As an alternative to mitophagy, neutrophils spontaneously extrude mitochondrial (mt) DNA devoid of oxidized residues (Ox). Activated lupus neutrophils or healthy neutrophils treated with IFN/αRNP release ox-mtDNA bound to TFAM, which induces high levels of IFN-α in pDCs.

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) 1 . Follicular helper T cells (Tfh) have long been implicated in SLE pathogenesis. Yet, a fraction of SLE patients’ autoantibodies are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers (GCs) 2 . Here, we describe a CXCR5 − CXCR3 + PD1 hi CD4 + T cell helper population distinct from Tfh and expanded in both SLE blood and the tubulointerstitial areas of patients with Proliferative Lupus Nephritis (PLN). These cells produce IL10 and accumulate mitochondrial ROS (mtROS) as the result of reverse electron transport (RET) fueled by succinate. Furthermore, they provide B cell help, independently of IL21, through IL10 and succinate. Similar cells are generated in vitro upon priming naïve CD4 + T cells with plasmacytoid DCs (pDCs) activated with Oxidized mitochondrial DNA (Ox mtDNA), a distinct class of interferogenic TLR9 ligand 3 . Targetting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

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