Type I interferon drives T cell cytotoxicity by upregulation of interferon regulatory factor 7 in autoimmune kidney diseases

In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases. A crescentic glomerulonephritis model was induced in wild-type C57BL/6 mice for 10 days. CD45⁺ cells were isolated from the spleen and blood by FACS for scRNA-seq analysis. From the kidneys of healthy wild-type C57BL/6 mice, CD3⁺ T cells were isolated by FACS for scCITE-seq analysis.

在抗中性粒细胞胞浆抗体相关性血管炎（anti-neutrophil cytoplasmic antibody-associated vasculitis, AAV）与系统性红斑狼疮（systemic lupus erythematosus, SLE）中，肾小球肾炎是一类由包括T细胞在内的免疫细胞介导的严重肾脏并发症。然而，此类疾病中T细胞激活的潜在分子机制仍尚不明确。本研究发现，在AAV与SLE患者体内，I型干扰素（type I interferon, IFN-I）可诱导T细胞分化为干扰素刺激基因表达型T细胞（interferon-stimulated genes-expressing T, ISG-T细胞），该类细胞以高表达I型干扰素特征基因、未成熟表型以及在炎症组织中具备细胞毒性为典型特征。机制层面，I型干扰素可促进T细胞内干扰素调节因子7（interferon regulatory factor 7, IRF7）的表达，进而诱导颗粒酶B（granzyme B）的产生。在小鼠模型中，阻断I型干扰素信号通路可降低T细胞内IRF7与颗粒酶B的表达水平，从而缓解肾小球肾炎的病理损伤。与此同时，对AAV或SLE患者肾脏活检组织的空间转录组学分析显示，其干扰素刺激基因特征表达上调，且ISG-T细胞与I型干扰素的主要产生细胞——浆细胞样树突状细胞（plasmacytoid dendritic cells）——紧密毗邻。综上，本研究通过患者样本与动物模型的联合分析表明，炎症组织中产生的I型干扰素可驱动ISG-T细胞分化，进而扩大自身免疫疾病中细胞毒性T细胞的功能群体。本研究将野生型C57BL/6小鼠诱导为新月体性肾小球肾炎模型，造模时长为10天。通过荧光激活细胞分选术（fluorescence-activated cell sorting, FACS）从脾脏与血液中分离CD45⁺细胞，用于单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）分析。从健康野生型C57BL/6小鼠的肾脏组织中分离CD3⁺ T细胞，通过FACS分选用于单细胞CITE-seq（scCITE-seq）分析。