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Sci Signal. 2019 Oct 22;12(604). pii: eaaw8151. doi: 10.1126/scisignal.aaw8151.

CD45 functions as a signaling gatekeeper in T cells.

Author information

1
Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. aweiss@medicine.ucsf.edu adamhc@umich.edu.
2
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Division of Molecular Immunology, Department of Internal Medicine, University Hospital Erlangen and Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
6
Howard Hughes Medical Institute (HHMI), San Francisco, CA 94143, USA.
7
Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic.
8
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9
Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
10
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
11
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.

PMID:
31641081
DOI:
10.1126/scisignal.aaw8151

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