Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production <i>in vivo</i>

Shalapour, Shabnam; Deiser, Katrin; Sercan, Özen; Tuckermann, Jan; Minnich, Kerstin; Willimsky, Gerald; Blankenstein, Thomas; Hämmerling, Günter J.; Arnold, Bernd; Schüler, Thomas

doi:10.1002/eji.201040441

Cited by 82 publications

(104 citation statements)

References 33 publications

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“…It has been reported that type 1 interferons and IFN-␥ are involved in IL-7 production in hepatocytes and IECs (18,26). We therefore next investigated whether C. rodentium-induced IL-7 expression in the colon was dependent on IFNs.…”

Section: Resultsmentioning

confidence: 97%

Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

Zhang

Yu³

et al. 2015

Infect Immun

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bInterleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacterium Citrobacter rodentium. C. rodentium infection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response to C. rodentium was dependent on gamma interferon (IFN-␥)-producing NK1.1 ؉ cells and IL-12. Treatment with anti-IL-7R␣ antibody during C. rodentium infection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity against C. rodentium during the first 6 days after infection. An impaired bacterial clearance upon IL-7R␣ blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover, C. rodentium-induced expansion and activation of intestinal CD4 ؉ lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7R␣ blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response to C. rodentium infection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium. Citrobacter rodentium is a mouse extracellular enteric pathogen that mimics human-enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E coli (EHEC). These bacterial pathogens attach intimately to intestinal epithelium and cause subcellular attaching and effacing lesions, which lead to severe diarrhea, vomiting, and fever, with high rates of fatality (1). C. rodentium infection of mice causes epithelial hyperplasia in the colon and cecum, goblet cell loss, and mucosal infiltration with macrophages, lymphocytes, and neutrophils (2). Therefore, this is an ideal model to dissect how immune cells interact with gut epithelial pathogens. The innate immune cells, including macrophages, dendritic cells (DCs), natural killer (NK) cells, neutrophils, and innate lymphoid cells (ILCs) have been shown to play an essential role in the clearance of C. rodentium infection (3-6). Moreover, the adaptive immune cells, mostly T and B cells, are also required for the clearance of this pathogen (7,8). Furthermore, the cytokines interleukin-6 (IL-6), IL-12, IL-17, IL-22, IL-23, and gamma interferon (IFN-␥) are upregulated in the colon tissues of C. rodentium-infected mice and are necessary for an effective immune defense against this pathogen (3-5, 7, 9).IL-7 is a stroma-derived cytokine that can be secreted by fetal liver cells, stromal cells in the bone marrow and thymus, and intestinal epithelial cells (IECs) (10). IL-7 acts on various cells through its receptor, a heterodimer consisting of an alpha-chain (IL-7R␣) and the common cytokine receptor gamma chain. The IL-7 receptor is expressed on lymphoid T and B precursors...

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Section: Resultsmentioning

confidence: 97%

Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

Zhang

Yu³

et al. 2015

Infect Immun

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“…RORgt + innate lymphoid cells and RORgt + NKT17 cells use IL-7 for their survival and expansion (19,28). Although IL-7 produced in the bone marrow, thymus, and lymph nodes clearly supports lymphocyte development and survival (29), more recent studies found that it can also be produced in nonlymphoid tissues, including intestine, skin, liver, and lung (30,31), and that it can even be induced in these sites by microbial signals (23,30,32). Because gdT-17 cells, NKT cells, and innate lymphoid cells are enriched in barrier tissues and their draining lymph nodes, we suggest that they are kept in balance, both in the steady-state and during an immune response, by competition for locally produced IL-7.…”

Section: Discussionmentioning

confidence: 99%

Differential Responsiveness of Innate-like IL-17– and IFN-γ–Producing γδ T Cells to Homeostatic Cytokines

Corpuz

Stolp

Kim

et al. 2016

The Journal of Immunology

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γδ T cells respond to molecules upregulated following infection or cellular stress using both TCR and non-TCR molecules. The importance of innate signals versus TCR ligation varies greatly. Both innate-like IL-17–producing γδ T (γδT-17) and IFN-γ–producing γδ T (γδT-IFNγ) subsets tune the sensitivity of their TCR following thymic development, allowing robust responses to inflammatory cytokines in the periphery. The remaining conventional γδ T cells retain high TCR responsiveness. We determined homeostatic mechanisms that govern these various subsets in the peripheral lymphoid tissues. We found that, although innate-like γδT-17 and γδT-IFNγ cells share elements of thymic development, they diverge when it comes to homeostasis. Both exhibit acute sensitivity to cytokines compared with conventional γδ T cells, but they do not monopolize the same cytokine. γδT-17 cells rely exclusively on IL-7 for turnover and survival, aligning them with NKT17 cells; IL-7 ligation triggers proliferation, as well as promotes survival, upregulating Bcl-2 and Bcl-xL. γδT-IFNγ cells instead depend heavily on IL-15. They display traits analogous to memory CD8+ T cells and upregulate Bcl-xL and Mcl-1 upon cytokine stimulation. The conventional γδ T cells display low sensitivity to cytokine-alone stimulation and favor IL-7 for their turnover, characteristics reminiscent of naive αβ T cells, suggesting that they may also require tonic TCR signaling for population maintenance. These survival constraints suggest that γδ T cell subsets do not directly compete with each other for cytokines, but instead fall into resource niches with other functionally similar lymphocytes.

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“…In addition to the thymus, IL-7-expressing cells were found in peripheral organs, such as abdomen, lung, skin, and intestine, where IL-17 + gd T cells were localized (50). Such peripheral and ontogenic heterogeneity of IL-7-expressing cells might explain the distribution of IL-17 + gd T cells, which receive important signals for their maintenance through IL-7Ra.…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

Nakamura

Shibata

Hatano

et al. 2015

The Journal of Immunology

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Notch signaling is an important regulator for the development and function of both αβ and γδ T cells, whereas roles of Notch signaling in T cell maintenance remain unclear. We reported previously that the Notch–Hes1 pathway was involved in the intrathymic development of naturally occurring IL-17–producing (IL-17+) γδ T cells. To gain insight into additional roles for the Notch axis in the homeostasis of γδ T cells, we performed a genome-wide analysis of Notch target genes and identified the novel promoter site of IL-7Rα driven by the Notch–RBP-Jκ pathway. Constitutive Notch signaling had the potential to induce IL-7Rα expression on γδ T cells in vivo, as well as in vitro, whereas conditional deletion of RBP-Jκ abrogated IL-7Rα expression, but not Hes1 expression, by γδ T cells and selectively reduced the pool size of IL-7Rαhigh IL-17+ γδ T cells in the periphery. In the absence of IL-7Rα–mediated signaling, IL-17+ γδ T cells were barely maintained in adult mice. Addition of exogenous IL-7 in vitro selectively expanded IL-17+ γδ T cells. Thus, our results revealed a novel role for the Notch–RBP-Jκ–IL-7Rα axis that is independent of Hes1 for homeostasis of IL-17+ γδ T cells.

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

Cited by 82 publications

References 33 publications

Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

Differential Responsiveness of Innate-like IL-17– and IFN-γ–Producing γδ T Cells to Homeostatic Cytokines

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

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