Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity

J Clin Invest. 2014 May;124(5):1966-75. doi: 10.1172/JCI74589. Epub 2014 Apr 17.


T cell activation is regulated by the interactions of surface receptors with stimulatory and inhibitory ligands. Programmed death-1 homolog (PD-1H, also called VISTA) is a member of the CD28 family of proteins and has been shown to act as a coinhibitory ligand on APCs that suppress T cell responses. Here, we determined that PD-1H functions as a coinhibitory receptor for CD4⁺ T cells. CD4⁺ T cells in mice lacking PD-1H exhibited a dramatically increased response to antigen stimulation. Furthermore, delivery of a PD-1H-specific agonist mAb directly inhibited CD4⁺ T cell activation both in vitro and in vivo, validating a coinhibitory function of PD-1H. In a murine model of acute hepatitis, administration of a PD-1H agonist mAb suppressed CD4⁺ T cell-mediated acute inflammation. PD-1H-deficient animals were highly resistant to tumor induction in a murine brain glioma model, and depletion of CD4⁺ T cells, but not CD8⁺ T cells, promoted tumor formation. Together, our findings suggest that PD-1H has potential as a target of immune modulation in the treatment of human inflammation and malignancies.

Publication types

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

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies, Monoclonal, Murine-Derived / pharmacology
  • Antigen Presentation / drug effects
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • B7 Antigens / antagonists & inhibitors
  • B7 Antigens / genetics
  • B7 Antigens / immunology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Disease Models, Animal
  • Glioma / genetics
  • Glioma / immunology
  • Glioma / pathology
  • Hepatitis / genetics
  • Hepatitis / immunology
  • Hepatitis / pathology
  • Humans
  • Immunity, Cellular*
  • Lymphocyte Activation*
  • Mice
  • Mice, Knockout


  • Antibodies, Monoclonal, Murine-Derived
  • B7 Antigens