Although absence of interleukin-7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, patients with severe combined immunodeficiency caused by mutations in the IL-7 receptor alpha... Show moreAlthough absence of interleukin-7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, patients with severe combined immunodeficiency caused by mutations in the IL-7 receptor alpha chain (IL-7R alpha) still generate peripheral blood B cells. Consequently, human B lymphopoiesis has been thought to be independent of IL-7 signaling. Using flow cytometric analysis and single-cell RNA sequencing of bone marrow samples from healthy controls and patients who are IL-7R alpha deficient, in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7R signaling plays a crucial role in human B lymphopoiesis. IL-7 drives proliferation and expansion of early B-cell progenitors but not of pre-BII large cells and has a limited role in the prevention of cell death. Furthermore, IL-7 guides cell fate decisions by enhancing the expression of BACH2, EBF1, and PAX5, which jointly orchestrate the specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of patients with IL-7R alpha deficiency still expressed myeloid-specific genes. Collectively, our results unveil a previously unknown role for IL-7 signaling in promoting the B-lymphoid fate and expanding early human B-cell progenitors while defining important differences between mice and humans. Our results have implications for hematopoietic stem cell transplantation strategies in patients with T- B+ severe combined immunodeficiency and provide insights into the role of IL-7R signaling in leukemogenesis. Show less
Korzhenevich, J.; Janowska, I.; Burg, M. van der; Rizzi, M. 2023
Early B cell development in the bone marrow ensures the replenishment of the peripheral B cell pool. Immature B cells continuously develop from hematopoietic stem cells, in a process guided by an... Show moreEarly B cell development in the bone marrow ensures the replenishment of the peripheral B cell pool. Immature B cells continuously develop from hematopoietic stem cells, in a process guided by an intricate network of transcription factors as well as chemokine and cytokine signals. Humans and mice possess somewhat similar regulatory mechanisms of B lymphopoiesis. The continuous discovery of monogenetic defects that impact early B cell development in humans substantiates the similarities and differences with B cell development in mice. These differences become relevant when targeted therapeutic approaches are used in patients; therefore, predicting potential immunological adverse events is crucial. In this review, we have provided a phenotypical classification of human and murine early progenitors and B cell stages, based on surface and intracellular protein expression. Further, we have critically compared the role of key transcription factors (Ikaros, E2A, EBF1, PAX5, and Aiolos) and chemo- or cytokine signals (FLT3, c-kit, IL-7R, and CXCR4) during homeostatic and aberrant B lymphopoiesis in both humans and mice. Show less
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... Show moreAccumulation 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(high)CD21(low) B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-gamma receptor (IFN gamma R) 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-kappa B, CD40, and IL-21 receptor or IL-12/IFN gamma/IFN gamma 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(high)CD21(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(high)CD21(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 IFN gamma signals. Thus, we identified important pathways to target autoreactive T-bet(high)CD21(low) B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression. Show less
Kalina, T.; Abraham, R.S.; Rizzi, M.; Burg, M. van der 2020
