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

• Published in: The Journal of clinical investigation Vol. 124; no. 5; pp. 1966 - 1975
• Main Authors: Flies, Dallas B, Han, Xue, Higuchi, Tomoe, Zheng, Linghua, Sun, Jingwei, Ye, Jessica Jane, Chen, Lieping
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-05-2014
• Subjects: 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI74589

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.