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Complementary Signaling through flt3 and Interleukin-7 Receptor Is Indispensable for Fetal and Adult B Cell Genesis

¹ Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, SE-221 84 Lund, Sweden
² Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
³ Developmental Immunology, Babraham Institute, CB2 4AT Cambridge, UK
⁴ Immunology Section, Department of Cell and Molecular Biology, University of Lund, 221 00 Lund, Sweden
⁵ Department of Paediatrics and Department of Endocrinology, Malmö University Hospital, SE 205 02 Malmö, Sweden
⁶ Ludwig Institute for Cancer Research, Heidelberg, Victoria, 3084, Australia
⁷ Amgen Corporation, Seattle, WA 98101

Address correspondence to Sten Eirik W. Jacobsen, Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, BMC 10, Klinikgatan 26, 221-84 Lund, Sweden. Phone: 46-46-2224852; Fax: 46-46-2223600; email: Sten.Jacobsen{at}stemcell.lu.se

Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7R, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7R and FL completely lack visible LNs, conventional IgM⁺ B cells, IgA⁺ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL^-/- x IL-7R^-/- BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7R^-/- mice, FL^-/- x IL-7R^-/- mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7R are indispensable for fetal and adult B cell development.

Key Words: lymphopoiesis • IL-7 receptor • Flt3 ligand • Pax5 • B1 cells

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