scholarly journals A Gata3 enhancer necessary for ILC2 development and function

2021 ◽  
Vol 118 (32) ◽  
pp. e2106311118
Author(s):  
Darshan N. Kasal ◽  
Zhitao Liang ◽  
Maile K. Hollinger ◽  
Crystal Y. O’Leary ◽  
Wioletta Lisicka ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Regulatory Pathways ◽  
Th2 Cell ◽  
Gata3 Expression ◽  
Gene Regulatory ◽  
High Level ◽  
And Function

The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4+ T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.

scholarly journals Group 2 Innate Lymphoid Cells: A Double-Edged Sword in Cancer?

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3452
Author(s):  
Enrico Maggi ◽  
Irene Veneziani ◽  
Lorenzo Moretta ◽  
Lorenzo Cosmi ◽  
Francesco Annunziato
Keyword(s):  
Immune Response ◽  
Inflammatory Responses ◽  
Cell Subset ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cell ◽  
Type 2 Immune Response ◽  
Group 2 ◽  
Lymphoid Organogenesis

Group 2 Innate Lymphoid Cells (ILC2s) belong to the family of helper ILCs which provide host defense against infectious agents, participate in inflammatory responses and mediate lymphoid organogenesis and tissue repair, mainly at the skin and mucosal level. Based on their transcriptional, phenotypic and functional profile, ILC2s mirror the features of the adaptive CD4+ Th2 cell subset, both contributing to the so-called type 2 immune response. Similar to other ILCs, ILC2s are rapidly activated by signals deriving from tissue and/or other tissue-resident immune cells. The biologic activity of ILCs needs to be tightly regulated in order to prevent them from contributing to severe inflammation and damage in several organs. Indeed, ILC2s display both enhancing and regulatory roles in several pathophysiological conditions, including tumors. In this review, we summarize the actual knowledge about ILC2s ability to induce or impair a protective immune response, their pro- or antitumor activity in murine models, human (children and adults) pathologies and the potential strategies to improve cancer immunotherapy by exploiting the features of ILC2s.

Single-cell analysis pinpoints distinct populations of cytotoxic CD4+ T cells and an IL-10+CD109+ TH2 cell population in nasal polyps

2021 ◽  
Vol 6 (62) ◽  
pp. eabg6356
Author(s):  
Junjie Ma ◽  
Christopher A. Tibbitt ◽  
Susanna Kumlien Georén ◽  
Murray Christian ◽  
Ben Murrell ◽  
...  
Keyword(s):  
T Cells ◽  
Nasal Polyps ◽  
Single Cell Analysis ◽  
D2 Receptor ◽  
Lymphoid Cells ◽  
Multiparameter Flow Cytometry ◽  
Prostaglandin D2 ◽  
Th2 Cell ◽  
Gata3 Expression

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic inflammatory process often associated with comorbid asthma. In this study, we analyzed the transcriptomes of single T helper (TH) cells from nasal polyps of patients with CRSwNP and validated these findings using multiparameter flow cytometry. Polyp tissue contained suppressive T regulatory (Treg) cells, TH2 cells, type 2 innate lymphoid cells, and three transcriptionally distinct subsets of cytotoxic CD4+ T cells (CD4+ CTL). GATA3 expression was a feature of polyp Treg cells, whereas TH2 cells highly expressed TCN1, CD200R, and HPGDS and were enriched for genes involved in lipid metabolism. Only a portion of polyp TH2 cells expressed the prostaglandin D2 receptor CRTH2, whereas a subpopulation of CD109+CRTH2− TH2 cells expressed mRNA for common inhibitor receptors including LAG3 and TIM3 and produced IL-10. Together, we resolved the complexity of TH cells in patients with CRSwNP, identifying several distinct clusters of CD4+ CTL and a population of CD109+CRTH2− TH2 cells with putative regulatory potential.

scholarly journals MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation

2017 ◽  
Vol 214 (12) ◽  
pp. 3627-3643 ◽  
Author(s):  
Priti B. Singh ◽  
Heather H. Pua ◽  
Hannah C. Happ ◽  
Christoph Schneider ◽  
Jakob von Moltke ◽  
...  
Keyword(s):  
Target Genes ◽  
Therapeutic Potential ◽  
Allergic Inflammation ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Signaling Inhibitors ◽  
Regulated Gene Expression ◽  
And Function

MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92–deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses.

scholarly journals Critical Involvement of CD44 in T Helper Type 2 Cell-Mediated Eosinophilic Airway Inflammation in a Mouse Model of Acute Asthma

2022 ◽  
Vol 12 ◽  
Author(s):  
Shigeki Katoh
Keyword(s):  
Monoclonal Antibodies ◽  
Airway Inflammation ◽  
Th17 Cells ◽  
Acute Asthma ◽  
Mite Allergen ◽  
Th2 Cells ◽  
T Helper ◽  
Th2 Cell ◽  
Helper Type

Interactions between CD44 and hyaluronan (HA) are crucial for recruiting leukocytes to inflamed tissues. This review summarizes findings from our studies of the roles of CD44-HA interactions in leukocyte trafficking, with a particular focus on airway T helper type 2 (Th2) cells in mouse models of acute asthma. In a mite allergen-induced model of acute asthma, intraperitoneal injection of anti-CD44 monoclonal antibodies blocked lymphocytes and eosinophils from accumulating in the lung, and suppressed both the antigen-induced increase in Th2 cytokines in the bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR). CD44 deficiency was associated with decreased mite allergen-induced Th2 cell-mediated airway inflammation and AHR in sensitized mice. Asthmatic responses to antigen-sensitized splenic CD4+ T cells transferred from CD44-deficient mice were weaker than in wild-type mice. Administration of anti-CD44 monoclonal antibodies preferentially suppressed the airway accumulation of antigen-specific Th2 cells induced by antigen challenge, without affecting Th1 and Th17 cells. Increased HA-binding ability of CD44 and expression of Neu1 sialidase were observed on antigen-specific Th2 cells compared with antigen-specific Th1 and Th17 cells. Finally, in a mouse model of acute asthma, neuraminidase 1-deficient SM/J mice exhibited a lower Th2 cytokine concentration and a lower absolute Th2 cell number in the BALF, as well as an attenuated AHR. Our findings indicate that CD44 critically contributes to the antigen challenge-induced airway accumulation of antigen-specific Th2 cells, without affecting Th1 and Th17 cells, in mice. Furthermore, neuraminidase 1 activity is necessary for the interaction between HA and CD44, and Th2 cell-mediated airway inflammation.

scholarly journals ILC2 Cells Promote Th2 Cell Differentiation in AECOPD Through Activated Notch-GATA3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Jiang ◽  
Ren Cai ◽  
Jing Wang ◽  
Zheng Li ◽  
Dan Xu ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Peripheral Blood ◽  
Culture Supernatant ◽  
Th2 Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Th2 Cell

This study is to investigate the capacity of type 2 innate lymphoid cells (ILC2s) in regulating the Th2 type adaptive immune response of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The study enrolled healthy people, stable chronic obstructive pulmonary disease (COPD) patients, and AECOPD patients. Flow cytometry was used to detect Th2 and ILC2 cells in the peripheral blood. In addition, ILC2s from the peripheral blood of AECOPD patients were stimulated with PBS, IL-33, Jagged1, DAPT, IL-33+Jagged1, IL-33+DAPT, and IL-33+Jagged-1+DAP in vitro. The levels of cytokines in the culture supernatant were detected by ELISA and the culture supernatant was used to culture CD4 + T cells. The mRNA and protein levels of Notch1, hes1, GATA3, RORα, and NF-κB of ILC2s were detected by real-time PCR and Western blot. The proportion of Th2 and ILC2s was significantly increased in the peripheral blood of AECOPD patients, alone with the increased Notch1, hes1, and GATA3 mRNA levels. In vitro results showed that the mRNA and protein levels of Notch1, hes1, GATA3 and NF-κB were significantly increased after stimulation with Notch agonist, meanwhile, the level of type 2 cytokines were increased in the supernatant of cells stimulated with Notch agonist, and significantly promoted differentiation of Th2 cells in vitro. Disruption of Notch pathway weakened GATA3 expression and cytokine production, and ultimately affected the differentiation of Th2 cells. In conclusion, our results suggest that ILC2s can promote Th2 cell differentiation in AECOPD via activated Notch-GATA3 signal pathway.

scholarly journals Metabolic Interdependency of Th2 Cell-Mediated Type 2 Immunity and the Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Simon Schreiber ◽  
Christoph M. Hammers ◽  
Achim J. Kaasch ◽  
Burkhart Schraven ◽  
Anne Dudeck ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Allergic Diseases ◽  
Building Blocks ◽  
Th2 Cells ◽  
Th Cells ◽  
Th2 Cell ◽  
Type 2 Immunity ◽  
Mediate Immunity

The function of T cells is critically dependent on their ability to generate metabolic building blocks to fulfil energy demands for proliferation and consecutive differentiation into various T helper (Th) cells. Th cells then have to adapt their metabolism to specific microenvironments within different organs during physiological and pathological immune responses. In this context, Th2 cells mediate immunity to parasites and are involved in the pathogenesis of allergic diseases including asthma, while CD8+ T cells and Th1 cells mediate immunity to viruses and tumors. Importantly, recent studies have investigated the metabolism of Th2 cells in more detail, while others have studied the influence of Th2 cell-mediated type 2 immunity on the tumor microenvironment (TME) and on tumor progression. We here review recent findings on the metabolism of Th2 cells and discuss how Th2 cells contribute to antitumor immunity. Combining the evidence from both types of studies, we provide here for the first time a perspective on how the energy metabolism of Th2 cells and the TME interact. Finally, we elaborate how a more detailed understanding of the unique metabolic interdependency between Th2 cells and the TME could reveal novel avenues for the development of immunotherapies in treating cancer.

scholarly journals Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
M. Sambucci ◽  
F. Laudisi ◽  
F. Novelli ◽  
E. Bennici ◽  
M. M. Rosado ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Inflammatory Responses ◽  
Inhibitory Effect ◽  
Th2 Cells ◽  
Cell Functions ◽  
Th2 Cell ◽  
Gene Ablation ◽  
Immune Mediated ◽  
Parp 1 ◽  
Th1 And Th2

T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosy)lation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose) polymerases (PARPs). Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT) activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+cells as well as IFN-γproduction, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.

scholarly journals Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration

2020 ◽  
Vol 21 (4) ◽  
pp. 1350 ◽  
Author(s):  
Melina Messing ◽  
Sia Cecilia Jan-Abu ◽  
Kelly McNagny
Keyword(s):  
T Regulatory Cells ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Helminth Infections ◽  
Neonatal Immunity ◽  
Group 2 ◽  
Transcription Factor Expression

Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.

scholarly journals Dendritic Cell-Mediated Th2 Immunity and Immune Disorders

2019 ◽  
Vol 20 (9) ◽  
pp. 2159 ◽  
Author(s):  
Sunil Kumar ◽  
Yideul Jeong ◽  
Muhammad Umer Ashraf ◽  
Yong-Soo Bae
Keyword(s):  
Genetic Defect ◽  
Lymphoid Cells ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Severe Atopic Dermatitis ◽  
Immune Disorders ◽  
Humoral Immune ◽  
Th2 Immune Response ◽  
Th2 Immunity

Dendritic cells (DCs) are the professional antigen-presenting cells that recognize and present antigens to naïve T cells to induce antigen-specific adaptive immunity. Among the T-cell subsets, T helper type 2 (Th2) cells produce the humoral immune responses required for protection against helminthic disease by activating B cells. DCs induce a Th2 immune response at a certain immune environment. Basophil, eosinophil, mast cells, and type 2 innate lymphoid cells also induce Th2 immunity. However, in the case of DCs, controversy remains regarding which subsets of DCs induce Th2 immunity, which genes in DCs are directly or indirectly involved in inducing Th2 immunity, and the detailed mechanisms underlying induction, regulation, or maintenance of the DC-mediated Th2 immunity against allergic environments and parasite infection. A recent study has shown that a genetic defect in DCs causes an enhanced Th2 immunity leading to severe atopic dermatitis. We summarize the Th2 immune-inducing DC subsets, the genetic and environmental factors involved in DC-mediated Th2 immunity, and current therapeutic approaches for Th2-mediated immune disorders. This review is to provide an improved understanding of DC-mediated Th2 immunity and Th1/Th2 immune balancing, leading to control over their adverse consequences.

scholarly journals Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Kun He ◽  
Angela Hettinga ◽  
Sagar Laxman Kale ◽  
Sanmei Hu ◽  
Markus M. Xie ◽  
...  
Keyword(s):  
Allergic Airway Inflammation ◽  
Cell Development ◽  
Th2 Cells ◽  
Th2 Response ◽  
Cell Responses ◽  
Th2 Cell ◽  
Th2 Immune Response ◽  
Upstream Promoter ◽  
Gata3 Expression ◽  
Anti Inflammatory Cytokine

A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10–STAT3–Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.

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