A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate

Abstract

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.

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

“…By contrast, Caielli et al showed that CXCR3 + Tph cells in SLE patients expressed high IL-10, IFN-γ, and succinate, but no IL-21 or CXCL13, and provided help to B cells in a manner dependent on IL-10 and succinate [61]. The study also showed that the frequency of CXCR3 + Tph cells in the blood was significantly lower in patients with class III and IV nephritis than patients without, and lupus nephritis tissues showed abundant T cells expressing IL-10 adjacent to B cells [61]. Collectively, these observations suggest that Tph cells also contribute to the increase of CD11c + DN B cells in SLE, yet the mechanism might vary among heterogeneous Tph subsets.…”

“…For example, in inflamed synovial tissues in rheumatoid arthritis, CD4 + T cells that lack CXCR5 but express PD-1 hi and CCR2 (named peripheral helper T cells: Tph) induce memory B cells to differentiate into ASCs in a manner dependent on IL-21 and ICOS [59]. Recent studies showed an increase of CXCR5 − PD-1 hi Tph cells expressing CXCR3 in the blood of active SLE patients [60,61]. Similar to Tph cells in inflamed synovial tissues in rheumatoid arthritis, Lin et al showed that the blood Tph cells in SLE expressed high IL-21 and IFN-γ, and the frequency in the blood correlated with disease activity [60].…”

“…Similar to Tph cells in inflamed synovial tissues in rheumatoid arthritis, Lin et al showed that the blood Tph cells in SLE expressed high IL-21 and IFN-γ, and the frequency in the blood correlated with disease activity [60]. By contrast, Caielli et al showed that CXCR3 + Tph cells in SLE patients expressed high IL-10, IFN-γ, and succinate, but no IL-21 or CXCL13, and provided help to B cells in a manner dependent on IL-10 and succinate [61]. The study also showed that the frequency of CXCR3 + Tph cells in the blood was significantly lower in patients with class III and IV nephritis than patients without, and lupus nephritis tissues showed abundant T cells expressing IL-10 adjacent to B cells [61].…”

IL‐10 induces MC3T3‐E1 cells differentiation towards osteoblastic fate in murine model

“…However, the lack of knowledge on the mechanisms underlying MC3T3‐E1 differentiation continues to hinder the progress of MC3T3‐E1‐based therapies for bone regeneration. IL‐10 has profound and indispensable functional effects on infection, inflammation, tissue homeostasis, autoimmunity and cancer . In recent years, the IL‐10 family have been shown to regulate arthritis, suggesting potential effects on osteoblast differentiation.…”

Immune cell metabolism in autoimmunity

“…Succinate is largely used by OXPHOS, which has a reduced activity in the T cells of RA patients and in other autoimmune diseases [74]. A recent study found, in a small subset of CD4 + CXCR3 + CXCR5 -PD-1 hi , T cells in the blood of SLE patients who have increased ROS due to reverse ETC regulated by succinate [75]. A recent study found, in a small subset of CD4 + CXCR3 + CXCR5 -PD-1 hi , T cells in the blood of SLE patients who have increased ROS due to reverse ETC regulated by succinate [75].…”