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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-05, Vol.44 (5), p.1190-1203
• Main Authors: Tinoco, Roberto, Carrette, Florent, Barraza, Monique L., Otero, Dennis C., Magaña, Jonathan, Bosenberg, Marcus W., Swain, Susan L., Bradley, Linda M.
• Format: Article
• Language: English
• Subjects: Animals; Cancer; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cytokines; Disease Models, Animal; Flow cytometry; Humans; Immune Evasion; immunopathology; Infections; inhibitory receptors; Interleukin-2 - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus - immunology; lymphocytic choriomeningitis virus clone 13; Melanoma; Melanoma - immunology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; P-selectin glycoprotein ligand-1; Pathology; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; programmed death-1; Receptors, Antigen, T-Cell - metabolism; Rodents; Signal Transduction; Software; Spleen; T cell exhaustion; T cell receptors; Tumors; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.04.015

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. [Display omitted] •T cell survival was increased in Selplg−/− mice after chronic virus infection•Multi-functional anti-viral T cells in Selplg−/− mice promoted viral control•Ligating PSGL-1 on exhausted CD8+ T cells silenced TCR signals•PSGL-1-deficiency enhanced T cell anti-tumor immunity to melanoma PSGL-1 is an adhesion molecule known to be important for migration of hematopoietic cells. Bradley and colleagues show that PSGL-1 on T cells dampens TCR signals, limits survival of effector T cells, and promotes immune inhibitory receptor expression, thereby supporting establishment of exhaustion in viral and tumor models.