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The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses

ABSTRACT: Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as “damage-associated molecular patterns” or “alarmins”, remains ill-defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8+ T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a MyD88-dependent, CTL-intrinsic fashion, determined polyfunctional effector cell differentiation and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE34392 | GEO | 2012/02/27

SECONDARY ACCESSION(S): PRJNA149569

REPOSITORIES: GEO

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The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses

Project description:Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as “damage-associated molecular patterns” or “alarmins”, remains ill-defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8+ T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a MyD88-dependent, CTL-intrinsic fashion, determined polyfunctional effector cell differentiation and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses. 2 groups (wt vs. ST-/- P14 cells), 3 replicates per group.

2012-02-27 | E-GEOD-34392 | biostudies-arrayexpress

Mus musculus

Project description:The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses

| PRJNA149569 | ENA

Mass spectrometry analysis of cleavage sites for different protease allergens in human IL-33

Project description:The cytokine interleukin-33 (IL-33) is an epithelial alarmin with critical roles in allergic inflammation and type 2 immunity. The project aims at the characterization of the direct cleavage of IL-33 by allergen proteases, resulting in its activation, and in the subsequent induction of type 2 cytokine production in group 2 innate lymphoid cells. The present dataset contains mass spectrometry analyses to map the cleavage sites for 9 distinct allergens proteases in the human IL-33 sequence.

2018-03-14 | PXD006081 | Pride

RNA-Seq of ST2+ cytotoxic T cells, T helper 1 and T helper 2 cells

2023-10-17 | GSE204692 | GEO

Development of live-attenuated lymphocytic choriomeningitis virus vectors for potent alarmin-driven CD8+ T cell induction in tumor immunotherapy

Project description:Effective cancer immunotherapy requires potent tumor antigen-specific effector CD8+ T cell (CTLeff) responses, culminating in an inflammatory activation of the tumor microenvironment. We describe the artificial reengineering of the lymphocytic choriomeningitis virus (LCMV) genome to serve as replication-competent but stably attenuated immunotherapy platform (artLCMV). artLCMV targeted dendritic cells, thereby delivering tumor-associated antigens for efficient CTL induction. Additionally, owing to in vivo spread, artLCMV infected lymphoid tissue stroma expressing interleukin-33, an alarmin released from necrotic cells. Interleukin-33 signals accounted for artLCMV-induced effector CTL responses of higher magnitude and functionality than those induced by replication-deficient LCMV-, adenovirus 5- or vaccinia virus-based vectors. Accordingly, superior immunotherapeutic efficacy of artLCMV in transplantable tumor models depended on interleukin-33 signaling, and massive CTLeff influx was associated with an inflammatory conversion of the tumor. These properties, together with low seroprevalence but excellent immunogenicity of LCMV in humans, suggest artLCMV holds promise as a cancer immunotherapy platform.

2017-03-08 | GSE84039 | GEO

A type 1 immunity-restricted promoter of the IL-33 receptor gene drives antiviral T cell responses

Project description:The pleiotropic alarmin interleukin-33 (IL-33) promotes the activity of many innate and adaptive immune cell subsets. Its receptor ST2 is constitutively expressed at high levels by type 2-biased immune cells including CD4+ T helper 2 (Th2) cells, innate lymphoid cells type 2 and highly potent regulatory T cells, allowing rapid sensing of IL-33 alarmin signals (Peine et al., 2015). In contrast, during viral infections, antiviral CD8+ cytotoxic T cells (CTLs) and CD4+ Th1 cells express ST2 at a low level in a transient and activation dependent way, suggesting that the ST2-coding gene Il1rl1 is regulated in a cell-type specific manner (Bonilla et al., 2012). To better understand the transcriptional regulation of the Il1rl1 gene in distinctly polarized T cells, we here performed RNA-Sequencing of in vitro activated, ST2 expressing CTLs, Th1 and Th2 cells. Further, to decipher the T cell subset-specific consequences of IL-33 sensing, we profiled early changes in transcriptional activity of CTLs, Th1 cells and Th2 cells upon stimulation with IL-33. Lastly, to better understand the role of IL-33 during an acute infection with lymphocytic choriomeningitis virus (LCMV), activated CD44+ CTLs were flowcytometrically sorted from infected C57BL/6 wildtype and Il1rl1 gene-targeted mice (Il1rl1-ExAB-/-) and subjected to combined single-cell gene expression and single cell TCR-Seq analysis. This SuperSeries is composed of the SubSeries listed below.

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Neuropeptide CGRP limits ILC2 responses and constrains type 2 inflammation

Project description:Innate and adaptive lymphocytes work in concert to maintain tissue homeostasis and to mediate host defense at mucosal barriers. Herein, we used single cell analysis to show substantial diversity of gene expression in ILCs and T helper cells during a helminth infection in the lung. Notably, we found that the Calca gene, which is spliced to generate the neuropeptide CGRP, was selectively transcribed in ILC2s and Th2 cells in an activation dependent manner. The Calca locus acquired chromatin accessibility at the ILC2 precursor stage and is pre-programmed for rapid production of CGRP upon ILC2 activation. CGRP globally antagonized actions of neuromedin U (NMU) and the alarmin IL-33. However, CGRP selectively acted in concert with NMU and IL-33 to promote IL-5 expression, but not IL-13. The complex interplay among neuropeptides and alarmin fine-tunes type 2 immune responses and will undoubtedly become more relevant as therapeutic neuropeptide blockade advances in the clinic.

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Oligodendrocyte-derived IL-33 functions as a microglial survival factor during neuroinvasive flavivirus infection

Project description:In order to recover from infection, organisms must balance robust immune responses to pathogens with the tolerance of immune-mediated pathology. This balance is particularly critical within the central nervous system, whose complex architecture, essential function, and limited capacity for self-renewal render it susceptible to both pathogen- and immune-mediated pathology. Here, we identify the alarmin IL-33 and its receptor ST2 as critical for host survival to neuroinvasive flavivirus infection. We identify oligodendrocytes as the critical source of IL-33, and microglia as the key cellular responders. Notably, we find that the IL-33/ST2 axis does not impact viral control or adaptive immune responses; rather, it is required to promote the activation and survival of microglia. In the absence of intact IL-33/ST2 signaling in the brain, neuroinvasive flavivirus infection triggered aberrant recruitment of monocyte-derived peripheral immune cells, increased neuronal stress, and neuronal cell death, effects that compromised organismal survival. These findings identify IL-33 as a critical mediator of CNS tolerance to pathogen-initiated immunity and inflammation.

2023-11-08 | GSE241804 | GEO

Charaterization club cell lineages in small airways of naïve WT mice

Project description:Mouse small airways are populated by different epithelial lineages that generate from club cell progenitors that can express IL-33 as alarmin which could be released after epithelial injury

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Gene expression data of naïve wildtype and IL-33 knockout ILC2s isolated from adult male mouse lungs

Project description:Group 2 innate lymphoid cells (ILC2s) in mouse lungs are activated by the epithelium-derived alarmin IL-33. Activated ILC2s proliferate and produce IL-5 and IL-13 that drive allergic responses. In neonatal lungs, IL-33 is spontaneously released resulting in activation of lung ILC2s. Here we report that neonatal lung ILC2 activation has significant effects on ILC2 functions in adulthood. Most neonatal lung ILC2s incorporated bromodeoxyuridine (BrdU) and persisted into adulthood. BrdU+ ILC2s in adult lungs responded more intensely to IL-33 treatment than BrdU- ILC2s. In IL-33 deficient (KO) mice, lung ILC2s develop normally but they are not activated in the neonatal period. Lung ILC2s in KO mice responded less intensely to IL-33 in adulthood compared to wild type (WT) ILC2s. While there was no difference in the number of lung ILC2s, there were fewer IL-13+ ILC2s in IL-33KO than IL-33WT mice. The impaired responsiveness of ILC2s in KO mice was reversed by intranasal injections of IL-33 in the neonatal period. These results suggest that activation of lung ILC2s by endogenous IL-33 in the neonatal period may “train” ILC2s seeding the lung after birth to become long-lasting resident cells that respond more efficiently to challenges later in life.

2020-04-14 | GSE148545 | GEO

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