{"title":"Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice.","authors":"Tetsuro Niri, Shin-Ichi Inoue, Satoru Akazawa, Shinpei Nishikido, Masaki Miwa, Masakazu Kobayashi, Katsuyuki Yui, Minoru Okita, Atsushi Kawakami, Norio Abiru","doi":"10.1093/cei/uxae093","DOIUrl":null,"url":null,"abstract":"<p><p>Haploinsufficiency of the transcription factor interferon-regulatory factor 4 (IRF4) prevents the onset of spontaneous diabetes in NOD mice. However, the immunological mechanisms of the IRF4-mediated disease regulation remain unclear. This study aims to investigate the role of IRF4 in the pathogenesis of autoimmune diabetes by conducting adoptive transfer experiments using donor IRF4 gene-deficient CD4+ T cells from BDC2.5-transgenic (Tg) NOD mice and recipient Rag1-knockout NOD mice, respectively. Through this approach, we analyzed both clinical and immunological phenotypes of the recipient mice. Additionally, IRF4-deficient BDC2.5 CD4+ T cells were stimulated to assess their immunological and metabolic phenotypes in vitro. The findings revealed that diabetes was completely prevented in the recipients with Irf4-/- T cells and was approximately 50% lower in those with Irf4+/- T cells than in wild type (WT) controls, whereas Irf4-/- recipients with WT T cells only showed a delayed onset of diabetes. Islet-infiltrating T cells isolated from recipients with Irf4+/- T cells exhibited significantly lower proliferation and IFN-γ/IL-17 double-positive cell fraction rates compared with those in WT controls. Irf4-/- BDC2.5 CD4+ T cells stimulated in vitro showed a reduced number of cell divisions, decreased antigen-specific T-cell markers, and impairment of glycolytic capacity compared with those observed in WT controls. We concluded that IRF4 predominantly regulates the diabetogenic potential in a dose-dependent manner by mediating the proliferation and differentiation of islet-infiltrating T cells while playing an adjunctive role in the innate immune responses toward diabetes progression in NOD mice.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and experimental immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/cei/uxae093","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Haploinsufficiency of the transcription factor interferon-regulatory factor 4 (IRF4) prevents the onset of spontaneous diabetes in NOD mice. However, the immunological mechanisms of the IRF4-mediated disease regulation remain unclear. This study aims to investigate the role of IRF4 in the pathogenesis of autoimmune diabetes by conducting adoptive transfer experiments using donor IRF4 gene-deficient CD4+ T cells from BDC2.5-transgenic (Tg) NOD mice and recipient Rag1-knockout NOD mice, respectively. Through this approach, we analyzed both clinical and immunological phenotypes of the recipient mice. Additionally, IRF4-deficient BDC2.5 CD4+ T cells were stimulated to assess their immunological and metabolic phenotypes in vitro. The findings revealed that diabetes was completely prevented in the recipients with Irf4-/- T cells and was approximately 50% lower in those with Irf4+/- T cells than in wild type (WT) controls, whereas Irf4-/- recipients with WT T cells only showed a delayed onset of diabetes. Islet-infiltrating T cells isolated from recipients with Irf4+/- T cells exhibited significantly lower proliferation and IFN-γ/IL-17 double-positive cell fraction rates compared with those in WT controls. Irf4-/- BDC2.5 CD4+ T cells stimulated in vitro showed a reduced number of cell divisions, decreased antigen-specific T-cell markers, and impairment of glycolytic capacity compared with those observed in WT controls. We concluded that IRF4 predominantly regulates the diabetogenic potential in a dose-dependent manner by mediating the proliferation and differentiation of islet-infiltrating T cells while playing an adjunctive role in the innate immune responses toward diabetes progression in NOD mice.
期刊介绍:
Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice.
The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.