Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice.

IF 3.4 3区 医学 Q3 IMMUNOLOGY Clinical and experimental immunology Pub Date : 2024-10-21 DOI:10.1093/cei/uxae093
Tetsuro Niri, Shin-Ichi Inoue, Satoru Akazawa, Shinpei Nishikido, Masaki Miwa, Masakazu Kobayashi, Katsuyuki Yui, Minoru Okita, Atsushi Kawakami, Norio Abiru
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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.

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干扰素调节因子 4 在 NOD 小鼠自身免疫性糖尿病中调节致糖尿病 CD4+ T 细胞和先天性免疫细胞的重要作用。
转录因子干扰素调节因子 4(IRF4)的单倍体缺陷可预防 NOD 小鼠自发性糖尿病的发生。然而,IRF4介导疾病调控的免疫学机制仍不清楚。本研究旨在通过分别使用来自BDC2.5转基因(Tg)NOD小鼠和受体Rag1基因敲除NOD小鼠的供体IRF4基因缺陷CD4+ T细胞进行收养转移实验,研究IRF4在自身免疫性糖尿病发病机制中的作用。通过这种方法,我们分析了受体小鼠的临床和免疫表型。此外,我们还刺激了IRF4缺陷的BDC2.5 CD4+ T细胞,以评估它们在体外的免疫和代谢表型。研究结果表明,Irf4-/- T细胞受体完全避免了糖尿病的发生,与野生型(WT)对照组相比,Irf4+/- T细胞受体的糖尿病发病率降低了约50%,而Irf4-/- WT T细胞受体的糖尿病发病率仅有所延迟。与WT对照组相比,从Irf4+/- T细胞受体中分离出的内浸润T细胞的增殖率和IFN-γ/IL-17双阳性细胞率明显较低。与 WT 对照组相比,体外刺激的 Irf4-/- BDC2.5 CD4+ T 细胞表现出细胞分裂次数减少、抗原特异性 T 细胞标记物减少以及糖酵解能力受损。我们的结论是,IRF4主要通过介导胰岛浸润T细胞的增殖和分化,以剂量依赖性方式调节致糖尿病潜能,同时在NOD小鼠糖尿病进展的先天性免疫反应中发挥辅助作用。
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来源期刊
CiteScore
8.40
自引率
2.20%
发文量
101
审稿时长
3-8 weeks
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.
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