IL7‐hCD25 and IL7‐Cre BAC transgenic mouse lines: New tools for analysis of IL‐7 expressing cells

Repass, John; Laurent, Micheline N.; Carter, Carla; Reizis, Boris; Bedford, Mark T.; Cardenas, Kim; Narang, Priyanka; Coles, Mark; Richie, Ellen R.

doi:10.1002/dvg.20497

Cited by 73 publications

(71 citation statements)

References 30 publications

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“…In these mice [22], the pattern of transgene expression was similar to our IL-7GCDL mouse. However, an unresolved issue remains why hCD25 mRNA is expressed at higher levels than IL-7 mRNA in the liver [22]. In contrast, our IL-7GCDL mouse shows hardly any luciferase activity in the liver, which is in agreement with a recent report showing that steady-state IL-7 production in the liver is low [8].…”

Section: Il-7supporting

confidence: 63%

“…These observations suggest that fluorescent proteins are not suitable to reliably visualize the relatively weak activity of the Il7 promoter. However, this sensitivity problem was overcome by two other BAC-transgenic IL-7 reporter mice, expressing either hCD25 or Cre instead of fluorescent proteins [22]. In these mice [22], the pattern of transgene expression was similar to our IL-7GCDL mouse.…”

mentioning

confidence: 85%

“…However, this sensitivity problem was overcome by two other BAC-transgenic IL-7 reporter mice, expressing either hCD25 or Cre instead of fluorescent proteins [22]. In these mice [22], the pattern of transgene expression was similar to our IL-7GCDL mouse. However, an unresolved issue remains why hCD25 mRNA is expressed at higher levels than IL-7 mRNA in the liver [22].…”

mentioning

confidence: 85%

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Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

et al. 2010

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IL-7 is a major regulator of lymphocyte homeostasis; however, little is known about the mechanisms that regulate IL-7 production. To study Il7 gene regulation in vivo, we generated a novel IL-7-reporter mouse, which allows the non-invasive quantification of Il7 gene activity in live mice and, additionally, the simultaneous activation/inactivation of target genes in IL-7-producing cells. With these IL-7-reporter mice, we identify thymus, skin and intestine as major sources of IL-7 in vivo. Importantly, we show that IFN-c and the commensal microflora promote steady-state IL-7 production in the intestine. Furthermore, we demonstrate that the blockade of IFN-c signaling in intestinal epithelial cells strongly reduces their IFN-c-driven IL-7 production. In summary, our data suggest a feedback loop in which commensal bacteria drive IFN-c production by lymphocytes, which in turn promotes epithelial cell IL-7 production and the survival of IL-7-dependent lymphocytes.Key words: Commensal microflora . IFN-c . IL-7 . Intestinal epithelial cells Supporting Information available onlineIntroduction IL-7 is a central regulator of immune cell development and homeostasis. The tight regulation of IL-7 availability is crucial for host survival. For instance, the lack of IL-7 leads to severe immunodeficiency [1] while its overexpression causes aberrant T-cell activation [2] and autoimmunity [3][4][5].For a long time, it was believed that lymphoid tissues are the major sources of IL-7 in the body. IL-7 expression was detected in thymus, bone marrow and lymph nodes and it was assumed that IL-7 production is constant and largely unaffected by external stimuli [6,7]. However, recent reports challenged this view demonstrating that Il7 gene activity is differentially regulated in hepatocytes and lymphoid stroma cells [8,9]. Despite its central importance for host survival, the mechanisms regulating IL-7 production in vivo are largely unknown.A better understanding of these mechanisms is hampered by the fact that the visualization and isolation of IL-7-producing cells by immunohistochemistry is sometimes difficult to achieve [10,11]. To circumvent this problem and define the impact of IL-7-producing cells on immune regulation, we have generated a bacterial artificial chromosome (BAC)-transgenic IL-7 reporter mouse that allows the non-invasive visualization of Il7 gene expression in live mice via bioluminescent imaging and the Eur. J. Immunol. 2010. 40: 2391-2400 DOI 10.1002 HIGHLIGHTS 2391Frontline simultaneous, Cre-mediated manipulation of target genes in IL-7-producing cells. With the help of this novel IL-7 reporter mouse, we identify thymus, skin and intestine as major sources of IL-7 in the body. In the steady state, the commensal microflora and IFN-g promote Il7 gene activity in intestinal epithelial cells (IEC). This can be blocked by the anti-inflammatory drug dexamethasone (Dex), which directly interferes with IFN-g signaling in IEC. Since IL-7 promotes T-cell survival and function, our data suggest that commensal-driven IFN-g p...

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Section: Il-7supporting

confidence: 63%

mentioning

confidence: 85%

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confidence: 85%

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Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

et al. 2010

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“…Several reports, including our own, have shown that IL-7 is predominantly produced by TECs within the thymus (13)(14)(15)(16). Using IL-7 reporter transgenic mice, in which YFP expression identifies a subset of TECs that coexpress high levels of Il7 (referred to as Il7 YFP+ TECs), we documented that Il7 YFP+ TECs gradually decay with age in a thymocyte-dependent manner that correlated inversely with the emergence of CD80-expressing mTECs, suggesting that these cells may define a particular cortical epithelial subset.…”

mentioning

confidence: 77%

Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Ribeiro

Rodrigues

Meireles

et al. 2013

The Journal of Immunology

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Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7YFP+ TECs) reside within a subset of CD205+Ly51+CD40low cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80+CD40high mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7YFP+ TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7YFP+ TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7YFP+ TECs dissociates from the receptor activator of NF-κB–mediated differentiation of CD80+ mTECs. Still, Il7YFP+ TECs can generate some CD80+ mTECs in a stepwise differentiation process via YFP−Ly51lowCD80low intermediates. Il7YFP+ TECs are sustained in Rag2−/− mice, even following in vivo anti-CD3ε treatment that mimics the process of pre-TCR β-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2−/− TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7YFP+ TECs, whereas negative selection provokes a striking loss of Il7YFP+ TECs. These results imply that the strength of MHC/peptide–TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7–expressing cTECs.

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“…Like other related cytokines (IL-2, IL-4, IL-9, IL-15, and IL-21), IL-7 is a member of the so-called common g-chain (g c ) family (2). It is produced by many different stromal cell types, including epithelial cells of the thymus and the intestine (3)(4)(5). The receptor for IL-7 consists of a heterodimer, the IL7Ra-chain, and the g c ; the IL-7Ra-chain is also part of the receptor for the thymic stromal lymphopoietin (TSLP) cytokine, and g c is also a component of other cytokine receptors (2).…”

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confidence: 99%

Genetic Evidence for an Evolutionarily Conserved Role of IL-7 Signaling in T Cell Development of Zebrafish

Iwanami

Mateos

Hess

et al. 2011

The Journal of Immunology

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In mammals, the cytokine IL-7 is a key regulator of various aspects of lymphocyte differentiation and homeostasis. Because of the difficulty of identifying cytokine homologs in lower vertebrates and the paucity of assay systems and reagents, the degree of functional conservation of cytokine signaling pathways, particularly those pertaining to lymphocyte development, is unclear. In this article, we report on the analysis and characterization of three zebrafish mutants with severely impaired thymopoiesis. The identification of affected genes by positional cloning revealed components of the IL-7 signaling pathway. A presumptive null allele of the zebrafish homolog of the IL-7Rα–chain causes substantially reduced cellularity of the thymus but spares B cell development in the kidney. Likewise, nonsense mutations in the zebrafish homologs of janus kinases JAK1 and JAK3 preferentially affect T cell development. The functional interactions of the cytokine receptor components were examined in the three groups of fish hetero- or homozygous for either il7r and jak1, il7r and jak3, or jak1 and jak3 mutations. The differential effects on T cell development arising from the different genotypes could be explained on the basis of the known structure of the mammalian IL-7R complex. Because IL-7 signaling appears to be a universal requirement for T cell development in vertebrates, the mutants described in this article represent alternative animal models of human immunodeficiency syndromes amenable to large-scale genetic and chemical screens.

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IL7‐hCD25 and IL7‐Cre BAC transgenic mouse lines: New tools for analysis of IL‐7 expressing cells

Cited by 73 publications

References 30 publications

Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Genetic Evidence for an Evolutionarily Conserved Role of IL-7 Signaling in T Cell Development of Zebrafish

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