title: PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion.
abstract: 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.
authors.affiliation: Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tinoco
authors.affiliation: Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA.
authors.forename: Florent
authors.initials: F
authors.lastname: Carrette
authors.affiliation: Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA.
authors.forename: Monique L
authors.initials: ML
authors.lastname: Barraza
authors.affiliation: Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Otero
authors.affiliation: Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Magaña
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Swain
authors.affiliation: Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA. Electronic address: lbradley@sbpdiscovery.org.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bradley
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D057131:Immune Evasion; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007376:Interleukin-2; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell
keywords: P-selectin glycoprotein ligand-1; T cell exhaustion; cancer; immunopathology; inhibitory receptors; lymphocytic choriomeningitis virus clone 13; melanoma; programmed death-1