PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion

Abstract

Summary Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1) that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+ T cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling, and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer where T cell dysfunction occurs, PSGL-1-deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology, and also functions to regulate T cell responses in the tumor microenvironment.

PSGL-1: A New Player in the Immune Checkpoint Landscape

“…Mechanistically, we found that engaging PSGL-1 with anti-PSGL-1 antibody (clone 4RA10) paired with TCR stimulation resulted in ERK and AKT early dephosphorylation, indicating that PSGL-1 signaling can extinguish TCR signaling events [67]. These findings are consistent with inhibitory receptors like PD-1 mediating T cell exhaustion through dampening TCR signals [98, 99], however how PSGL-1 signaling contributes to this is unknown (Figure 4C).…”

“…Interestingly, one report showed that Selplg −/− mice had increased numbers of T cell effectors producing IFN-γ, IL-4, and IL-17 in skin, corresponding to Th1, Th2, and Th17 populations, but no differences in Tregs [86]. This spontaneous autoimmune phenotype was not reported in other studies [23, 67, 70] indicating that potential microbiota and/or strain differences may modulate effector responses in Selplg −/− animals.…”

“…PSGL-1 also becomes excluded from the immune synapse on T cells, and then localizes to the uropod, suggesting that PSGL-1 would not influence TCR signaling. However, we found reduced TCR signaling via the downstream ERK and AKT pathways when PSGL-1 was cross-linked with antibody at the time of TCR stimulation [67] (Figure 3, Key Figure). While it is possible that crosslinking PSGL-1 prevents optimal formation of the synapse, additional studies on the localization of PSGL-1 in T cells are needed to resolve the intracellular binding-partners and mechanisms of signaling.…”

“…Indeed, Selplg −/− CD8 + T cells were shown to be hyper-responsive to high concentrations of the homeostatic cytokines IL-2, IL-4, and IL-15 in vitro but this was not observed for Selplg −/− CD4 + T cells [70]. Selplg −/− CD8 + T cells also displayed greater turnover at steady state, suggesting that they could increase in number over time; however this increase was not observed in aged Selplg −/− mice [67]. Thus, it is conceivable that naïve Selplg −/− CD8 + T cells are more susceptible to apoptosis in vivo .…”

“…We found that virus-specific CD8 + T cells upregulated PSGL-1 in infected tissues after chronic LCMV Cl13 infection and that the majority of CD8 + T cells expressed PSGL-1 that was not terminally glycosylated, leaving the molecule available to engage other ligands independently of selectin binding. The negative regulatory function of PSGL-1 was revealed in Selplg −/− mice only after infection with LCMV Cl13 [67]. These mice had an accumulation of virus-specific CD4 + and CD8 + T cells in lymphoid and non-lymphoid tissues due to enhanced survival.…”