| Literature DB >> 34623902 |
Baerbel Keller1,2, Valentina Strohmeier1,2,3, Ina Harder1,2, Susanne Unger1,2, Kathryn J Payne4, Geoffroy Andrieux5,6,7, Melanie Boerries5,6,7, Peter Tobias Felixberger1,2, Jonathan J M Landry8, Alexandra Nieters9,10, Anne Rensing-Ehl9, Ulrich Salzer1,2, Natalie Frede1, Susanne Usadel11, Roland Elling9,12, Carsten Speckmann9,13, Ina Hainmann14, Elizabeth Ralph15, Kimberly Gilmour15, Marjolein W J Wentink16, Mirjam van der Burg17, Hye Sun Kuehn18, Sergio D Rosenzweig18, Uwe Kölsch19, Horst von Bernuth19,20,21, Petra Kaiser-Labusch22, Florian Gothe23,24, Sophie Hambleton23,25, Alexandru Daniel Vlagea26,27, Ana Garcia Garcia27,28,29, Laia Alsina27,28,29,30, Gašper Markelj31, Tadej Avcin31, Julia Vasconcelos32, Margarida Guedes33, Jing-Ya Ding34, Cheng-Lung Ku34,35, Bella Shadur4,36,37, Danielle T Avery4, Nils Venhoff1, Jens Thiel1, Heiko Becker6,38, Lucía Erazo-Borrás39, Claudia Milena Trujillo-Vargas40, José Luis Franco40, Claire Fieschi41,42, Satoshi Okada43, Paul E Gray44, Gulbu Uzel45, Jean-Laurent Casanova46,47,48,49, Manfred Fliegauf9,50, Bodo Grimbacher9,50,51,52, Hermann Eibel1,2, Stephan Ehl9, Reinhard E Voll1,2, Marta Rizzi1, Polina Stepensky36, Vladimir Benes5, Cindy S Ma4,37, Claudia Bossen2, Stuart G Tangye4,37, Klaus Warnatz1,2.
Abstract
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.Entities:
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Year: 2021 PMID： 34623902 DOI： 10.1126/sciimmunol.abh0891
Source DB: PubMed Journal: Sci Immunol ISSN： 2470-9468