IL-7 receptor signaling drives human B-cell progenitor differentiation and expansion.
Fabian Marc Philipp Kaiser, Iga Janowska, Roberta Menafra, Melanie de Gier, Jakov Korzhenevich, Ingrid Pico-Knijnenburg, Indu Khatri, Ansgar S Schulz, Taco W Kuijpers, Arjan C Lankester, Lukas Konstantinidis, Miriam Erlacher, Susan L Kloet, Pauline A van Schouwenburg, Marta Rizzi, Mirjam van der Burg
Blood 2023 Jun 27Whereas 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 α 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 α 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-7Rα-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.Copyright © 2023 American Society of Hematology.
Citation
Fabian Marc Philipp Kaiser, Iga Janowska, Roberta Menafra, Melanie de Gier, Jakov Korzhenevich, Ingrid Pico-Knijnenburg, Indu Khatri, Ansgar S Schulz, Taco W Kuijpers, Arjan C Lankester, Lukas Konstantinidis, Miriam Erlacher, Susan L Kloet, Pauline A van Schouwenburg, Marta Rizzi, Mirjam van der Burg. IL-7 receptor signaling drives human B-cell progenitor differentiation and expansion. Blood. 2023 Jun 27
PMID: 37369082
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