PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion
Copyright policy )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.
- Yale University United States
- University of Massachusetts Medical School United States
- University of California, San Diego United States
- University of California, San Diego United States
- University of California, San Francisco United States
CD4-Positive T-Lymphocytes, 1.1 Normal biological development and functioning, Knockout, Oncology and Carcinogenesis, Immunology, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, 610, CD8-Positive T-Lymphocytes, Lymphocytic Choriomeningitis, Inbred C57BL, Lymphocyte Activation, Mice, Clinical Research, Receptors, melanoma, 2.1 Biological and endogenous factors, cancer, immunopathology, Animals, Humans, Lymphocytic choriomeningitis virus, Melanoma, Cancer, programmed death-1, Immune Evasion, T cell exhaustion, Mice, Knockout, Membrane Glycoproteins, Biomedical and Clinical Sciences, Animal, T-Cell, lymphocytic choriomeningitis virus clone 13, Mice, Inbred C57BL, Disease Models, Animal, inhibitory receptors, Antigen, Disease Models, Interleukin-2, Immunotherapy, Infection, P-selectin glycoprotein ligand-1, Signal Transduction
CD4-Positive T-Lymphocytes, 1.1 Normal biological development and functioning, Knockout, Oncology and Carcinogenesis, Immunology, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, 610, CD8-Positive T-Lymphocytes, Lymphocytic Choriomeningitis, Inbred C57BL, Lymphocyte Activation, Mice, Clinical Research, Receptors, melanoma, 2.1 Biological and endogenous factors, cancer, immunopathology, Animals, Humans, Lymphocytic choriomeningitis virus, Melanoma, Cancer, programmed death-1, Immune Evasion, T cell exhaustion, Mice, Knockout, Membrane Glycoproteins, Biomedical and Clinical Sciences, Animal, T-Cell, lymphocytic choriomeningitis virus clone 13, Mice, Inbred C57BL, Disease Models, Animal, inhibitory receptors, Antigen, Disease Models, Interleukin-2, Immunotherapy, Infection, P-selectin glycoprotein ligand-1, Signal Transduction
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