Citrobacter rodentium: a model enteropathogen for understanding the interplay of innate and adaptive components of type 3 immunity

Silberger, Daniel J.; Zindl, Carlene L.; Weaver, Casey T.

doi:10.1038/mi.2017.47

Cited by 80 publications

(62 citation statements)

References 107 publications

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“…We next determined whether Treg cell could suppress IL-22 producing ILC3 in T cell-sufficient mice. We chose two models, the anti-CD40 colitis model where IL-22-expressing ILC3 are pathogenic (Buonocore et al, 2010;Eken et al, 2014) and the Citrobacter rodentium model where protective IL-22 produced by ILC3 is required to clear bacteria during first week of infection (Silberger et al, 2017). We depleted Treg cells in Foxp3-DTR mice and analyzed colons 3-4 days after induction of colitis in both models (Figure 2A).…”

Section: Regulatory T Cells Prevent Il-22 Producing Ilc3-mediated Colmentioning

confidence: 99%

LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

et al. 2018

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Interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (ILC3) maintains gut homeostasis but can also promote inflammatory bowel disease (IBD). The regulation of ILC3-dependent colitis remains to be elucidated. Here we show that Foxp3 regulatory T cells (Treg cells) prevented ILC3-mediated colitis in an IL-10-independent manner. Treg cells inhibited IL-23 and IL-1β production from intestinal-resident CX3CR1 macrophages but not CD103 dendritic cells. Moreover, Treg cells restrained ILC3 production of IL-22 through suppression of CX3CR1 macrophage production of IL-23 and IL-1β. This suppression was contact dependent and was mediated by latent activation gene-3 (LAG-3)-an immune checkpoint receptor-expressed on Treg cells. Engagement of LAG-3 on MHC class II drove profound immunosuppression of CX3CR1 tissue-resident macrophages. Our study reveals that the health of the intestinal mucosa is maintained by an axis driven by Treg cells communication with resident macrophages that withhold inflammatory stimuli required for ILC3 function.

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Section: Regulatory T Cells Prevent Il-22 Producing Ilc3-mediated Colmentioning

confidence: 99%

LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

et al. 2018

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“…We used the well-described Citrobacter rodentium model to investigate CD4 ϩ T RM cells (12,13). C. rodentium breaches the epithelial barrier with systemic spread, resulting in a transient infection characterized by diarrhea and weight loss.…”

mentioning

confidence: 99%

Citrobacter rodentium Induces Tissue-Resident Memory CD4 ⁺ T Cells

et al. 2019

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Tissue-resident memory T cells (T RM cells) are a novel population of tissue-restricted antigen-specific T cells. T RM cells are induced by pathogens and promote host defense against secondary infections. Although T RM cells cannot be detected in circulation, they are the major memory CD4 ϩ and CD8 ϩ T-cell population in tissues in mice and humans. Murine models of CD8 ϩ T RM cells have shown that CD8 ϩ T RM cells maintain tissue residency via CD69 and though tumor growth factor ␤-dependent induction of CD103. In contrast to CD8 ϩ T RM cells, there are few models of CD4 ϩ T RM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4 ϩ T RM cells. Citrobacter rodentium is known to induce IL-17 ϩ and IL-22 ϩ CD4 ϩ T cells (T h 17 and T h 22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22 ϩ cells in the colon 3 months after C. rodentium infection are CD4 ϩ T cells. This collectively suggests that C. rodentium may induce CD4 ϩ T RM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A ϩ CD4 ϩ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4 ϩ T RM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4 ϩ T RM cells can promote host defense.

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“…The pathogen Citrobacter rodentium causes intestinal infection in mice and has virulence factors similar to those of the human pathogen, enteropathogenic and enterohemorrhagic E. coli (27). C. rodentium infection is therefore used as a model to study chronic human intestinal diseases, such as ulcerative colitis and Crohn's disease (28), and intestinal host defense (27). IL-17 and IL-22 play an important role during the resolution of C. rodentium infection (29).…”

Section: Significancementioning

confidence: 99%

Intestinal host defense outcome is dictated by PGE ₂ production during efferocytosis of infected cells

Dejani

Orlando

Castaño

et al. 2018

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

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Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-β, PGE, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-β, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic -infected macrophages by dendritic cells triggers PGE production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic -infected cells by dendritic cells promoted high levels of PGE, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.

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Citrobacter rodentium: a model enteropathogen for understanding the interplay of innate and adaptive components of type 3 immunity

Cited by 80 publications

References 107 publications

LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

Citrobacter rodentium Induces Tissue-Resident Memory CD4 ⁺ T Cells

Intestinal host defense outcome is dictated by PGE ₂ production during efferocytosis of infected cells

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Citrobacter rodentium: a model enteropathogen for understanding the interplay of innate and adaptive components of type 3 immunity

Cited by 80 publications

References 107 publications

LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

Citrobacter rodentium Induces Tissue-Resident Memory CD4 + T Cells

Intestinal host defense outcome is dictated by PGE 2 production during efferocytosis of infected cells

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Citrobacter rodentium Induces Tissue-Resident Memory CD4 ⁺ T Cells

Intestinal host defense outcome is dictated by PGE ₂ production during efferocytosis of infected cells