Gamma Interferon Produced by Antigen-Specific CD4<sup>+</sup>T Cells Regulates the Mucosal Immune Responses to<i>Citrobacter rodentium</i>Infection

Shiomi, Hideyuki; Masuda, Atsuhiro; Nishiumi, Shin; Nishida, Masayuki; Takagawa, Tetsuya; Shiomi, Yuuki; Kutsumi, Hiromu; Blumberg, Richard S.; Azuma, Takeshi; Yoshida, Masaru

doi:10.1128/iai.01343-09

Cited by 67 publications

(69 citation statements)

References 29 publications

(32 reference statements)

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“…In C. rodentium infection of C57BL/6 mice, overproduction of both TH1-derived IFNγ and TH17-derived IL17 mediates the pathology [8,38]. Importantly, we show that the infection of WT BALB/c mice with C. rodentium leads to an enhanced TH17 response in the colon but no alteration in the TH1 response was detectable, showing that the genetic background significantly defines the susceptibility and the immune response to infection.…”

Section: Discussionmentioning

confidence: 73%

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

Seiffart

Zoeller

Klopfleisch

et al. 2015

Cell Physiol Biochem

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Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4⁺ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4⁺ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4⁺ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4⁺ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4⁺ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.

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Section: Discussionmentioning

confidence: 73%

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

Seiffart

Zoeller

Klopfleisch

et al. 2015

Cell Physiol Biochem

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“…Similar to the colitis models, IkB NS deficiency resulted in impaired Th17 and IL-17A + IFN-g + T cell generation in infected mice. Because IFN-g, as well as the p40 and the p19 subunit of IL-23, which is known to stabilize the Th17 phenotype (33), are required for C. rodentium clearance (25,34,35), it is conceivable that the lack of IL-17A + and IFN-g + T cells in IkB NS 2/2 mice upon C. rodentium infection is responsible for the increased bacterial burden in these mice. Interestingly, NF-kB1/ p50 2/2 mice also are defective in C. rodentium clearance (36), which is in line with the observation that IkB NS preferentially interacts with this NF-kB family member (17,37).…”

Section: Discussionmentioning

confidence: 99%

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Annemann

Wang

Plaza-Sirvent

et al. 2015

The Journal of Immunology

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IL-17–producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A–producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS−/− Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS−/− mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.

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“…Mice lacking Th17 cells or their associated cytokines are also susceptible to C. rodentium (26)(27)(28)(29). Although mechanisms of Th1 and Th17 induction after C. rodentium infection have been reported (25,28,(30)(31)(32), it is not clear whether these effector T cells are also counterregulated and controlled during and after infection.…”

mentioning

confidence: 93%

“…Infection elicits both Th1 and Th17 responses at the site of infection (23,24). Th1 cells are important for controlling pathology and bacterial clearance by secreting gamma interferon (IFN-␥), which promotes macrophage phagocytosis and activates antigen-specific CD4 ϩ T cells (25). Mice lacking Th17 cells or their associated cytokines are also susceptible to C. rodentium (26)(27)(28)(29).…”

mentioning

confidence: 99%

Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

Dann

Choudhury

et al. 2014

Infect Immun

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dInterleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogen Citrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transient C. rodentium infection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppress in vitro Th17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolving C. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.

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Gamma Interferon Produced by Antigen-Specific CD4⁺T Cells Regulates the Mucosal Immune Responses toCitrobacter rodentiumInfection

Cited by 67 publications

References 29 publications

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

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Gamma Interferon Produced by Antigen-Specific CD4+T Cells Regulates the Mucosal Immune Responses toCitrobacter rodentiumInfection

Cited by 67 publications

References 29 publications

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

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Gamma Interferon Produced by Antigen-Specific CD4⁺T Cells Regulates the Mucosal Immune Responses toCitrobacter rodentiumInfection