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. Overall design: 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.

抗中性粒细胞胞浆抗体相关血管炎（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。然而此类病理背景下T细胞活化的潜在机制仍未明确。
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细胞分化为表达干扰素刺激基因的T细胞（interferon-stimulated genes-expressing T, ISG-T），这类细胞以I型干扰素特征基因表达上调、未成熟表型以及在炎症组织中具备细胞毒性为主要特征。
机制层面，IFN-I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的产生。在小鼠模型中，阻断IFN-I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症状。
与此同时，对AAV或SLE患者肾脏活检组织的空间转录组分析显示，ISG特征基因表达上调，且ISG-T细胞与IFN-I的主要产生群体——浆细胞样树突状细胞（plasmacytoid dendritic cells）紧密邻近。
综上，我们在患者与动物模型中获得的研究结果表明，炎症组织中产生的IFN-I可驱动ISG-T细胞分化，从而扩增自身免疫疾病中的细胞毒性T细胞库。
整体实验设计：将野生型C57BL/6小鼠诱导为新月体性肾小球肾炎模型，造模周期为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，经FACS分选后用于单细胞CITE测序（single-cell indexing of transcriptomes and epitopes by sequencing, scCITE-seq）分析。