Immune Checkpoint Activation Targeting PD-1H (VISTA) Reinforces Human T-Cell Tolerance in Autoimmunity 2335053

Abstract

Abstract Introduction Immune checkpoints enforce tolerance, while their inhibition boosts antitumor immunity, autoimmunity may benefit from the opposite approach. Immune checkpoint activators (ICAs) offer a promising approach to restore tolerance without broad immunosuppression. PD-1H (VISTA/VSIR) is an inhibitory checkpoint on T cells and myeloid cells implicated in autoimmune regulation. Here, we investigate PD-1H activation as a strategy to suppress pathogenic T-cell responses and reinforce immune balance in autoimmunity. Methods We analyzed public single-cell RNA-seq datasets and performed flow cytometry of healthy and lupus PBMCs to assess PD-1H expression and clinical associations. An in vitro T-cell exhaustion model was employed, with PD-1H disrupted by CRISPR—Cas9. An agonistic human PD-1H monoclonal antibody (hPD-1H.ICA.1) was identified and evaluated in vitro and in vivo in humanized GvHD and lupus PDX models. Results PD-1H was upregulated on antigen-experienced T cells and sustained under chronic stimulation. PD-1H deficiency enhanced T-cell effector function and reduced PD-1+TIM-3+ exhausted subsets. Analysis of the public datasets revealed elevated PD-1H expression on renal-infiltrating T cells, exceeding other inhibitory checkpoints. Flow cytometry confirmed PD-1H+ T cells in lupus PBMCs, with expression correlating with disease activity. The hPD-1H.ICA.1 suppressed early T-cell activation, and under chronic stimulation reinforced an exhaustion-like program. In humanized GvHD models, hPD-1H.ICA.1 reduced disease severity. In lupus PDX models, hPD-1H.ICA.1 ameliorated renal pathology and selectively depleted pathogenic T-cell populations while enriching exhausted subsets. Conclusion Our findings identify PD-1H as a key checkpoint regulating chronic human T-cell responses and provide preclinical proof-of-concept that immune checkpoint activation can restore immune tolerance by enforcing exhaustion of pathogenic T cells, supporting PD-1H agonism as a promising therapeutic strategy for autoimmune disease. Funding Source This work was supported by startup funds from The Ohio State University Comprehensive Cancer Center and the College of Medicine, as well as funding from the Leukemia Research Foundation, the Cancer Research Institute, and the NIH. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)