The Alarmin Interleukin-33 Drives Protective Antiviral CD8
 +
 T Cell Responses

Bonilla, Weldy V.; Fröhlich, Andreas; Senn, Karin; Kallert, Sandra M.; Fernandez, Marylise; Johnson, Susan C.; Kreutzfeldt, Mario; Hegazy, Ahmed N.; Schrick, Christina; Fallon, Padraic G.; Klemenz, Roman; Nakae, Susumu; Adler, Heiko; Merkler, Doron; Löhning, Max; Pinschewer, Daniel D.

doi:10.1126/science.1215418

Cited by 386 publications

(459 citation statements)

References 40 publications

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“…Although we found that the levels of total CD3 + CD8 + T cells were similar in the two strains of mice post CVB5 infection, we showed that in the absence of T1/ST2, there was a significant reduction in the number of IFNg-and TNF-a-producing CD3 + CD8 + T cells, which have been implicated in a range of antiviral activities (33,34). This is consistent with a recent report indicating that IL-33 could drive protective antiviral CD8 + T cell responses during LCMV infection in mice (35). NK cells were also thought to be important in controlling CVB5 infection (36).…”

Section: Discussionsupporting

confidence: 80%

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The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Sesti-Costa

Silva

Proença-Modena

et al. 2013

The Journal of Immunology

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Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8+ T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2−/− mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.

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Section: Discussionsupporting

confidence: 80%

“…Importantly, the Stat6-mediated increase in M2 macrophages and Tregs is likely to depend on mast cells, whereas the Stat6-mediated induction of multifunctional CD8 + T cells and viral clearance is mast cell independent. Therefore, it is possible that IL-33 may act directly on CD8 + T cells as previously shown in an LCMV model (35).…”

Section: Discussionmentioning

confidence: 99%

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Sesti-Costa

Silva

Proença-Modena

et al. 2013

The Journal of Immunology

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“…The function of IL-33 induced by P. gingivalis during the development of periodontal diseases remains unknown. Recently, other investigators reported that IL-33 plays an important role for DC-mediated CD8 + cytotoxic T lymphocyte responses (3,6). In our study, fimbriae and PGTP2 promoted DC-meingly, gingival epithelial cells express low levels of TLR2 (19), and IL-33 induction by gingipains is dependent on PAR-2 signaling in gingival epithelial cells.…”

Section: Discussion the Expression Of Il-33 Increases In Response Tosupporting

confidence: 49%

Increases in IL-33 production by fimbriae and lipopeptide from Porphyromonas gingivalis in mouse bone marrow-derived dendritic cells via Toll-like receptor 2

et al. 2017

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Interleukin-33 (IL-33) is an IL-1 cytokine family member that is involved in the development of chronic inflammatory diseases and the initiation of allergic inflammation in response to pathogens. Porphyromonas gingivalis is a primary pathogen that is involved in chronic periodontitis and its bacterial components induce inflammatory responses. Dendritic cells (DCs) recognize pathogenassociated molecular patterns by expression of pattern-recognition receptors, such as Toll-like receptors (TLRs). DCs play an essential role in resistance to infection and maintenance of mucosal immune system. In this study, we investigated whether P. gingivalis increases the expression of IL-33 in mouse bone marrow-derived DCs (BMDCs). BMDCs exhibited an increased expression of IL-33 mRNA upon stimulation with P. gingivalis whole cells. Furthermore, fimbriae and lipopeptide derived from P. gingivalis exhibited higher IL-33 mRNA expression than P. gingivalis whole cells. In contrast, lipopolysaccharide derived from P. gingivalis did not induce IL-33 mRNA expression in BMDCs. The IL-33 mRNA expression after stimulation with fimbriae or lipopeptide was up-regulated in BMDCs from wild-type mice but not from TLR2-deficient (TLR2

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“…Viral, bacterial, fungal, and parasitic infections can each produce a unique inflammatory environment. For instance, lymphocytic choriomeningitis virus (LCMV) infection triggers IFNα and IFNβ production (5), in addition to IL-1, IL-6, IL-10, IL-15, IL-21, IL-33, and TRAIL (6). Furthermore, LCMV-specific T cells readily produce IFNγ, TNFα, IL-2, and CD40L following stimulation with viral peptide antigen (7).…”

mentioning

confidence: 99%

Regulation of innate CD8⁺T-cell activation mediated by cytokines

Freeman

Hammarlund

Raué

et al. 2012

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

201

184

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Virus-specific CD8 + T cells develop the ability to function in an "innate" capacity by responding to a remarkable array of cytokines in a TCR-independent manner. Although several cytokines such as IL-12 and IL-18 have been identified as key regulators of CD8 + T-cell activation, the role of other cytokines and the ways in which they interact with each other remain unclear. Here, we have used an unbiased, systematic approach to examine the effects of 1,849 cytokine combinations on virus-specific CD8 + T-cell activation. This study identifies several unexpected cytokine combinations that synergize to induce antigen-independent IFNγ production and CD69 up-regulation by CD8 + T cells in addition to cytokines that exhibit differential regulatory functions, with the ability to either enhance or inhibit T-cell IFNγ production, depending on which cytokine partner is present. These findings underscore the complexity of cytokine interactions while also providing insight into the multifaceted regulatory network controlling virusspecific CD8 + T-cell functions.lymphocytic choriomeningitis virus | mouse | interleukin | lymphocyte

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The Alarmin Interleukin-33 Drives Protective Antiviral CD8 ⁺ T Cell Responses

Cited by 386 publications

References 40 publications

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

<b>Increases in IL-33 production by fimbriae and lipopeptide from </b><i><b>Porphyromonas gingivalis</b></i><b> in mouse bone marrow-derived dendritic cells via Toll-like receptor </b><b>2 </b>

Regulation of innate CD8⁺T-cell activation mediated by cytokines

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The Alarmin Interleukin-33 Drives Protective Antiviral CD8 + T Cell Responses

Cited by 386 publications

References 40 publications

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

<b>Increases in IL-33 production by fimbriae and lipopeptide from </b><i><b>Porphyromonas gingivalis</b></i><b> in mouse bone marrow-derived dendritic cells via Toll-like receptor </b><b>2 </b>

Regulation of innate CD8+T-cell activation mediated by cytokines

Contact Info

Product

Resources

About

The Alarmin Interleukin-33 Drives Protective Antiviral CD8 ⁺ T Cell Responses

Regulation of innate CD8⁺T-cell activation mediated by cytokines