The expansion of human T-bethighCD21low B cells is T cell dependent
Description T cell–derived IFNγ and CD40L/IL-21R signals are crucial for the differentiation of human T-bethighCD21low B cells. The factors behind autoimmune B cells T-bethighCD21low B cells are expanded in various autoimmune disorders and infections, but it is unclear how these cells develop. Determining essential factors related to T-bethighCD21low B cell development might allow for the therapeutic inhibition of these cells and the amelioration of autoimmunity. Here, Keller et al. used RNAseq, ATACseq, and flow cytometry of T-bethighCD21low B cells and ex vivo cell culture of CD21posB cells from healthy donors to identify the factors and cells that contribute to the establishment of T-bethighCD21low B cells. Samples from patients with monogenic immunodeficiencies corroborated that the combination of the B cell receptor and T cell–derived CD40 ligand, IL-21, and IFNγ signals to control differentiation of T-bethighCD21low B cells. These developmental pathways point to potential therapeutic targets for various autoimmune disease. 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.