Journal article
PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion
Cell reports (Cambridge), v 42(5), 112436
30 May 2023
PMID: 37115668
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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•PSGL-1 restrains TCR signaling and glycolytic potential of CD8+ T cells•PSGL-1 deficiency limits CD8+ T cell exhaustion and supports precursor populations•Co-ligation of PSGL-1 and the TCR promotes T cell exhaustion in CD8+ T cells•PSGL-1 therapeutic blockade promotes T cell responses and melanoma tumor control
In this study, Hope et al. reveal intrinsic mechanisms through which the cell surface molecule PSGL-1 (P-selectin glycoprotein-1) modulates T cell responses and drives differentiation to terminal exhaustion in chronic virus infection and melanoma. Their study highlights the targetability of PSGL-1 as an emerging immune checkpoint blockade strategy.
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Details
- Title
- PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion
- Creators
- Jennifer L. Hope - Discovery InstituteDennis C. Otero - Discovery InstituteEun-Ah Bae - Discovery InstituteChristopher J. Stairiker - Discovery InstituteAshley B. Palete - Discovery InstituteHannah A. Faso - Discovery InstituteMichelle Lin - Discovery InstituteMonique L. Henriquez - Discovery InstituteSreeja Roy - Discovery InstituteHyungseok Seo - La Jolla Institute for ImmunologyXue Lei - Sanford Burnham Prebys Medical Discovery InstituteEric S. Wang - Discovery InstituteSavio Chow - Discovery InstituteRoberto Tinoco - Discovery InstituteGregory A. Daniels - UC San Diego Health SystemKevin Yip - Discovery InstituteAlexandre Rosa Campos - Discovery InstituteJun Yin - Discovery InstitutePeter D. Adams - Discovery InstituteAnjana Rao - La Jolla Institute for ImmunologyLinda M. Bradley - Discovery Institute
- Publication Details
- Cell reports (Cambridge), v 42(5), 112436
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000989369300001
- Scopus ID
- 2-s2.0-85153508853
- Other Identifier
- 991021463602204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology