scholarly journals CD8+ Tc2 cells: underappreciated contributors to severe asthma

2019 ◽  
Vol 28 (154) ◽  
pp. 190092 ◽  
Author(s):  
Timothy S.C. Hinks ◽  
Ryan D. Hoyle ◽  
Erwin W. Gelfand
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Stable State ◽  
Lavage Fluid ◽  
Leukotriene B4 ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Prostaglandin D2 ◽  
Eosinophilic Asthma

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8+ T-cells. Extensive murine data reveal the plasticity of CD8+ T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8+ Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8+ T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.

scholarly journals SAT0025 NEUROMEDIN U SUPPRESSES COLLAGEN-INDUCED ARTHRITIS THROUGH ACTIVATION OF ILC2

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 942.2-942
Author(s):  
Y. Zhang ◽  
Y. Qin ◽  
Z. Chen
Keyword(s):  
Flow Cytometry ◽  
Molecular Mechanisms ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Repeated Injection ◽  
Collagen Induced Arthritis ◽  
Clinical Onset ◽  
Deficient Mice

Background:Reduction and dysregulation of ILC2 was linked to delayed resolution of arthritis. The neuropeptide Neuromedin U (NMU) has been reported to rapidly activate ILC2 and initiate a Th2 type immune response through NMUR1 expressed on the surface of ILC2. However, one previous study reported that NMU promoted autoantibody-mediated arthritis.Objectives:The aim of this work was to investigate the effect of NMU on collagen-induced arthritis (CIA) mice and the potential mechanisms.Methods:CIA was induced in C57BL/6 WT and C57BL/6Nmudeficient mice on day 1. WT mice were treated i.p. daily by NMU-23 (20ug/mice) or by PBS for 10 days from day 1 to 5 and day 21 to 25. The clinical scores of CIA mice were assessed every two days from day 22 and determined on a scale of 0–4 for each paw. The proportion of ILC2 as well as Th1, Th2, Th17 and Treg in spleen, mesenteric lymph node (mLN) and joints of arthritic mice were analyzed by flow cytometry on day 42.Results:NMU-23 dramatically inhibited clinical onset and severity of arthritis in treated WT mice compared with control mice. Interestingly, NMU-deficient mice also developed significantly less severe arthritis compared with WT control (Fig 1). Flow cytometry analyses showed that the proportion of ILC2, which defined as Lin-CD45+CD127+KLRG1+ICOS+ST2+, was elevated in the joint but not in the spleen and mLN of arthritic mice treated with NMU-23. In contrast, the proportion of ILC2 was significantly lower in the spleen of NMU-deficient mice than WT control. The percentage of Th2 cells in the spleen and mLN tend to be higher in NMU-23 treated mice, but there is no statistical significance. Surprisingly, Th1 cells were increased in the mLN of NMU-23 treated and NMU-deficient mice compared with control whereas Th17 was comparable among groups. In addition, the proportion of Treg was decreased in the joint of NMU-23 treated and NMU-deficient mice compared with control mice.Conclusion:Our preliminary results show that repeated injection of NMU-23 during induction (early) and development (late) stage of CIA strongly suppressed clinical onset and severity of arthritis, which might be ascribed to activation of ILC2 in the joint. Further study is needed to explore other cellular and molecular mechanisms in the effect.References:[1] Cardoso V, Chesne J, Ribeiro H et al (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549 (7671):277-281.[2] Klose CSN, Mahlakoiv T, Moeller JB et al (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549 (7671):282-286.[3] Wallrapp A, Riesenfeld SJ, Burkett PR et al (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549 (7672):351-356.[4] Sindhuja M Rao, Jennifer L Auger, Philippe Gaillard et al (2012) The Neuropeptide Neuromedin U Promotes Autoantibody-Mediated Arthritis. Arthritis Res Ther, 14 (1), R29.Disclosure of Interests:None declared

scholarly journals Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s

2016 ◽  
Vol 214 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Jakob von Moltke ◽  
Claire E. O’Leary ◽  
Nora A. Barrett ◽  
Yoshihide Kanaoka ◽  
K. Frank Austen ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Inflammation ◽  
Primary Source ◽  
Cell Receptor ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Deficient Mice

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33– and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.

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 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 Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism

2015 ◽  
Vol 309 (10) ◽  
pp. L1208-L1218 ◽  
Author(s):  
Timothy P. Moran ◽  
Keiko Nakano ◽  
Gregory S. Whitehead ◽  
Seddon Y. Thomas ◽  
Donald N. Cook ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Allergic Asthma ◽  
House Dust ◽  
Lavage Fluid ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cell Responses ◽  
Th2 Responses ◽  
Th2 Differentiation

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

Stat6 Inhibits Human Interleukin-4 Promoter Activity in T Cells

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4529-4538 ◽  
Author(s):  
Steve N. Georas ◽  
John E. Cumberland ◽  
Thomas F. Burke ◽  
Rongbing Chen ◽  
Ulrike Schindler ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Regulatory Elements ◽  
Jurkat Cells ◽  
Proximal Promoter ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th Cells

Abstract The differentiation of naive T-helper (Th) cells into cytokine-secreting effector Th cells requires exposure to multiple signals, including exogenous cytokines. Interleukin-4 (IL-4) plays a major role in this process by promoting the differentiation of IL-4–secreting Th2 cells. In Th2 cells, IL-4 gene expression is tightly controlled at the level of transcription by the coordinated binding of multiple transcription factors to regulatory elements in the proximal promoter region. Nuclear factor of activated T cell (NFAT) family members play a critical role in regulating IL-4 transcription and interact with up to five sequences (termed P0 through P4) in the IL-4 promoter. The molecular mechanisms by which IL-4 induces expression of the IL-4 gene are not known, although the IL-4–activated transcription factor signal transducer and activator of transcription 6 (Stat6) is required for this effect. We report here that Stat6 interacts with three binding sites in the human IL-4 promoter by electrophoretic mobility shift assays. These sites overlap the P1, P2, and P4 NFAT elements. To investigate the role of Stat6 in regulating IL-4 transcription, we used Stat6-deficient Jurkat T cells with different intact IL-4 promoter constructs in cotransfection assays. We show that, whereas a multimerized response element from the germline IgE promoter was highly induced by IL-4 in Stat6-expressing Jurkat cells, the intact human IL-4 promoter was repressed under similar conditions. We conclude that the function of Stat6 is highly dependent on promoter context and that this factor promotes IL-4 gene expression in an indirect manner.

Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 alleviate allergic rhinitis in mice by restoring Th2/Treg imbalance and gut microbiota disturbance

2019 ◽  
Vol 10 (1) ◽  
pp. 55-67 ◽  
Author(s):  
W.-G. Kim ◽  
G.-D. Kang ◽  
H.I. Kim ◽  
M.J. Han ◽  
D.-H. Kim
Keyword(s):  
T Cells ◽  
Allergic Rhinitis ◽  
Regulatory T Cells ◽  
Gut Microbiota ◽  
Lactobacillus Plantarum ◽  
Immunoglobulin E ◽  
Bifidobacterium Longum ◽  
Lavage Fluid ◽  
Th2 Cells

This study aimed to examine whether probiotics, which suppressed the differentiation of splenic T cells into type 2 helper T (Th2) cells and induced into regulatory T cells in vitro, alleviate allergic rhinitis (AR) and gut microbiota disturbance. We isolated Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 from human faecal microbiota and kimchi, respectively, and examined their effects on ovalbumin (OVA)-induced AR and gut microbiota disturbance in mice. Treatment with IM55, IM76, or their probiotic mixture (PM) significantly reduced OVA-induced allergic nasal symptoms and blood immunoglobulin E (IgE) levels in mice. These also reduced OVA-induced interleukin (IL)-4 and IL-5 levels in nasal tissues and bronchoalveolar lavage fluid (BALF) but increased OVA-suppressed IL-10 levels. Treatment with IM55, IM76, or PM reduced OVA-induced increase in the populations of mast cells, eosinophils, and Th2 cells and increased OVA-suppressed population of regulatory T cells in the BALF. Treatment with IM55, IM76, or PM also inhibited OVA-induced expression of IL-5 in lung and colon tissues and restored OVA-disturbed composition of gut microbiota Proteobacteria, Bacteroidetes, and Actinobacteria. These results suggest that IM55 and IM67 can alleviate AR by restoring Th2/Treg imbalance and gut microbiota disturbance.

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 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.

The role of type 2 innate lymphoid cells in eosinophilic asthma

2019 ◽  
Vol 106 (4) ◽  
pp. 889-901 ◽  
Author(s):  
Brittany M. Salter ◽  
Michael Aw ◽  
Roma Sehmi
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Eosinophilic Asthma
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