PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion.
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 in which 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.
['Tinoco|Roberto|R|', 'Carrette|Florent|F|', 'Barraza|Monique L|ML|', 'Otero|Dennis C|DC|', 'Magaña|Jonathan|J|', 'Bosenberg|Marcus W|MW|', 'Swain|Susan L|SL|', 'Bradley|Linda M|LM|']
D000818:Animals D015496:CD4-Positive T-Lymphocytes D018414:CD8-Positive T-Lymphocytes D004195:Disease Models, Animal D006801:Humans D057131:Immune Evasion D007376:Interleukin-2 D008213:Lymphocyte Activation D008216:Lymphocytic Choriomeningitis D008217:Lymphocytic choriomeningitis virus D008545:Melanoma D008562:Membrane Glycoproteins D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D061026:Programmed Cell Death 1 Receptor D011948:Receptors, Antigen, T-Cell D015398:Signal Transduction
T cell exhaustion cancer P-selectin glycoprotein ligand-1 inhibitory receptors immunopathology melanoma lymphocytic choriomeningitis virus clone 13 programmed death-1