Permissive roles of cytokines interleukin-7 and Flt3 ligand in mouse B-cell lineage commitment

Significance The generation of different blood lineages is regulated by hematopoietic cytokines, either in an instructive or in a permissive manner. The cytokines Interleukin-7 and fms-like tyrosine kinase-3 (Flt3) ligand are required for B-cell development but their precise mode of action remains controversial. Our study has addressed the role of these cytokines in B-cell commitment by analyzing the progenitor stage where B-cell commitment occurs in mice overexpressing one of the two cytokines in the absence of the other. Our results demonstrate a permissive role for both cytokines in B-cell commitment. Interleukin-7 promotes survival of progenitors instead of up-regulation of B-cell commitment factors early B-cell factor 1 (Ebf1) and paired box 5 (Pax5), as previously hypothesized, whereas Flt3 ligand facilitates progenitor expansion by inducing their proliferation. Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence. However, their precise role in regulating B-cell commitment has been the subject of debate. In the present study we assessed the rescue of B-cell commitment in mice lacking IL-7 but simultaneously overexpressing FL. Results obtained demonstrate that FL overexpression in IL-7–deficient mice rescues B-cell commitment, resulting in significant Ebf1 and Pax5 expression in Ly6D+CD135+CD127+CD19− precursors and subsequent generation of normal numbers of CD19+ B-cell progenitors, therefore indicating that IL-7 can be dispensable for commitment to the B-cell lineage. Further analysis of Ly6D+CD135+CD127+CD19− progenitors in IL-7– or FL-deficient mice overexpressing Bcl2, as well as in IL-7 transgenic mice suggests that both FL and IL-7 regulate B-cell commitment in a permissive manner: FL by inducing proliferation of Ly6D+CD135+CD127+CD19− progenitors and IL-7 by providing survival signals to these progenitors.

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