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.

Division of Molecular Immunology Department of Internal Medicine University Hospital Erlangen and Friedrich Alexander University of Erlangen Nürnberg 91054 Erlangen Germany

Howard Hughes Medical Institute San Francisco CA 94143 USA

Institute for Medical Engineering and Science Massachusetts Institute of Technology Cambridge MA 02139 USA

Institute for Medical Engineering and Science Massachusetts Institute of Technology Cambridge MA 02139 USA Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA Department of Physics Massachusetts Institute of Technology Cambridge MA 02139 USA Ragon Institute of Massachusetts General Hospital Massachusetts Institute of Technology and Harvard University Cambridge MA 02139 USA Department of Chemistry Massachusetts Institute of Technology Cambridge MA 02139 USA

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

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

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 Department of Pharmacology University of Michigan Ann Arbor MI 48109 USA

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 Howard Hughes Medical Institute San Francisco CA 94143 USA

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