期刊
NATURE MEDICINE
卷 25, 期 1, 页码 75-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0254-9
关键词
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资金
- NIH [P50 AR054083-01, U19 AIO82715]
- Baylor Scott & White Health Care Research Foundation
- Drukier Institute for Children's Health at Weill Cornell Medicine
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 (T-FH 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(2). Here, we describe a CXCR5(-)CXCR3(+) programmed death 1 (PD1)(hi)CD4(+) helper T cell population distinct from T-FH 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(3). Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.
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