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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; Kölsch, U; von, Bernuth, H; Kaiser-Labusch, P; Gothe, F; Hambleton, S; Vlagea, AD; Garcia, Garcia, A; Alsina, L; Markelj, G; Avcin, T; Vasconcelos, J; Guedes, M; Ding, JY; Ku, CL; Shadur, B; Avery, DT; Venhoff, N; Thiel, J; Becker, H; Erazo-Borrás, L; Trujillo-Vargas, CM; Franco, JL; Fieschi, C; Okada, S; Gray, PE; Uzel, G; Casanova, JL; Fliegauf, M; Grimbacher, B; Eibel, H; Ehl, S; Voll, RE; Rizzi, M; Stepensky, P; Benes, V; Ma, CS; Bossen, C; Tangye, SG; Warnatz, K.
The expansion of human T-bet^highCD21^low B cells is T cell dependent.
Sci Immunol. 2021; 6(64):eabh0891 Doi: 10.1126/sciimmunol.abh0891
Web of Science PubMed FullText FullText_MUG

Co-authors Med Uni Graz: Thiel Jens
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Abstract:: 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^highCD21^low 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 CD21^low 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-bet^highCD21^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^highCD21^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 IFNγ signals. Thus, we identified important pathways to target autoreactive T-bet^highCD21^low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.
Find related publications in this database (using NLM MeSH Indexing): Adult - administration & dosage; B-Lymphocytes - immunology; Cohort Studies - administration & dosage; Female - administration & dosage; Humans - administration & dosage; Male - administration & dosage; Middle Aged - administration & dosage; Receptors, Complement 3d - immunology; T-Box Domain Proteins - immunology; T-Lymphocytes - immunology