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Lookup NU author(s): Dr Florian Gothe,
Professor Sophie HambletonORCiD
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Copyright © 2021 The Authors,Accumulation of human CD21low 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 CD21low 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-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) 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 CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ 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-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low 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 IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.
Author(s): Keller B, Strohmeier V, Harder I, Unger S, Payne KJ, Andrieux G, Boerries M, Felixberger PT, Landry JJM, Nieters A, Rensing-Ehl A, Salzer U, Frede N, Usadel S, Elling R, Speckmann C, Hainmann I, Ralph E, Gilmour K, Wentink MWJ, van der Burg M, Kuehn HS, Rosenzweig SD, Kolsch U, von Bernuth H, Kaiser-Labusch P, Gothe F, Hambleton S, Vlagea AD, Garcia AG, Alsina L, Markelj G, Avcin T, Vasconcelos J, Guedes M, Ding J-Y, Ku C-L, Shadur B, Avery DT, Venhoff N, Thiel J, Becker H, Erazo-Borras L, Trujillo-Vargas CM, Franco JL, Fieschi C, Okada S, Gray PE, Uzel G, Casanova J-L, Fliegauf M, Grimbacher B, Eibel H, Ehl S, Voll RE, Rizzi M, Stepensky P, Benes V, Ma CS, Bossen C, Tangye SG, Warnatz K
Publication type: Article
Publication status: Published
Journal: Science Immunology
Online publication date: 01/10/2021
Acceptance date: 25/08/2021
ISSN (electronic): 2470-9468
Publisher: American Association for the Advancement of Science
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