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
