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 cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5−CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.
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Expression array data from pDCs is available at the Gene Expression Omnibus (GEO) database under accession GSE93679. Expression array data from in vitro–generated CD4+ cells is available at the GEO database under accession GSE118951. Expression array data from ex vivo–isolated CD4+ cells is available at the GEO database under accession GSE109843. ATAC-seq data is available at the GEO database under accession GSE110017. Uncropped data for Supplementary Fig. 2g can be accessed in Supplementary Fig. 8a. All other relevant data are available from the corresponding author directly.
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The authors thank C. Kusminski and R. Gordillo for helping with the metabolic Seahorse experiments. We also thank N. Baldwin, R. Marches and especially our study subjects, healthy donors and their parents. This work was supported by NIH grants P50 AR054083-01 and U19 AIO82715 (V.P.), by the Baylor Scott & White Health Care Research Foundation and by the Drukier Institute for Children’s Health at Weill Cornell Medicine.
V.P. has received a research grant and consulting honorarium from Sanofi-Pasteur.
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Caielli, S., Veiga, D.T., Balasubramanian, P. et al. A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat Med 25, 75–81 (2019). https://doi.org/10.1038/s41591-018-0254-9
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