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Keller, Baerbel; Strohmeier, Valentina; Harder, Ina; Unger, Susanne; Payne, Kathryn J.; Andrieux, Geoffroy; Boerries, Melanie; Felixberger, Peter Tobias; Landry, Jonathan J. M.; Nieters, Alexandra; Rensing-Ehl, Anne; Salzer, Ulrich; Frede, Natalie; Usadel, Susanne; Elling, Roland; Speckmann, Carsten; Hainmann, Ina; Ralph, Elizabeth; Gilmour, Kimberly; Wentink, Marjolein W. J.; Burg, Mirjam van der; Kuehn, Hye Sun; Rosenzweig, Sergio D.; Kolsch, Uwe; Bernuth, Horst von; Kaiser-Labusch, Petra; Gothe, Florian; Hambleton, Sophie; Daniel Vlagea, Alexandru; Garcia Garcia, Ana; Alsina, Laia; Markelj, Gasper; Avcin, Tadej; Vasconcelos, Julia; Guedes, Margarida; Ding, Jing-Ya; Ku, Cheng-Lung; Shadur, Bella; Avery, Danielle T.; Venhoff, Nils; Thiel, Jens; Becker, Heiko; Erazo-Borras, Lucia; Milena Trujillo-Vargas, Claudia; Luis Franco, Jose; Fieschi, Claire; Okada, Satoshi; Gray, Paul E.; Uzel, Gulbu; Casanova, Jean-Laurent; Fliegauf, Manfred; Grimbacher, Bodo; Eibel, Hermann; Ehl, Stephan; Voll, Reinhard E.; Rizzi, Marta; Stepensky, Polina; Benes, Vladimir; Ma, Cindy S.; Bossen, Claudia; Tangye, Stuart G. and Warnatz, Klaus (2021): The expansion of human T-bet(high)CD21(low) B cells is T cell dependent. In: Science Immunology, Vol. 6, No. 64, eabh0891

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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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