Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell–mediated immunity
Dallas B. Flies, Xue Han, Tomoe Higuchi, Linghua Zheng, Jingwei Sun, Jessica Jane Ye, Lieping Chen
Dallas B. Flies, Xue Han, Tomoe Higuchi, Linghua Zheng, Jingwei Sun, Jessica Jane Ye, Lieping Chen
View: Text | PDF
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

×

Figure 1

Analysis of CD4+ T cells in PD-1H–deficient mice.

Options: View larger image (or click on image) Download as PowerPoint
Analysis of CD4+ T cells in PD-1H–deficient mice. (A) Total cell numbe...
(A) Total cell numbers calculated in the spleen and liver of 4-, 8-, 16-, and 36-week-old PD-1H–KO mice and WT littermates. (B) Absolute CD4+ cell numbers were determined by total cell count multiplied by percentage of total cells/100 as determined by flow cytometry. (C) CD44+CD62L– and CD44+CD62L+ populations were determined as a percentage of CD4+ T cells at 4 and 36 weeks in both the spleen and liver. 5 to 6 mice were analyzed per group at each time point. PD-1H–deficient CD4+ T cell proliferation and cytokine production are enhanced in vitro. 96-well plates were coated overnight with anti-CD3 mAb, and purified CD4+ T cells were added to the wells. Plates were pulsed overnight with 3-HTdR thymidine. (D) Proliferation of PD-1H–KO or WT CD4+ T cells at serial dilutions of anti-CD3 was determined at 96 hours. Other time points were similar. (E) Proliferation at an anti-CD3 mAb of 0.63 μg/ml is shown at 24, 48, 72, and 96 hours. (F and G) Supernatants were harvested from 96-well proliferation plates at 24, 48, 72, and 96 hours and analyzed for IFN-γ, IL-17A, and TNF-α. In F, cytokine concentrations at 96 hours are shown at serial dilutions of anti-CD3 mAb. In E, cytokine concentrations are shown at 24, 48, 72 and 96 hours at a single anti-CD3 concentration. All experiments were repeated at least 3 times in triplicate. *P < 0.05.