Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 64, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abh0891
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Funding
- German Research Foundation [TRR130 TP07, WA 1597/4-2, TRR130 TP1, SFB1160/2 Z02]
- German Federal Ministry of Education and Research BMBF [01EO1303]
- BMBF Netzwerke Seltener Erkrankungen [GAIN_01GM1910A]
- National Health and Medical Research Council of Australia
- New South Wales Government
- NIHR BRC at Great Ormond Street Hospital
- Boehringer Ingelheim Stiftung Exploration Grant
- BMBF Netzwerke Seltener Erkrankungen [GAIN_01GM1910A]
- German Research Foundation RESIST-EXC 2155 [390874280, SFB1160/2_B5, GR1617/14-1/iPAD]
- German Research Foundation CIBSS-EXC-2189 [390939984]
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The accumulation of CD21(low) B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The transcription factor T-bet plays a prominent role in the regulation of T-bet(high)CD21(low) B cells, and essential signals such as BCR and IFN gamma R are crucial for the differentiation and expansion of these cells. Identification of important pathways provides potential targets for auto-reactive T-bet(high)CD21(low) B cells in autoimmune conditions.
Accumulation of human CD21(low) B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21(low) B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bet(high)CD21(low) B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-gamma receptor (IFN gamma R) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21(low) B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-kappa B, CD40, and IL-21 receptor or IL-12/IFN gamma/IFN gamma receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell-derived signals in the in vivo expansion of T-bet(high)CD21(low) B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21(low) B cell proportions. The expansion of human T-bet(high)CD21(low) B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFN gamma signals. Thus, we identified important pathways to target autoreactive T-bet(high)CD21(low) B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.
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