TY - JOUR
T1 - CD45 functions as a signaling gatekeeper in T cells
AU - Courtney, Adam H.
AU - Shvets, Alexey A.
AU - Lu, Wen
AU - Griffante, Gloria
AU - Mollenauer, Marianne
AU - Horkova, Veronika
AU - Lo, Wan Lin
AU - Yu, Steven
AU - Stepanek, Ondrej
AU - Chakraborty, Arup K.
AU - Weiss, Arthur
N1 - Publisher Copyright:
Copyright © 2019 The Authors
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073762207&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aaw8151
DO - 10.1126/scisignal.aaw8151
M3 - Article
C2 - 31641081
AN - SCOPUS:85073762207
SN - 1945-0877
VL - 12
JO - Science Signaling
JF - Science Signaling
IS - 604
M1 - eaaw8151
ER -