AV ČR CZ Czech Republic (CZ) Massachusetts Institute of Technology (MIT) US United States (USA) (US)

How to cite

APA:

Courtney, A.H., Shvets, A.A., Lu, W., Griffante, G., Mollenauer, M., Horkova, V.,... Weiss, A. (2019). CD45 functions as a signaling gatekeeper in T cells. Science Signaling, 12(604). https://dx.doi.org/10.1126/scisignal.aaw8151

MLA:

Courtney, Adam H., et al. "CD45 functions as a signaling gatekeeper in T cells." Science Signaling 12.604 (2019).

BibTeX: Download