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 2

PD-1H inhibits antigen-specific CD4+ T cell responses in vitro.

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PD-1H inhibits antigen-specific CD4+ T cell responses in vitro. OT-II+...
OT-II+/+ and OT-II–/– T cells were evaluated for response to antigen. (A) Expression of PD-1H on naive OT-II+/+ T cells (white) and OT-II–/– T cells (gray). (B–F) Purified PD-1H–/– or PD-1H+/+ OT-II T cells were added to 96-well plates with irradiated PD-1H–KO splenocytes. Proliferation was assessed at specific peptide concentration (B) and at specific time points (C). Supernatants from proliferation assays were assessed for cytokines at specific peptide concentrations (D) and at time points using 0.5 μg/ml OVA peptide (E). (F) Proliferation was assessed in the presence of 2 μg/ml of PD-1H mAb or mouse Ig. (G) Irradiated WT APCs or PD1H KO APCs were cultured with either OT-II+/+ or OT-II–/– T cells and analyzed for proliferation. (H and I) Naive purified OT-II+/+ T cells were adoptively transferred (i.v.) on day –1 to PD-1H–KO recipient mice. OVA and polyI:C were injected on day 0 with either mouse Ig or anti–PD-1H. OT-II T cell numbers (H) and activation (I) as determined by CD44 expression were assessed on day 3. (J and K) Naive OT-II+/+ or OT-II–/– T cells were purified and identical numbers were transferred (i.v.) on day –1 to PD-1H–KO mice. OVA and polyI:C were injected on day 0. Mice bled at indicated time points were analyzed for percentage of OT-II T cells of total CD4+ T cells (J) and PD-1H expression (K). All experiments were repeated a minimum of 3 times. *P < 0.05.