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

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 inhib-itor 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 func-tion. This outcome is coupled to an increased abundance of CD8+ T cell stem cell-like progenitors that main-tain 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.

Automated summary

PSGL-1 is a T cell-intrinsic checkpoint regulator that acts upstream of PD-1 and requires co-ligation with the TCR to attenuate T cell activation and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. Deficiency of PSGL-1 empowers CD8+ T cells to respond to low-affinity TCR ligands and inhibit the growth of PD-1-blockade-resistant melanoma.