The Earliest Step in B Lineage Differentiation from Common Lymphoid Progenitors Is Critically Dependent upon Interleukin 7

Abstract

Little is known about the signals that promote early B lineage differentiation from common lymphoid progenitors (CLPs). Using a stromal-free culture system, we show that interleukin (IL)-7 is sufficient to promote the in vitro differentiation of CLPs into B220+ CD19+ B lineage progenitors. Consistent with current models of early B cell development, surface expression of B220 was initiated before CD19 and was accompanied by the loss of T lineage potential. To address whether IL-7 receptor (R) activity is essential for early B lineage development in vivo, we examined the frequencies of CLPs and downstream pre–pro- and pro-B cells in adult mice lacking either the α chain or the common gamma chain (γc) of the IL-7R. The data indicate that although γc −/− mice have normal frequencies of CLPs, both γc −/− and IL-7Rα−/− mice lack detectable numbers of all downstream early B lineage precursors, including pre–pro-B cells. These findings challenge previous notions regarding the point in B cell development affected by the loss of IL-7R signaling and suggest that IL-7 plays a key and requisite role during the earliest phases of B cell development.

B cells and aging: Balancing the homeostatic equation

“…Age related changes in bone marrow B cell commitment and development include declines in the frequency of precursors, lowered expression of key genes, reductions in pro-and pre-B cell compartments, and attenuated responsiveness to differentiation factors (Frasca, Nguyen et al 2004;Labrie, Sah et al 2004;Miller, Izon et al 2002;Riley, Kruger et al 1991;Sherwood, Xu et al 2000;Stephan, Reilly et al 1998;Stephan, Sanders et al 1996;Szabo, Shen et al 2003). Overall, these findings suggest reductions in the generation and throughput of B cell progenitors.…”

Impaired B‐1 and B‐2 B cell development and atypical splenic B cell structures in IL‐7 receptor‐deficient mice

“…FL were collected from 15-dpc embryos, and single-cell suspensions were prepared using conventional techniques. Cells were stained at 10Â10 6 cells/ml using the following mAb, in addition to those previously described [41]: FITC anti-CD43 (S7); PE anti-CD19 (1D3); PE anti-CD25 (PC61); FITC anti-IgM (R6-60.2); PE or biotin anti-CD23 (B3B4) and FITC anti-CD21 (7G3) (BD BioSciences); R-PE anti-IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and FITC anti-IgM (Southern Biotechnology Ass, Inc.); Cy5 anti-IgM (Jackson Immuno Research). Biotinylated mAb were revealed using PE (BD BioSciences), Tricolor (Caltag) or QuantumRed (Sigma).…”

“…It has been reported that BM B cell development is blocked at the generation of CD19 + cells in adult IL-7R -/-mice [7][8][9]. While other studies on adult IL-7R -/-mice have confirmed impairment in B cell development, they differ as to the developmental stage at which this occurs [10][11][12]. As with IL-7R -/-mice, adult IL-7 -/-mice also show arrest at the generation of CD19 + BM B cells [13].…”

Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage

“…The loss of either the IL-7 receptor alpha (IL-7R␣) chain or the IL-7 ligand also results in a complete block in adult B lymphopoiesis at the prepro-B cell stage, with either modest or no reduction in the numbers of CLP being present in IL-7 knockout animals (21)(22)(23)(24). In IL-7R␣Ϫ or IL-7-deficient mice, E2A proteins are expressed at wild-type levels and yet Ebf1 and Pax5 are absent, which suggests that other factors participate in Ebf1 induction in addition to E2A, that E2A requires posttranslational modification to activate Ebf1 expression, or that inhibitory proteins suppress the ability of E2A to activate Ebf1 expression in this context (23)(24)(25).…”