CD45 functions as a signaling gatekeeper in T cells

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.

CD8+ Tregs revisited: A heterogeneous population with different phenotypes and properties

“…CD45RC is an isoform of a transmembrane protein tyrosine phosphatase, CD45, which regulates the TCR signaling in both positive and negative manners [100, 101]. Notably, CD45RC marker is variably expressed on CD8 + T cells of humans and rats, but not mice [102, 103].…”

CD45 pre-exclusion from the tips of microvilli establishes a phosphatase-free zone for early TCR triggering

“…While its cytoplasmic domain, including the catalytic domain, shares 95% homology among mammalian species, the highly glycosylated extracellular domain, which includes several splicing variants, shares only 35% homology (Thomas, 1989). CD45 is known to be critical for restraining the adaptive T cell response by negatively regulating T cell receptor (TCR) signaling, unless the T cell encounters a high-affinity cognate antigen (Courtney et al, 2019;Sibener et al, 2018).…”

MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

“…The receptor protein tyrosine phosphatase CD45 constitutes a key positive regulator as it dephosphorylates inhibitory phospho-tyrosines of Lck. However, it may also act as a negative regulator through dephosphorylation of CD3ζ, suggesting that it contributes to tuning of TCR signals in response to antigen [ 4 ]. Calcineurin, in response to increased Ca 2+ levels, dephosphorylates, and thereby induces nuclear translocation of NFAT transcription factors [ 5 ].…”