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

Immunity. 2016 May 17;44(5):1190-203. doi: 10.1016/j.immuni.2016.04.015.

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.

Keywords: P-selectin glycoprotein ligand-1; T cell exhaustion; cancer; immunopathology; inhibitory receptors; lymphocytic choriomeningitis virus clone 13; melanoma; programmed death-1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Disease Models, Animal
  • Humans
  • Immune Evasion
  • Interleukin-2 / metabolism
  • Lymphocyte Activation
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology*
  • Melanoma / immunology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction

Substances

  • Interleukin-2
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell