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

TitleA CD4 T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate.
Publication TypeJournal Article
Year of Publication2019
AuthorsCaielli S, Veiga DTroggian, Balasubramanian P, Athale S, Domic B, Murat E, Banchereau R, Xu Z, Chandra M, Chung C-H, Walters L, Baisch J, Wright T, Punaro M, Nassi L, Stewart K, Fuller J, Ucar D, Ueno H, Zhou J, Banchereau J, Pascual V
JournalNat Med
Date Published2019 01
KeywordsB-Lymphocytes, CD4-Positive T-Lymphocytes, Cell Proliferation, Dendritic Cells, DNA, Mitochondrial, Humans, Immunologic Memory, Interleukin-10, Lupus Erythematosus, Systemic, Lupus Nephritis, Oxidation-Reduction, Succinic Acid

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE). Follicular helper T cells (T 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 centers. Here, we describe a CXCR5CXCR3 programmed death 1 (PD1)CD4 helper T cell population distinct from T 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 ligand. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

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Alternate JournalNat. Med.
PubMed ID30478422
PubMed Central IDPMC6325012
Grant ListP50 AR054083 / AR / NIAMS NIH HHS / United States
P50 AR070594 / AR / NIAMS NIH HHS / United States
U19 AI082715 / AI / NIAID NIH HHS / United States

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