Research ArticleImmunology

CD45 functions as a signaling gatekeeper in T cells

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Science Signaling  22 Oct 2019:
Vol. 12, Issue 604, eaaw8151
DOI: 10.1126/scisignal.aaw8151

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T cell gatekeeper

T cells are activated by contact with antigens on the surface of antigen-presenting cells (APCs). The protein tyrosine phosphatase CD45 is necessary for both the activation and suppression of T cells upon interaction with APCs. Using a computational approach, Courtney et al. discovered that CD45 fine-tunes T cell receptor activity in response to antigen presentation, enabling receptor activation in response to strongly binding antigen, but suppressing that in response to weakly binding antigen. Thus, these findings suggest that CD45 regulates T cell activation by acting as a gatekeeper of antigen presentation, filtering out weak signals that could induce unnecessary, and potentially harmful, T cell–mediated immune responses.

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.

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