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PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion

Cited 0 time in Web of Science Cited 5 time in Scopus
Authors

Hope, Jennifer L.; Otero, Dennis C.; Bae, Eun-Ah; Stairiker, Christopher J.; Palete, Ashley B.; Faso, Hannah A.; Lin, Michelle; Henriquez, Monique L.; Roy, Sreeja; Seo, Hyungseok; Lei, Xue; Wang, Eric S.; Chow, Savio; Tinoco, Roberto; Daniels, Gregory A.; Yip, Kevin; Campos, Alexandre Rosa; Yin, Jun; Adams, Peter D.; Rao, Anjana; Bradley, Linda M.

Issue Date
2023-05
Publisher
Cell Press
Citation
Cell Reports, Vol.42 No.5, p. 112436
Abstract
PSGL-1 (P-selectin glycoprotein-1) is a T cell-intrinsic checkpoint regulator of exhaustion with an unknown mechanism of action. Here, we show that PSGL-1 acts upstream of PD-1 and requires co-ligation with the T cell receptor (TCR) to attenuate activation of mouse and human CD8+ T cells and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. PSGL-1 deficiency empowers CD8+ T cells to respond to low-affinity TCR ligands and inhibit growth of PD-1-blockade-resistant melanoma by enabling tumor-infiltrating T cells to sustain an elevated metabolic gene signature supportive of increased glycolysis and glucose uptake to promote effector function. This outcome is coupled to an increased abundance of CD8+ T cell stem cell-like progenitors that maintain effector functions. Additionally, pharmacologic blockade of PSGL-1 curtails T cell exhaustion, indicating that PSGL-1 represents an immunotherapeutic target for PD-1-blockade-resistant tumors.
ISSN
2211-1247
URI
https://hdl.handle.net/10371/195805
DOI
https://doi.org/10.1016/j.celrep.2023.112436
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Research Area Gene Signalling, Immunology, Transcriptional Networking

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