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

PSGL-1 is an adhesion molecule expressed by T cells and many other hematopoietic cells. PSGL-1 binds to members of the selectin family, but this binding depends on post-translational modifications that are cell type- and context-dependent. Naïve, effector, and memory T cell migration can be regulated by PSGL-1. PSGL-1-deficiency results in enhanced proliferation of naïve T cells to homeostatic cytokines, and increased effector cytokine production by activated T cells. PSGL-1 downregulation is important for follicular T helper cell migration in germinal centers. In chronic viral infection and melanoma tumor models, PSGL-1 promotes T cell exhaustion. Ligating PSGL-1 during antigen stimulation decreases T cell receptor signals, cell survival and function, and also increases inhibitory receptor expression. P-selectin glycoprotein ligand-1 (PSGL-1) has long been studied as an adhesion molecule involved in immune cell trafficking and is recognized as a regulator of many facets of immune responses by myeloid cells. PSGL-1 also regulates T cell migration during homeostasis and inflammatory settings. However, recent findings indicate that PSGL-1 can also negatively regulate T cell function. Because T cell differentiation is finely tuned by multiple positive and negative regulatory signals that appropriately scale the magnitude of the immune response, PSGL-1 has emerged as an important checkpoint during this process. We summarize what is known regarding PSGL-1 structure and function and highlight how it may act as an immune checkpoint inhibitor in T cells. P-selectin glycoprotein ligand-1 (PSGL-1) has long been studied as an adhesion molecule involved in immune cell trafficking and is recognized as a regulator of many facets of immune responses by myeloid cells. PSGL-1 also regulates T cell migration during homeostasis and inflammatory settings. However, recent findings indicate that PSGL-1 can also negatively regulate T cell function. Because T cell differentiation is finely tuned by multiple positive and negative regulatory signals that appropriately scale the magnitude of the immune response, PSGL-1 has emerged as an important checkpoint during this process. We summarize what is known regarding PSGL-1 structure and function and highlight how it may act as an immune checkpoint inhibitor in T cells.