IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development

Stier, Matthew T.; Mitra, Ramkrishna; Nyhoff, Lindsay E.; Goleniewska, Kasia; Zhang, Jian; Puccetti, Matthew V.; Casanova, Holly C.; Seegmiller, Adam C.; Newcomb, Dawn C.; Kendall, Peggy L.; Eischen, Christine M.; Peebles, R. Stokes

doi:10.4049/jimmunol.1900408

Cited by 26 publications

(27 citation statements)

References 49 publications

(66 reference statements)

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“…Evidence for a nuclear role for IL‐33 has been put forward mainly using cultures of epithelial and endothelial cell lines where IL‐33 knockdown strategies led to changes in the expression of selected genes [10‐12, 21], with other studies on similar cells coming to the opposite conclusion, including in more global transcriptomic and proteomic approaches highlighting the ST2 dependence of IL‐33‐mediated effects on transcription [14, 15]. More recently, the first ex vivo study with cells isolated from WT and Il33 −/− mice was reported [16]. It indicates a cell‐intrinsic role for IL‐33 as negative regulator of pro‐B‐cell development and fitness with distinct differences observed at the transcript level.…”

Section: Discussionmentioning

confidence: 99%

“…Yet another study described the overexpression of IL‐33 in an epithelial cell line with no transcriptional changes observed in a genome‐wide analysis [15]. So far, only one recent study compared ex vivo cells, namely wt versus Il33 −/− pro‐B cells, and uncovered many transcriptional changes in absence of IL‐33 with mixed BM chimera experiments indicating these effects are cell intrinsic [16]. Together, these data suggest that IL‐33 can regulate gene transcription but that this property is cell‐type and context‐dependent.…”

Section: Introductionmentioning

confidence: 99%

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Fibroblast‐derived IL‐33 is dispensable for lymph node homeostasis but critical for CD8 T‐cell responses to acute and chronic viral infection

Aparicio‐Domingo

Cannelle

Buechler³

et al. 2020

Eur J Immunol

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Upon viral infection, stressed or damaged cells can release alarmins like IL‐33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL‐33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8+ T cells. In LN the critical cellular source of IL‐33 is unknown, as is its potential cell‐intrinsic function as a chromatin‐associated factor. Using IL‐33‐GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL‐33 source. In homeostasis, IL‐33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL‐33 protein expression suggesting cytokine release, correlating timewise with IL‐33 receptor expression by reactive CD8+ T cells and their greatly augmented expansion in WT versus ll33−/− mice. Using mice lacking IL‐33 selectively in FRC versus LEC, we identify FRC as key IL‐33 source driving acute and chronic antiviral T‐cell responses. Collectively, these findings show that LN T‐zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fibroblast‐derived IL‐33 is dispensable for lymph node homeostasis but critical for CD8 T‐cell responses to acute and chronic viral infection

Aparicio‐Domingo

Cannelle

Buechler³

et al. 2020

Eur J Immunol

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“…Vaccines 2020, 8, x 6 of 25 [97] and also functions as a cell-intrinsic regulator of fitness during the early development of B-cells [98]. Not all inflammasome substrates are pro-inflammatory.…”

Section: Inflammasome-mediated Activation Of Adaptive Immunitymentioning

confidence: 99%

Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants

et al. 2020

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In modern vaccines, adjuvants can be sophisticated immunological tools to promote robust and long-lasting protection against prevalent diseases. However, there is an urgent need to improve immunogenicity of vaccines in order to protect mankind from life-threatening diseases such as AIDS, malaria or, most recently, COVID-19. Therefore, it is important to understand the cellular and molecular mechanisms of action of vaccine adjuvants, which generally trigger the innate immune system to enhance signal transition to adaptive immunity, resulting in pathogen-specific protection. Thus, improved understanding of vaccine adjuvant mechanisms may aid in the design of “intelligent” vaccines to provide robust protection from pathogens. Various commonly used clinical adjuvants, such as aluminium salts, saponins or emulsions, have been identified as activators of inflammasomes - multiprotein signalling platforms that drive activation of inflammatory caspases, resulting in secretion of pro-inflammatory cytokines of the IL-1 family. Importantly, these cytokines affect the cellular and humoral arms of adaptive immunity, which indicates that inflammasomes represent a valuable target of vaccine adjuvants. In this review, we highlight the impact of different inflammasomes on vaccine adjuvant-induced immune responses regarding their mechanisms and immunogenicity. In this context, we focus on clinically relevant adjuvants that have been shown to activate the NLRP3 inflammasome and also present various experimental adjuvants that activate the NLRP3-, NLRC4-, AIM2-, pyrin-, or non-canonical inflammasomes and could have the potential to improve future vaccines. Together, we provide a comprehensive overview on vaccine adjuvants that are known, or suggested, to promote immunogenicity through inflammasome-mediated signalling.

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“…In the adaptive immune system, ST2 has been shown to be preferentially expressed by Th2 cells, where IL-33 stimulation has been shown to induce the production of IL-4, IL-5 and IL-13 (Schmitz et al, 2005;Paul and Zhu, 2010). IL-33 has also been shown to suppress T helper type 1 (Th1) responses (Rostan et al, 2013;Stier et al, 2019), though some studies have shown that it may potentiate Th1 responses as well in an IL-12 dependent manner (Smithgall et al, 2008;Komai-Koma et al, 2016). A compiled meta-analysis study of the IL-33/ST2 axis has revealed the enormous extent of the complexity and involvement of this signaling pathway, revealing just how much remains to be understood (Pinto et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications

Ryan

Anderson

Volpedo

et al. 2020

Front. Cell. Infect. Microbiol.

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Parasitic infections pose a wide and varying threat globally, impacting over 25% of the global population with many more at risk of infection. These infections are comprised of, but not limited to, toxoplasmosis, malaria, leishmaniasis and any one of a wide variety of helminthic infections. While a great deal is understood about the adaptive immune response to each of these parasites, there remains a need to further elucidate the early innate immune response. Interleukin-33 is being revealed as one of the earliest players in the cytokine milieu responding to parasitic invasion, and as such has been given the name "alarmin." A nuclear cytokine, interleukin-33 is housed primarily within epithelial and fibroblastic tissues and is released upon cellular damage or death. Evidence has shown that interleukin-33 seems to play a crucial role in priming the immune system toward a strong T helper type 2 immune response, necessary in the clearance of some parasites, while disease exacerbating in the context of others. With the possibility of being a double-edged sword, a great deal remains to be seen in how interleukin-33 and its receptor ST2 are involved in the immune response different parasites elicit, and how those parasites may manipulate or evade this host mechanism. In this review article we compile the current cutting-edge research into the interleukin-33 response to toxoplasmosis, malaria, leishmania, and helminthic infection. Furthermore, we provide insight into directions interleukin-33 research may take in the future, potential immunotherapeutic applications of interleukin-33 modulation and how a better clarity of early innate immune system responses involving interleukin-33/ST2 signaling may be applied in development of much needed treatment options against parasitic invaders.

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IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development

Cited by 26 publications

References 49 publications

Fibroblast‐derived IL‐33 is dispensable for lymph node homeostasis but critical for CD8 T‐cell responses to acute and chronic viral infection

Fibroblast‐derived IL‐33 is dispensable for lymph node homeostasis but critical for CD8 T‐cell responses to acute and chronic viral infection

Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants

The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications

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