The expansion of human T-bethighCD21low B cells is T cell dependent

Baerbel Keller*, Valentina Strohmeier, Ina Harder, Susanne Unger, Kathryn J. Payne, Geoffroy Andrieux, Melanie Boerries, Peter Tobias Felixberger, Jonathan J.M. Landry, Alexandra Nieters, Anne Rensing-Ehl, Ulrich Salzer, Natalie Frede, Susanne Usadel, Roland Elling, Carsten Speckmann, Ina Hainmann, Elizabeth Ralph, Kimberly Gilmour, Marjolein W.J. WentinkMirjam van der Burg, Hye Sun Kuehn, Sergio D. Rosenzweig, Uwe Kölsch, Horst von Bernuth, Petra Kaiser-Labusch, Florian Gothe, Sophie Hambleton, Alexandru Daniel Vlagea, Ana Garcia Garcia, Laia Alsina, Gašper Markelj, Tadej Avcin, Julia Vasconcelos, Margarida Guedes, Jing Ya Ding, Cheng Lung Ku, Bella Shadur, Danielle T. Avery, Nils Venhoff, Jens Thiel, Heiko Becker, Lucía Erazo-Borrás, Claudia Milena Trujillo-Vargas, José Luis Franco, Claire Fieschi, Satoshi Okada, Paul E. Gray, Gulbu Uzel, Jean Laurent Casanova, Manfred Fliegauf, Bodo Grimbacher, Hermann Eibel, Stephan Ehl, Reinhard E. Voll, Marta Rizzi, Polina Stepensky, Vladimir Benes, Cindy S. Ma, Claudia Bossen, Stuart G. Tangye, Klaus Warnatz*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

90 Scopus citations

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.

Original languageEnglish
Article numbereabh0891
JournalScience Immunology
Volume6
Issue number64
DOIs
StatePublished - 2021

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