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

• Published in: Science immunology 2021-10, Vol.6 (64), p.eabh0891-eabh0891
• Main Authors: 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, van der Burg, Mirjam, Kuehn, Hye Sun, Rosenzweig, Sergio D, Kölsch, Uwe, von Bernuth, Horst, Kaiser-Labusch, Petra, Gothe, Florian, Hambleton, Sophie, Vlagea, Alexandru Daniel, Garcia Garcia, Ana, Alsina, Laia, Markelj, Gašper, Avcin, Tadej, Vasconcelos, Julia, Guedes, Margarida, Ding, Jing-Ya, Ku, Cheng-Lung, Shadur, Bella, Avery, Danielle T, Venhoff, Nils, Thiel, Jens, Becker, Heiko, Erazo-Borrás, Lucía, Trujillo-Vargas, Claudia Milena, Franco, José Luis, 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, Warnatz, Klaus
• Format: Article
• Language: English
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abh0891

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.