Murine and Human IL-7 Activate STAT5 and Induce Proliferation of Normal Human Pro-B Cells

Johnson, Sonja E.; Shah, Nisha; Panoskaltsis‐Mortari, Angela; LeBien, Tucker W.

doi:10.4049/jimmunol.175.11.7325

Cited by 70 publications

(72 citation statements)

References 55 publications

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“…S2A). This is in agreement with the kinetics for the burst of conventional B-lineage development from fresh CB SCs or CLPs in other systems (17,18). Indeed, fresh CB CLPs (CD34 + CD10 int CD19 − ) developed into an early-B-committed intermediate (CD10 high CD19 − ) (11) and 45 ± 7% pro-B (CD10 high CD19 + ) cells after 21 days (yield of 146.3 ± 15-fold initial seeded cells) (Fig.…”

Section: Cd19supporting

confidence: 71%

“…The time kinetic was optimized here to enable visualization of pre/pro-B, CLP/early-B, and pro-B cells, the CD34 + progenitors that were undetectable in prior reports (15)(16)(17)(18). Although, many CD34 int cells lose CD34 expression between the ninth and 11th generations, this CD34 − progeny subset was only approximately one-fifth of cells in 10-day cultures and it included an ∼25% pre-B-cell fraction (Fig.…”

Section: Cd19mentioning

confidence: 99%

“…Development of the latter CD34 − pre-B cells and their B-cell and Ig-secreting plasma cell progeny can be reconstituted after coculture of purified CD34 + Lineage − (Lin − ) progenitors with bone marrow (BM) stroma lines (e.g., S17) (15)(16)(17)(18).…”

mentioning

confidence: 99%

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Ordering human CD34⁺CD10⁻CD19⁺pre/pro-B-cell and CD19⁻common lymphoid progenitor stages in two pro-B-cell development pathways

Sanz

Muñoz-A.

Monserrat

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Studies here respond to two long-standing questions: Are human "pre/pro-B" CD34 + CD10 − CD19 + and "common lymphoid progenitor (CLP)/early-B" CD34 + CD10 + CD19 − alternate precursors to "pro-B" CD34 + CD19 + CD10 + cells, and do the pro-B cells that arise from these progenitors belong to the same or distinct B-cell development pathways? Using flow cytometry, gene expression profiling, and Ig V H -D-J H sequencing, we monitor the initial 10 generations of development of sorted cord blood CD34 high Lineage − pluripotential progenitors growing in bone marrow S17 stroma cocultures. We show that (i) multipotent progenitors (CD34 + CD45RA + CD10 − CD19 − ) directly generate an initial wave of Pax5 + TdT − "unilineage" pre/ pro-B cells and a later wave of "multilineage" CLP/early-B cells and (ii) the cells generated in these successive stages act as precursors for distinct pro-B cells through two independent layered pathways. Studies by others have tracked the origin of B-lineage leukemias in elderly mice to the mouse B-1a pre/pro-B lineage, which lacks the TdT activity that diversifies the V H -D-J H Ig heavy chain joints found in the early-B or B-2 lineage. Here, we show a similar divergence in human B-cell development pathways between the Pax5 + TdT − pre/ pro-B differentiation pathway that gives rise to infant B-lineage leukemias and the early-B pathway. Ordered stages in the current human model are termed the "common lymphoid progenitor" (CLP) and the "early-B," "progenitor-B," and "precursor-B" subsets that follow it (i.e., SC → CLP → early-B → pro-B → pre-B → B) (5). In this pathway, CLP and early-B stages, which both express the CD34 + CD45RA + CD10 + CD19 − surface phenotype, are actually "multilineage" progenitors of B, T, dendritic (DC), and natural killer (NK) cells (5, 10-12).Pro-B cells, which retain CD34 and CD10 expression but also express CD19 (CD34 + CD10 + CD19 + ), constitute the first Pax-5 + committed B-lineage stage, which is followed by pre-B (CD34 − CD10 + CD19 + ) cells that have ceased expression of CD34 and now express the surface μH-VpreB-λ5/CD79 surrogate Ig receptor complex (1-5, 13-15). Development of the latter CD34 − pre-B cells and their B-cell and Ig-secreting plasma cell progeny can be reconstituted after coculture of purified CD34 + Lineage − (Lin − ) progenitors with bone marrow (BM) stroma lines (e.g., S17) (15-18).Before the CLP subset and the above developmental pathway were recognized, a subset called "pre/pro-B," which expresses the CD34 + CD10 − CD19 + surface phenotype, was commonly considered to be the first human B-lineage stage (19). It occurs in fetal liver, fetal bone marrow (FBM), and umbilical cord blood (CB) (19-21). An FBM pre/pro-B cell stage was shown to distinctively lack TdT and to bear CD7 unlike concurrent conventional CD10 + CD19 − B-cell progenitors, leading to the idea that these cells might belong to a distinct B lineage (20). This lack of TdT-mediated "N-nucleotide additions" between D and J H segments is further associated with differential V-D-J gene...

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Section: Cd19supporting

confidence: 71%

Section: Cd19mentioning

confidence: 99%

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Ordering human CD34⁺CD10⁻CD19⁺pre/pro-B-cell and CD19⁻common lymphoid progenitor stages in two pro-B-cell development pathways

Sanz

Muñoz-A.

Monserrat

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…1,20,21 Signal transduction initiated by IL-7 and its downstream effectors is essential for the expansion and differentiation of B-cell precursors. 22,23 In this study, we present evidence that LPS-induced signals via TLR4 crosstalk with IL-7 signals have a profound influence on early B-cell development.…”

Section: Synergism Of Lps and Il-7 Signals In The Promotion Of Pre-bcmentioning

confidence: 92%

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

Han

Wang

et al. 2013

Cell Mol Immunol

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Lipopolysaccharide (LPS) is known to be a potent activator of mature B cells by signaling through Toll-like receptor 4 (TLR4). Its impact on early B-cell development, however, is not well defined. When comparing to C3H/HeN mice, TLR4-mutant C3H/HeJ mice showed an increase in the number of pro-B and pre-B cells in the bone marrow. When cultured in the presence of IL-7, the proliferation of pro-B and large pre-B cells was significantly inhibited by LPS, possibly due to reduced IL-7 receptor-a (IL-7Ra) expression. Meanwhile, the generation of IgM 1 /IgD 1 B cells was greatly enhanced in IL-7 cultures of pro-B and pre-B cells. Consistent with these results, treatment with LPS facilitated the progression of adoptively transferred B220 1 IgM 2 IgD 2 precursors into IgD 1 cells. Overall, these data suggest that LPS has a profound influence on early B-cell development, which may contribute to the deregulated B-cell development under physiological and pathological conditions such as bacterial infections.

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“…The differential pattern of STAT activation by IL-21 and IL-15 in CLL cells is consistent with the opposite biologic effects of these cytokines. Thus, STAT5 activation by IL-15 may be related to its mitogenic activity, since pSTAT5 is known to induce cyclin D2 expression and mitogenic effects in lymphoid cells, [57][58][59] and STAT5 is required for lymphoid cell development. 60 Conversely, STAT1 activation has been linked to apoptosis in lymphoid 61 as well as in other cell types.…”

Section: Discussionmentioning

confidence: 99%

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Totero

Meazza

Capaia

et al. 2008

Blood

108

103

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The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common ␥ chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and pre- IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in adults, is characterized by the progressive accumulation of CD5 ϩ neoplastic B cells, 1-3 which results from a dynamic balance between cell death and proliferation. 3,4 The finding that purified CLL cells do not proliferate and tend to undergo spontaneous apoptosis in vitro suggests that factors inducing CLL cell survival and proliferation might be present in the microenvironment of lymphoid organs or of the bone marrow. 5,6 Several cytokines such as the TNF family members BAFF and APRIL, 7,8 the chemokine SDF-1, 9,10 and interleukin-2 (IL-2) 11,12 and IL-15 13 stimulate CLL cell proliferation and/or survival in vitro. IL-2 and IL-15 share the usage of the IL-2R␤ (CD122) and of the common ␥ chain (␥ c ; CD132) 14,15 and thus have similar functional effects on IL-2R␤/␥ c ϩ cells. 16,17 The IL-2R␤ and ␥ c chains signal through the JAK1 and JAK3 tyrosine kinases, which activate downstream STAT pathways. 18,19 In addition to the IL-2R␤/␥ c complex, specific 21 molecules are required for high-affinity binding of each cytokine. Unlike IL-2R␣, IL-15R␣ is a high-affinity receptor also when expressed as an isolated chain, and is present on both lymphoid and nonlymphoid cell types. 20,21 IL-15R␣ is crucial for IL-15 activity, since both IL-15-and IL-15R␣-deficient mice display similar defects in the development of natural killer (NK) cells, of intraepithelial T lymphocytes, and of CD8 ϩ memory-type T cells. 22,23 IL-15 gene is expressed in several tissues, and IL-15 can be either secreted in low amounts or displayed as a membrane-bound cytokine by several cell types. [24][25][26][27][28] Therefore IL-15 is considered a microenvironmental factor, which supports lymphoid cell homeostasis and survival. 29-31 IL-15 is a growth or survival factor not only for CLL cells 13 but also for cells of other lymphoid neoplasias, 32-34 at least in vitro. Moreover, in IL-15-transgenic mice, IL-15 overexpression induces fatal T or NK lymphoproliferative disorders. 35 We and others recently demonstrated that IL-21, the last identified member of the IL-2 family, 36-38 is unable to trigger CLL cell proliferation, but rather induces their apoptosis. 39,40 This effect is potentiated by cell activation with CD40L, 39 with CpG synthetic oligonucleotides, or by BCR cross-linking. 40 IL-21 induces the JAK1 and JAK3 and the STAT1, STAT3, and STAT5 tyrosine phosphorylation in CLL B cells. 39 Similar early signaling events are also activated by IL-21, IL-2, or IL-1...

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Murine and Human IL-7 Activate STAT5 and Induce Proliferation of Normal Human Pro-B Cells

Cited by 70 publications

References 55 publications

Ordering human CD34⁺CD10⁻CD19⁺pre/pro-B-cell and CD19⁻common lymphoid progenitor stages in two pro-B-cell development pathways

Ordering human CD34⁺CD10⁻CD19⁺pre/pro-B-cell and CD19⁻common lymphoid progenitor stages in two pro-B-cell development pathways

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

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Murine and Human IL-7 Activate STAT5 and Induce Proliferation of Normal Human Pro-B Cells

Cited by 70 publications

References 55 publications

Ordering human CD34+CD10−CD19+pre/pro-B-cell and CD19−common lymphoid progenitor stages in two pro-B-cell development pathways

Ordering human CD34+CD10−CD19+pre/pro-B-cell and CD19−common lymphoid progenitor stages in two pro-B-cell development pathways

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

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Ordering human CD34⁺CD10⁻CD19⁺pre/pro-B-cell and CD19⁻common lymphoid progenitor stages in two pro-B-cell development pathways

Ordering human CD34⁺CD10⁻CD19⁺pre/pro-B-cell and CD19⁻common lymphoid progenitor stages in two pro-B-cell development pathways