A novel CD4+ T cell helper population in Lupus Nephritis

系统性红斑狼疮(SLE)是一种自身免疫性疾病，其特征是 对核酸的耐受性(NAS)和广泛的炎症。当核小体DNA释放时 被认为是系统性红斑狼疮自身免疫反应的重要启动者。 另一些人报告说，活的中性粒细胞可能通过以下方式参与疾病的发病 释放蛋白结合的氧化线粒体DNA(Ox MtDNA)激活浆细胞 树突状细胞(PDCs)产生干扰素(干扰素)。我们的新数据支持Ox线粒体DNA被激活 PDC使初始的CD4+T细胞分化为一种独特的表型，其特征是 类细胞因子干扰素、白介素10、PD1的高表达及细胞毒作用的上调 程序。这些细胞通过柠檬酸为燃料的反向电子转移(RET)产生mtROS 酸性代谢物琥珀酸。重要的是，它们帮助B细胞通过一种独特而新颖的 细胞因子/代谢产物组合：IL10和琥珀酸。此外，卵泡外(CXCR5neg)CD4+ 具有相似特征的T辅助细胞(Th10)在SLE患者的血液中扩增并发现 在增生性狼疮性肾炎(PLN)患者的肾小管间质区域 与B细胞相关。事实上，我们假设这些CD4+T细胞对卵泡外有贡献 自身抗体的产生和肾脏损害，它们是PLN的一个有价值的生物标志物。 在此，我们建议：1)表征SLE患者外周血中的CD4+T辅助细胞亚群 在纵向研究中，确定Th10细胞作为狼疮性肾炎生物标志物的价值； 2)为了确定Th10细胞-B细胞帮助中涉及的机制和细胞靶点，确定 独特的B细胞亚群是否对细胞因子/代谢物组合有反应 在这些条件下优先选择自身反应性B细胞；3)确定 产生琥珀酸的Th10细胞与髓系细胞的相互作用在SLE发病中的作用 发病机制。总体而言，我们预计这些研究将为以下方面提供有价值的见解 系统性红斑狼疮中的这种新的T细胞群。此外，这项工作可能会识别有用的生物标志物进行分层。 干扰Th10细胞生成/激活并最终改善其功能的新途径 我们病人的前景。

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by breakdown of tolerance to nucleic acids (NAs) and widespread inflammation. While nucleosomal DNA released from apoptotic cells is considered an important initiator of the autoimmune response in SLE, we and others have reported that live neutrophils might contribute to disease pathogenesis by releasing protein-bound oxidized mitochondrial DNA (Ox mtDNA) that activate plasmacytoid dendritic cells (pDCs) to produce Interferon (IFN). Our new data support that Ox MtDNA-activated pDCs prime and polarize naive CD4+ T cells towards a distinctive phenotype characterized by a Tr1-like cytokine profile (IFN, IL10), high expression of PD1 and the upregulation of a cytotoxic program. These cells generate mtROS through reverse electron transfer (RET) fueled by the citric acid metabolite succinate. Importantly, they help B cells through a unique and novel cytokine/metabolite combination: IL10 and succinate. Moreover, extrafollicular (CXCR5neg) CD4+ T helper cells with similar characteristics (Th10) are expanded in SLE patient’s blood and found in the tubulointerstitial areas of proliferative lupus nephritis (PLN) patients where they often associate with B cells. Indeed, we hypothesize that these CD4+ T cells contribute to extrafollicular autoantibody production and kidney damage and that they represent a valuable biomarker of PLN. Here, we propose: 1) to characterize the blood CD4+ T helper cell compartment of SLE patients and to determine, in longitudinal studies, the value of Th10 cells as a biomarker of Lupus nephritis; 2) to identify the mechanisms and cellular targets involved in Th10 cell-B cell help, determine whether unique B cell subsets respond to the cytokine/metabolite combination and whether autoreactive B cells are preferentially selected under these conditions; 3) to determine whether the interaction between succinate-producing Th10 cells and myeloid cells contributes to SLE pathogenesis. Overall, we expect that these studies will provide valuable insights into the role of this new T cell population in SLE. Furthermore, this work may identify useful biomarkers to stratify LN and new ways to interfere with Th10 cell generation/activation and ultimately improve the outlook of our patients.