Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell–mediated immunity
Dallas B. Flies, … , Jessica Jane Ye, Lieping Chen
Dallas B. Flies, … , Jessica Jane Ye, Lieping Chen
Published April 17, 2014
Citation Information: J Clin Invest. 2014;124(5):1966-1975. https://doi.org/10.1172/JCI74589.
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Research Article

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

Abstract

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.

Authors

Dallas B. Flies, Xue Han, Tomoe Higuchi, Linghua Zheng, Jingwei Sun, Jessica Jane Ye, Lieping Chen

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Figure 4

PD-1H expression on hematopoietic cells regulates the severity of acute Con A–induced hepatitis.

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PD-1H expression on hematopoietic cells regulates the severity of acute ...
(A) Depiction of BM chimeric models for the Con A hepatitis experiments and analysis of chimerism in blood for CD4+ and CD8+ T cell reconstitution at 3 weeks. (B) Chimeric mice were bled 3 weeks after reconstitution, and CD4+ and CD8+ percentages were determined. (C) Rag-1–KO mice adoptively transferred with either PD-1H–KO or WT TCD-BM and injected with 15 mg/kg Con A were bled at 3 hours for analysis of serum cytokine levels as indicated. (D) As in C, liver lymphocytes were stained with anti-CD4 and anti-NK1.1 to determine absolute cell numbers in liver. (E) PD-1H–KO mice reconstituted with PD-1H–KO or WT TCD-BM were injected (i.v.) with 15 mg/kg of Con A and bled at 2, 5, and 24 hours for analysis of serum ALT concentrations. (F) As in C, serum at the 2- hour time point was analyzed for cytokines. *P < 0.05.