IL-7 receptor signaling drives human B-cell precursor differentiation and expansion

Whereas absence of interleukin 7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, severe combined immunodeficiency patients with mutations in the IL-7 receptor a chain 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 of IL-7 receptor a chain-deficient patients and healthy controls in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7 receptor signaling has 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. In addition, IL-7 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 specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of IL-7Ra-deficient patients still expressed myeloid-specific genes. Collectively, our results unveil a thus-far 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-7 receptor signaling in leukemogenesis. Overall design: Sorted mononuclear cells from bone marrow of two healthy donors and two patients with IL7RA deficiency were stained with CITEseq antibodies (IL7RA, CD34, CD19 and IgM) and analyzed using scRNAseq