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，其特征在于 对核酸（NAs）的耐受性和广泛的炎症。当核小体DNA释放时 从凋亡细胞被认为是一个重要的启动系统性红斑狼疮的自身免疫反应，我们 和其他人已经报道，活的中性粒细胞可能通过以下方式促进疾病的发病机制： 释放蛋白质结合的氧化线粒体DNA（Ox mtDNA）， 树突状细胞（pDC）产生干扰素（IFN）。我们的新数据支持牛MtDNA激活 pDCs将初始和未免疫的CD 4 + T细胞导向一种独特的表型，其特征在于 Tr 1样细胞因子谱（IFN γ，IL 10），PD 1的高表达和细胞毒性因子的上调 程序.这些细胞通过由柠檬酸提供燃料的反向电子转移（RET）产生mtROS。 酸性代谢产物琥珀酸。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/代谢物组合：IL 10和琥珀酸。此外，滤泡外（CXCR 5阴性）CD 4 + 具有相似特征的辅助性T细胞（Th 10）在SLE患者的血液中扩增， 在增生性狼疮肾炎（PLN）患者的肾小管间质区域， 与B细胞结合。事实上，我们假设这些CD 4 + T细胞有助于滤泡外 自身抗体产生和肾损伤，它们代表PLN的有价值的生物标志物。 在这里，我们提出：1）描述SLE患者血液中的CD 4 + T辅助细胞区室 并在纵向研究中确定Th 10细胞作为狼疮性肾炎生物标志物的价值; 2)为了确定参与Th 10细胞-B细胞帮助的机制和细胞靶点，确定 独特的B细胞亚群是否对细胞因子/代谢物组合有应答，以及 在这些条件下优先选择自身反应性B细胞; 3）确定是否 产生琥珀酸的Th 10细胞和髓样细胞之间的相互作用有助于SLE 发病机制总的来说，我们希望这些研究将提供有价值的见解， 这种新的T细胞群。此外，这项工作可能会发现有用的生物标志物分层 LN和干扰Th 10细胞生成/活化并最终改善免疫功能的新方法 我们的病人的前景。

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.