Emerging Functions of IL-33 in Homeostasis and Immunity

2022 ◽  
Vol 40 (1) ◽  
Author(s):  
Gaelen K. Dwyer ◽  
Louise M. D'Cruz ◽  
Hēth R. Turnquist
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tissue Repair ◽  
Inflammatory Diseases ◽  
Lymphoid Cells ◽  
Annual Review ◽  
Publication Date ◽  
Molecular Pattern ◽  
Allergy And Asthma

Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals 2019 ATVB Plenary Lecture

2020 ◽  
Vol 40 (4) ◽  
pp. 853-864 ◽  
Author(s):  
Tian X. Zhao ◽  
Stephen A. Newland ◽  
Ziad Mallat
Keyword(s):  
Cardiovascular Disease ◽  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Interleukin 2 ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Myocardial Repair

Regulatory T cells and type-2 innate lymphoid cells represent 2 subsets of immune cells, which have been shown in preclinical models to be important in atherosclerosis and myocardial repair. Regulatory T cells play a crucial role in immune homeostasis and tolerance via their interactions with effector T cells, dendritic cells, and monocytes/macrophages. They also utilize and secrete inhibitory cytokines, including interleukin 10 and transforming growth factor β, to regulate or suppress pathogenic immune responses. Type-2 innate lymphoid cells have an important role in type-2 immune responses and tissue repair through secreting interleukins 5 and 13, as well as a variety of biological mediators and growth factors. Intriguingly, interleukin-2 has emerged as a common cytokine, which can be harnessed to upregulate both cell types, and also has important translational consequences as clinical trials are ongoing for its use in cardiovascular disease. Here, we briefly review the biology of these regulatory immune cell types, discuss the preclinical and clinical evidence for their functions in cardiovascular disease, examine the prospects for clinical translation and current ongoing trials, and finally, postulate how overlap in the mechanisms of upregulation may be leveraged in future treatments for patients.

scholarly journals Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

2018 ◽  
Vol 49 (1) ◽  
pp. 349-358 ◽  
Author(s):  
Wei-Yu Chen ◽  
Tzu-Hsien Tsai ◽  
Jenq-Lin Yang ◽  
Lung-Chih Li
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Lymphoid Cells ◽  
Gastrointestinal System ◽  
Immune Functions ◽  
Central Nerve System ◽  
Nerve System

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

scholarly journals Group 2 Innate Lymphoid Cells Exhibit Tissue-Specific Dynamic Behaviour During Type 2 Immune Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurence S. C. Lok ◽  
Jennifer A. Walker ◽  
Helen E. Jolin ◽  
Seth T. Scanlon ◽  
Masaru Ishii ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Intestinal Mucosa ◽  
Dynamic Behaviour ◽  
Helminth Infection ◽  
Lymphoid Cells ◽  
Group 2

Group 2 innate lymphoid cells (ILC2s) are early effectors of mucosal type 2 immunity, producing cytokines such as interleukin (IL)-13 to mediate responses to helminth infection and allergen-induced inflammation. ILC2s are also present in lymph nodes (LNs) and can express molecules required for antigen presentation, but to date there are limited data on their dynamic behaviour. We used a CD2/IL-13 dual fluorescent reporter mouse for in vivo imaging of ILC2s and Th2 T cells in real time following a type 2 priming helminth infection or egg injection. After helminth challenge, we found that ILC2s were the main source of IL-13 in lymphoid organs (Peyer’s patches and peripheral LNs), and were located in T cell areas. Intravital imaging demonstrated an increase in IL-13+ ILC2 size and movement following helminth infection, but reduced duration of interactions with T cells compared with those in homeostasis. In contrast, in the intestinal mucosa, we observed an increase in ILC2-T cell interactions post-infection, including some of prolonged duration, as well as increased IL-13+ ILC2 movement. These data suggest that ILC2 activation enhances cell motility, with the potential to increase the area of distribution of cytokines to optimise the early generation of type 2 responses. The prolonged ILC2 interactions with T cells within the intestinal mucosa are consistent with the conclusion that contact-based T cell activation may occur within inflamed tissues rather than lymphoid organs. Our findings have important implications for our understanding of the in vivo biology of ILC2s and the way in which these cells facilitate adaptive immune responses.

Group 2 Innate Lymphoid Cells: Team Players in Regulating Asthma

2021 ◽  
Vol 39 (1) ◽  
Author(s):  
Noe Rodriguez-Rodriguez ◽  
Mayuri Gogoi ◽  
Andrew N.J. McKenzie
Keyword(s):  
Allergic Asthma ◽  
Cell Activation ◽  
Innate Lymphoid Cells ◽  
Experimental Models ◽  
Lymphoid Cells ◽  
Annual Review ◽  
Publication Date ◽  
Effector Cytokines ◽  
Group 2

Type 2 immunity helps protect the host from infection, but it also plays key roles in tissue homeostasis, metabolism, and repair. Unfortunately, inappropriate type 2 immune reactions may lead to allergy and asthma. Group 2 innate lymphoid cells (ILC2s) in the lungs respond rapidly to local environmental cues, such as the release of epithelium-derived type 2 initiator cytokines/alarmins, producing type 2 effector cytokines such as IL-4, IL-5, and IL-13 in response to tissue damage and infection. ILC2s are associated with the severity of allergic asthma, and experimental models of lung inflammation have shown how they act as playmakers, receiving signals variously from stromal and immune cells as well as the nervous system and then disseminating cytokine cues to elicit effector functions and potentiate CD4+ T helper cell activation, both of which characterize the pathology of allergic asthma. Recent breakthroughs identifying stromal- and neuronal-derived microenvironmental cues that regulate ILC2s, along with studies recognizing the potential plasticity of ILC2s, have improved our understanding of the immunoregulation of asthma and opened new avenues for drug discovery. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Type 2 immunity in intestinal homeostasis and inflammatory bowel disease

2021 ◽  
Author(s):  
Xinxin Luo ◽  
Eduardo J. Villablanca
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Responses ◽  
Bowel Disease ◽  
Tissue Repair ◽  
Lymphoid Cells ◽  
Helminth Parasites ◽  
Cellular Mechanisms ◽  
Intestinal Homeostasis ◽  
Inflammatory Bowel

Type 2 immune responses commonly emerge during allergic reactions or infections with helminth parasites. Most of the cytokines associated with type 2 immune responses are IL-4, IL-5, and IL13, which are mainly produced by T helper 2 cells (TH2), eosinophils, basophils, mast cells, and group 2 innate lymphoid cells (ILC2s). Over the course of evolution, humans have developed type 2 immune responses to fight infections and to protect tissues from the potential collateral damage caused by inflammation. For example, worm parasites induce potent type 2 immune responses, which are needed to simultaneously clear the pathogen and to promote tissue repair following injury. Due to the strong type 2 immune responses induced by helminths, which can promote tissue repair in the damaged epithelium, their use has been suggested as a possible treatment for inflammatory bowel disease (IBD); however, the role of type 2 immune responses in the initiation and progression of IBD is not fully understood. In this review, we discuss the molecular and cellular mechanisms that regulate type 2 immune responses during intestinal homeostasis, and we briefly discuss the scarce evidence linking type 2 immune responses with the aetiology of IBD.

scholarly journals PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation

2017 ◽  
Vol 214 (10) ◽  
pp. 3015-3035 ◽  
Author(s):  
Samuel Philip Nobs ◽  
Sara Natali ◽  
Lea Pohlmeier ◽  
Katarzyna Okreglicka ◽  
Christoph Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Inflammatory Diseases ◽  
Th2 Cells ◽  
M2 Macrophage ◽  
Airway Responses

Type-2 immune responses are well-established drivers of chronic inflammatory diseases, such as asthma, and represent a large burden on public health systems. The transcription factor PPARγ is known to promote M2-macrophage and alveolar macrophage development. Here, we report that PPARγ plays a key role in both T cells and dendritic cells (DCs) for development of type-2 immune responses. It is predominantly expressed in mouse Th2 cells in vitro and in vivo as well as human Th2 cells from allergic patients. Using conditional knockouts, we show that PPARγ signaling in T cells, although largely dispensable for IL-4 induction, is critical for IL-33–driven Th2 effector function in type-2 allergic airway responses. Furthermore, we demonstrate that IL-4 and IL-33 promote up-regulation of PPARγ in lung-resident CD11b+ DCs, which enhances migration to draining lymph nodes and Th2 priming capacity. Thus, we uncover a surprising proinflammatory role for PPARγ and establish it as a novel, important mediator of DC–T cell interactions in type-2 immunity.

scholarly journals Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

2019 ◽  
Vol 20 (21) ◽  
pp. 5493 ◽  
Author(s):  
Meunier ◽  
Chea ◽  
Garrido ◽  
Perchet ◽  
Petit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Inflammatory Conditions ◽  
Airway Diseases ◽  
Type 2 Cytokines ◽  
Lymphoid Organogenesis ◽  
Deficient Mice

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2– subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

scholarly journals Differential Activation of CD8+Tumor-Specific Tc1 and Tc2 Cells by an IL-10-Producing Murine Plasmacytoma

1998 ◽  
Vol 6 (3-4) ◽  
pp. 331-342 ◽  
Author(s):  
Christoph Specht ◽  
Hans-Gerd Pauels ◽  
Christian Becker ◽  
Eckehart Kölsch
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tumor Cells ◽  
T Cell Subsets ◽  
Early Stages ◽  
Specific Tolerance

The involvement of counteractiveCD8+T-cell subsets during tumor-specific immune responses was analyzed in a syngeneic murine plasmacytoma model.CD8+Tc cells against the immunogenic IL-10-producing BALB/c plasmacytoma ADJ-PC-5 can be easily induced by immunization of BALB/c mice with X-irradiated ADJ-PC-5 tumor cellsin vivoandin vitro. However, the failure of recipient mice to mount a protective Tc response against the tumor during early stages of a real or simulated tumor growth is not due to immunological ignorance, but depends on the induction of tumor-specific tolerance, involving a population of tumorinducedCD8+T cells that are able to inhibit the generation of tumor-specific Tc cells in a primary ADJ-PC-5-specific MLTC, using IFN-γas a suppressive factor. Whereas most longterm cultivated CD8+ADJ-PC-5-specific Tc lines produce type-1 cytokines on stimulation, at least two of them, which were derived from a primary MLTC, display a type-2 cytokine spectrum. Furthermore, the primaryin vitroTc response against ADJ-PC-5 cells shows characteristics of a Tc2 response. The Tc response is strictly depending on tumor-derived IL-10.CD8+Tc cells that are induced in a primary MLTC do not produce IFN-γ, and the tumor-specific Tc response is enhanced by IL-4 but suppressed by IFN-γor IL-12. In contrast, ADJ-PC- 5-specificCD8+Tc cells from immunized mice are IFN-γproducing Tc1 cells. Since the primaryin vitroTc response against the tumor is suppressed even by the smallest numbers of irradiated ADJ-PC-5-specific Tc1 cells via IFN-γthese Tc1 cells behave similar to the suppressiveCD8+T cells that are induced during early stages of ADJ-PC-5 tumorigenesis.

COVID-19 and Diabetes

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Awadhesh Kumar Singh ◽  
Kamlesh Khunti
Keyword(s):  
Conclusive Evidence ◽  
Annual Review ◽  
Publication Date ◽  
Β Cells ◽  
Oral Antidiabetic Agents ◽  
Randomized Controlled ◽  
Conclusive Data ◽  
New Onset

The prevalence of diabetes in people with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has varied worldwide. Most of the available evidence suggests a significant increase in severity and mortality of COVID-19 in people with either type 1 (T1DM) or type 2 diabetes mellitus (T2DM), especially in association with poor glycemic control. While new-onset hyperglycemia and new-onset diabetes (both T1DM and T2DM) have been increasingly recognized in the context of COVID-19 and have been associated with worse outcome, no conclusive evidence yet suggests direct tropism of SARS-CoV-2 on the β cells of pancreatic islets. While all approved oral antidiabetic agents appear to be safe in people with T2DM having COVID-19, no conclusive data are yet available to indicate a mortality benefit with any class of these drugs, in the absence of large randomized controlled trials. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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