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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 Article has an altmetric score of 33

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

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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 6

Resistance to GL261 tumor growth in PD-1H–KO mice is mediated by CD4+ T cell immunity.

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Resistance to GL261 tumor growth in PD-1H–KO mice is mediated by CD4+ T ...
3 × 105 GL261-luc tumor cells were injected into the left hemisphere of the brains of PD-1H–KO or WT mice. Mice were treated with a total dose of 4 Gy radiotherapy of the whole brain on day 5 after tumor inoculation. (A) Ten days after radiotherapy, splenocytes and brain lymphocytes were isolated and restimulated with irradiated GL261 cells for 5 days. Percentages of IFN-γ–producing CD4+ T cells of total CD4+ T cells (left panels) or IFN-γ–producing CD8+ T cells of total CD8+ T cells (middle panels) were detected by intracellular staining. IFN-γ levels in culture supernatant were detected by CBA (right panels). One point indicates the result from 1 mouse (n = 6). Naive mice (n = 2) without tumor inoculation were used as negative control. (B) CD4+ T cells or CD8+ T cells were depleted by i.p. injection of anti-CD4 (GK1.5) or anti-CD8a (53-6.72) antibody at 500 μg every 5 to 7 days from 5 days before tumor inoculation. Survival of mice was monitored daily up to 50 days (n = 5). *P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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