PD-1H Signaling in the Regulation of the Tissue Immune Microenvironment of Lupus

About This Grant

SUMMARY Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by systemic immune dysregulation, with lupus nephritis (LN) being one of its most severe manifestations. While systemic immune abnormalities in lupus are well recognized, the immune landscape within lupus-affected tissues remains poorly characterized, and the role of immune checkpoint-mediated regulation in autoimmune microenvironments is a critical yet largely unexamined frontier. PD-1H (Programmed Death-1 Homolog, also known as VISTA) is a unique immune checkpoint expressed on both T cells and myeloid cells, functioning as a key regulator of immune suppression. Our preliminary studies reveal that PD-1H deficiency leads to spontaneous autoimmunity resembling lupus, and PD-1H is upregulated in lupus-affected tissues, suggesting its critical role in local immune regulation. These findings set the stage for investigating how PD-1H regulates immune pathogenesis in lupus and evaluating PD-1H-targeted immune checkpoint activators (ICAs) as a novel therapeutic approach. Aim 1 will determine the role and mechanisms of PD-1H signaling in the regulation of pathogenesis in the lupus affected tissue microenvironment. We hypothesize that PD-1H functions as a checkpoint receptor on pathogenic T cells and anti-inflammatory macrophages, mitigating inflammation and reducing tissue damage. To test this, we will (1) map the spatial distribution of PD-1H in kidney and skin biopsies from lupus patients using multiplex immunofluorescence and spatial transcriptomics and (2) determine how PD-1H regulates immune infiltration and modulates pathogenic immune activity using induced lupus models in tissue-specific PD-1H- deficient mice. Furthermore, our preliminary studies reveal that PD-1H interacts with key kinases in T cell receptor (TCR) signaling. We hypothesize that this interaction mediates PD-1H’s inhibitory effects on T cell activation, which we will test using structural mutants, co-immunoprecipitation assays, and phosphor-proteomics- based analyses to map PD-1H-regulated signaling networks in lupus pathogenesis. Aim 2 will Develop Novel Therapeutic Strategies for Lupus Using PD-1H Immune Checkpoint Activator (ICA). We will assess the efficacy of mouse PD-1H ICA in lupus and LN models, performing functional assays to determine its impact on T cell suppression and macrophage modulation. To advance these findings toward clinical translation, we will evaluate the effects of a newly developed human PD-1H ICA in a lupus patient-derived xenograft (PDX) model. These studies will establish PD-1H ICA as a novel strategy to modulate autoimmune pathogenesis while preserving immune homeostasis. This project integrates mechanistic studies with innovative therapeutic strategies to establish PD-1H as an essential regulator of lupus pathogenesis. These findings will not only reshape our understanding of immune regulation in lupus but also provide a foundation for developing next-generation immune checkpoint-targeted therapies for autoimmune diseases.