IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells

Tortola, Luigi; Pawelski, Helga; Sonar, Sanchaita Sriwal; Ampenberger, Franziska; Kurrer, Michael; Köpf, Manfred

doi:10.1016/j.jaci.2018.11.047

Cited by 32 publications

(25 citation statements)

References 50 publications

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“…FACS analysis of lamina propria cells revealed that the frequencies of IL‐13‐ and IL‐9‐producing CD4 + T cells were significantly decreased in IL‐21R −/− mice as compared with that in WT mice, whereas the frequency of IFN‐γ‐producing CD4 + T cells was comparable between these mice (Figure E). On the other hand, the frequency of Foxp3 + CD4 + T cells was significantly higher in OVA‐sensitized and OVA‐challenged IL‐21R −/− mice than that in OVA‐sensitized and OVA‐challenged WT mice (Figure E), in agreement with a previous study showing the increased generation of Foxp3 + CD4 + T cells in IL‐21R −/− mice in an asthma model . Furthermore, the frequency of ILC2s was lower but that of ILC3s was higher in lamina propria in OVA‐sensitized and OVA‐challenged IL‐21R −/− mice than that in OVA‐sensitized and OVA‐challenged WT mice (Figure F).…”

supporting

confidence: 92%

“…On the other hand, the frequency of Foxp3 + CD4 + T cells was significantly higher in OVA-sensitized and OVA-challenged IL-21R −/− mice than that in OVA-sensitized and OVA-challenged WT mice ( Figure 2E), in agreement with a previous study showing the increased generation of Foxp3 + CD4 + T cells in IL-21R −/− mice in an asthma model. 7 Furthermore, the frequency of ILC2s was lower but that of ILC3s was higher in lamina propria in OVA-sensitized and OVA-challenged IL-21R −/− mice than that in OVA-sensitized and OVA-challenged WT mice ( Figure 2F). These results suggest that IL-21 signalling enhances mast cell accumulation in lamina propria possibly by enhancing the accumulation of Th2 cells, Th9 cells or ILC2s or by suppressing the accumulation of Foxp3 + CD4 + T cells in the intestine and thus exacerbates the development of food allergy.…”

mentioning

confidence: 92%

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IL‐21 enhances mast cell accumulation in the intestine and exacerbates the development of experimental food allergy

Kono

Hirose

Makita

et al. 2019

Clin Experimental Allergy

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supporting

confidence: 92%

mentioning

confidence: 92%

IL‐21 enhances mast cell accumulation in the intestine and exacerbates the development of experimental food allergy

Kono

Hirose

Makita

et al. 2019

Clin Experimental Allergy

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“…1E). In addition to its impact on effector cells, IL21 is a negative regulator of suppressive Tregs (33,34). We also previously reported that DTA-1 hampers the differentiation of na€ ve CD4 þ T cells into Tregs, which resulted in reduced Treg populations in tumor tissue (11) Research.…”

Section: Il21 Drives Dta-1-induced Antitumor Immunity By Potentiatingmentioning

confidence: 98%

GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells

Koh

Kim

Shin

et al. 2020

Cancer Immunology Research

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Although treatment with the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21-producing follicular helper T (Tfh) cells play a crucial role in DTA-1-induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in Bcl6 fl/fl Cd4 Cre mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.

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“…While the IL-21/IL-21R pathway has been shown to be important in protection against several microbial pathogens, the IL-21/IL-21R signaling axis has been linked to excessive inflammation and associated pathogenesis observed during infectious and non-infectious inflammatory conditions (Stolfi et al, 2011; Tortola et al, 2019). Consistent with this notion, dysregulated IL-21 expression is associated with multiple inflammatory conditions, including Crohn's disease, celiac disease and arthritis (Stolfi et al, 2011; Gensous et al, 2018; Wang et al, 2018).…”

Section: Il-21/il-21r Signaling Pathwaymentioning

confidence: 99%

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

Solaymani-Mohammadi

Eckmann

Singer

2019

Front. Cell. Infect. Microbiol.

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Parasitic diseases cause significant morbidity and mortality in the developing and underdeveloped countries. No efficacious vaccines are available against most parasitic diseases and there is a critical need for developing novel vaccine strategies for care. IL-21 is a pleiotropic cytokine whose functions in protection and immunopathology during parasitic diseases have been explored in limited ways. IL-21 and its cognate receptor, IL-21R, are highly expressed in parasitized organs of infected humans as well in murine models of the human parasitic diseases. Prior studies have indicated the ability of the IL-21/IL-21R signaling axis to regulate the effector functions (e.g., cytokine production) of T cell subsets by enhancing the expression of T-bet and STAT4 in human T cells, resulting in an augmented production of IFN-γ. Mice deficient for either IL-21 (Il21−/−) or IL-21R (Il21r−/−) showed significantly reduced inflammatory responses following parasitic infections as compared with their WT counterparts. Targeting the IL-21/IL-21R signaling axis may provide a novel approach for the development of new therapeutic agents for the prevention of parasite-induced immunopathology and tissue destruction.

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IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells

Cited by 32 publications

References 50 publications

IL‐21 enhances mast cell accumulation in the intestine and exacerbates the development of experimental food allergy

IL‐21 enhances mast cell accumulation in the intestine and exacerbates the development of experimental food allergy

GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

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