1. PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion
- Author
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Jennifer L. Hope, Dennis C. Otero, Eun-Ah Bae, Christopher J. Stairiker, Ashley B. Palete, Hannah A. Faso, Michelle Lin, Monique L. Henriquez, Sreeja Roy, Hyungseok Seo, Xue Lei, Eric S. Wang, Savio Chow, Roberto Tinoco, Gregory A. Daniels, Kevin Yip, Alexandre Rosa Campos, Jun Yin, Peter D. Adams, Anjana Rao, and Linda M. Bradley
- Subjects
CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: 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.
- Published
- 2023
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