FLT3 ligand and not TSLP is the key regulator of IL-7–independent B-1 and B-2 B lymphopoiesis

Jensen, Christina T.; Kharazi, Shabnam; Böiers, Charlotta; Cheng, Min; Lübking, Anna; Sitnicka, Ewa; Jacobsen, Sten Eirik W.

doi:10.1182/blood-2008-04-150508

Cited by 46 publications

(40 citation statements)

References 35 publications

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“…Few molecules have been reported to act in such a way, with IL-7 and IL-7R being the prototypical examples (26). Because Flt3 (also called FLK2) signal can compensate IL-7 signal in the fetal liver, B lymphopoiesis is independent of IL-7 in the fetal liver, which is indispensable for that in bone marrow (27,28). However, no study has shown that fetal and adult NK cell development is regulated by distinct cytokine signal or transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Y Chromosome–Linked B and NK Cell Deficiency in Mice

Sun

Horino

Itoh-Nakadai

et al. 2013

The Journal of Immunology

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There are no primary immunodeficiency diseases linked to the Y chromosome, because the Y chromosome does not contain any vital genes. We have established a novel mouse strain in which all males lack B and NK cells and have Peyer’s patch defects. By 10 wk of age, 100% of the males had evident immunodeficiencies. Mating these immunodeficient males with wild-type females on two different genetic backgrounds for several generations demonstrated that the immunodeficiency is linked to the Y chromosome and is inherited in a Mendelian fashion. Although multicolor fluorescence in situ hybridization analysis showed that the Y chromosome in the mutant male mice was one third shorter than that in wild-type males, exome sequencing did not identify any significant gene mutations. The precise molecular mechanisms are still unknown. Bone marrow chimeric analyses demonstrated that an intrinsic abnormality in bone marrow hematopoietic cells causes the B and NK cell defects. Interestingly, fetal liver cells transplanted from the mutant male mice reconstituted B and NK cells in lymphocyte-deficient Il2rg−/− recipient mice, whereas adult bone marrow transplants did not. Transducing the EBF gene, a master transcription factor for B cell development, into mutant hematopoietic progenitor cells rescued B cell but not NK cell development both in vitro and in vivo. These Y chromosome–linked immunodeficient mice, which have preferential B and NK cell defects, may be a useful model of lymphocyte development.

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Section: Discussionmentioning

confidence: 99%

Y Chromosome–Linked B and NK Cell Deficiency in Mice

Sun

Horino

Itoh-Nakadai

et al. 2013

The Journal of Immunology

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“…We do not exclude the possibility, however, that TSLP or IL-7 in combination with other growth factors are able to induce proliferation of HSC, but this remains to be addressed. In the absence of IL-7R-mediated signaling, a vital role for FLT3L has been implicated to drive mouse fetal B-cell development [7,39]. The importance of FLT3L has not been directly tested in human, but it might explain why severe combined immune-deficient patients with IL-7R deficiency appear to have normal B-cell numbers [2,40,41].…”

Section: Discussionmentioning

confidence: 99%

Thymic stromal lymphopoietin induces early human B‐cell proliferation and differentiation

et al. 2010

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Thymic stromal lymphopoietin (TSLP) is a cytokine that binds the IL-7-receptor-a chain and a unique TSLP receptor (TSLPR) chain. The role of TSLP in human B-cell development has not been elucidated. We show that TSLPR transcripts are expressed most prominently in CD341 cells from fetal liver and BM. In general, cell surface expression of TSLPR was low, except on a subset of multilineage-commited progenitor cells. TSLP induced the tyrosine-phosphorylation of STAT5 and the proliferation of multilineage-commited progenitor cells, pro-B cells and pre-B cells. Compared with IL-7, the levels of proliferation after stimulation of the B-cell progenitors with TSLP were lower. Expression of the BCR on the cell surface of fetal cells was inversely correlated to TSLP or IL-7 responsiveness. Pre-B cells from fetal BM, but not fetal liver, were refractory to TSLP or IL-7 stimulation. When employing an in vitro B-cell differentiation culture system starting from CD34 1 CD38À multipotent HSC, IL-7 induced a short wave of precursor cell expansion but did not result in long-term survival of mature B cells. TSLP was capable of increasing the proportion and the absolute numbers of more mature human B cells. Overall, we provide evidence that TSLP supports human B-cell differentiation from fetal hematopoietic progenitors.Key words: Fetal . Human B-cell development . IL-7 . Thymic stromal lymphopoietin Supporting Information available online IntroductionHuman immunodeficiencies have uncovered the key role of cytokine signaling pathways in lymphocyte development.Patients suffering from X-linked SCID (X-SCID), which is caused by a loss of function mutation in the common g (Cg) chain, or patients with defective IL-7-receptor-a (IL-7Ra) chain expression, are accompanied by severely diminished T-lymphopoiesis but apparently normal B-cell numbers [1,2]. This has raised the suggestion that in humans, B-cell development is IL-7 independent. In contrast, in mice, IL-7 is a major cytokine involved in B-cell development, since both IL-7-deficient and IL-7Ra-deficient mice showed a profound block at an early stage of B-cell development, i.e. at the pro-B cell to pre-B cell transition [1,[3][4][5]. Interestingly, fetal and early postnatal B-lymphopoiesis in the mouse have been described to be largely driven by IL-7-independent mechanisms [3,5,6]. It has been proposed that thymic stromal lymphopoietin (TSLP) acts as a primary regulator of IL-7-independent fetal B-lymphopoiesis [7,8]. This, together with the fact that B-cell development in SCID patients has been analyzed only in infants, questions the importance of TSLP during fetal human B-cell genesis. TSLP and IL-7 have overlapping biological activities, although they are not homologous [9]. Both IL-7 and TSLP signal via a [10,11]. A common downstream event of both IL-7 and TSLP-induced signaling is the tyrosine phosphorylation of the transcription factor STAT5 [13], which then translocates to the nucleus where it initiates transcription of target genes. Most cytokine receptors, including the re...

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“…IL-7Ra 2/2 mice have been previously shown to be defective in adult pro-B and pre-B cell development but have normal pre-pro-B development (13,14). Overexpression of TSLP can induce the expansion of progenitor B cells in the bone marrow (15); however, TSLPR 2/2 mice have no reported defect in B cell development (16), suggesting it has a nonessential role in normal B cell development. There are three conserved tyrosines in the cytoplasmic domain of IL-7Ra found in all mammals.…”

mentioning

confidence: 97%

The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449

Patton

Plumb

Abraham

2014

The Journal of Immunology

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IL-7 is critical for murine T and B cell development and survival and plays a significant role in lymphoblastic leukemia in both humans and mice. We evaluated the role of the IL-7Rα Tyr449 cytoplasmic SH2-binding motif in IL-7–mediated B cell development using a knock-in mouse with a Tyr to Phe mutation (IL-7Rα449F/449F mouse). IL-7Rα449F/449F and IL-7Rα−/− mice showed no defect in the number of pre–pro-B cells, although IL-7Rα449F/449F mice had decreased Ebf1 in pre–pro-B cells and impairment in B cell–committed CLPs. We identified that IL-7Rα Tyr449 was critical for both pro-B and pre-B stages of development in the bone marrow. IL-7Rα449F/449F and IL-7Rα−/− mice had comparable precursor B cell defects, indicating that signaling from the IL-7Rα required this motif. Although the defect in IL-7Rα449F/449F pro-B cells was associated with loss of STAT5 activation and diminished expression of Mcl1, this was not rescued by overexpression of Bcl-2. IL-7Rα449F/449F and IL-7Rα−/− pre-B cells also showed defective cyto-Igμ and CD25 expression, associated with reduced levels of Rag1, Rag2, and Irf4. Pre-B cells from IL-7Rα449F/449F mice also failed to proliferate, perhaps as a result of the failure to rearrange Igμ. Our data suggest that IL-7Rα Tyr449 was essential for IL-7Rα signaling in bone marrow B cell development and survival.

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FLT3 ligand and not TSLP is the key regulator of IL-7–independent B-1 and B-2 B lymphopoiesis

Cited by 46 publications

References 35 publications

Y Chromosome–Linked B and NK Cell Deficiency in Mice

Y Chromosome–Linked B and NK Cell Deficiency in Mice

Thymic stromal lymphopoietin induces early human B‐cell proliferation and differentiation

The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449

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