A novel CD4+ T cell helper population in Lupus Nephritis

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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.