Activation Of Lymphoid Cells Research Articles

Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization

Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization

Glucagon-like Peptide 1 Receptor (GLP-1R) Signaling Inhibits Aeroallergen-Induced IL-33 Release and Reduces Group 2 Innate Lymphoid Cell (ILC2) Activation In Vivo

Glucagon-like Peptide 1 Receptor (GLP-1R) Signaling Inhibits Aeroallergen-Induced IL-33 Release and Reduces Group 2 Innate Lymphoid Cell (ILC2) Activation In Vivo

Study of immunogenic properties of transmissible gastroenteritis virus antigen conjugated to gold nanoparticles

There was performed the study of immunogenic properties of the transmissible gastroenteritis virus antigen conjugated to gold nanoparticles. In comparative immunobiological studies there was found that immunization of guinea pigs driven by the colloidal gold conjugated to transmissible gastroenteritis virus antigen of swine, leads to activation of the respiratory activity of lymphoid cells and peritoneal macrophages, which is directly related to increased activity of antibody-producing cells and activation of antibody generating. The obtained data suggest that the colloid particles promote antigen presentation to the reticuloendothelial system organs. In addition, there was established that these carriers stimulate production of proinflammatory cytokines, which leads to a complete and consistent immune response of both cellular and humoral components of immune system.

Expression of the activation markers Blimp1, Foxp1 and pStat3 in extranodal diffuse large B-cell lymphomas.

Different studies have suggested that the expression of biomarkers related to lymphoid cell activation may provide information on the behavior of DLBCL. Most studies have concentrated on nodal or a mixture of nodal and extranodal lymphomas. The differential expression and potential clinical impact of these markers in a homogeneous group of extranodal DLBCLs are not well defined. In this study, we investigated the expression of three activation markers, Blimp1, Foxp1 and pStat3, in a cohort of 35 extranodal DLBCLs homogeneously treated with R-CHOP. Immunohistochemical stains were evaluated using an immunoreactivity score on representative paraffin sections. Blimp1 was positive in 55% (19/35), Foxp1 in 60% (21/35), and pStat3 in 69% (24/35) of our cases. We did not observe any statistical differences in the expression of these markers in GCB and non-GCB tumors or in gastrointestinal and non-gastrointestinal tumors. Blimp1 expression was negatively correlated with overall survival (OS) (p=0.001) in the whole series and in the non-GCB group (Muris algorithm) (p=0.002). Foxp1 positivity and pStat3 positivity had no impact on the outcome of the patients in the global cohort, but they were associated with a better survival in the non-GCB subgroup (p=0.033, p=0.044 respectively). Multivariate analysis showed that Blimp1 expression but not COO was an independent negative prognostic factor for OS (HR=17.5, 95%, CI=2.2-141.1, p=0.007). Our results suggest that these markers are differentially expressed and have different impacts on outcome in extranodal DLBCLs compared to nodal tumors, emphasizing the need to evaluate separately these and probably other markers in these subsets of tumors.

IL-1R1-MyD88 axis elicits papain-induced lung inflammation.

Allergic asthma is characterized by a strong Th2 response with inflammatory cell recruitment and structural changes in the lung. Papain is a protease allergen disrupting the airway epithelium triggering a rapid inflammation with eosinophilia mediated by innate lymphoid cell activation (ILC2) and leading to a Th2 immune response. In this study, we focused on inflammatory responses to a single exposure to papain and showed that intranasal administration of papain results in the recruitment of inflammatory cells, including neutrophils and eosinophils with a rapid production of IL-1α, IL-1β, and IL-33. The inflammatory response is abrogated in the absence of IL-1R1 and MyD88. To decipher the cell type(s) involved in MyD88-dependent IL-1R1/MyD88 signaling, we used new cell-specific MyD88-deficient mice and found that the deletion of MyD88 signaling in single cell types such as T cells, epithelial cells, CD11c-positive or myeloid cells leads to only a partial inhibition compared to complete absence of MyD88, suggesting that several cell types contribute to the response. Importantly, the inflammatory response is largely ST2 and IL-36R independent. In conclusion, IL-1R1 signaling via MyD88 is critical for the first step of inflammatory response to papain.

Morphostructure of Immune System Organs in Cattle of Different Age.

This article provides comprehensive consideration of the age-dependent morphofunctional state of organs and tissues of the immune system (thymus, spleen, superficial and deep lymph nodes) in cattle. The morphofunctional maturity of organs and tissues of the immune system in cattle will be taken into account in various experimental studies, preventive and therapeutic measures. Performed analysis provides description of the spleen formation as well as the thymus and lymph nodes in post-natal ontogenesis and the macro- and microscopic structure of lymphoid cells and macrophages. The obtained results can be used to study immune responses of the thymus, spleen, lymph nodes in the pathological immunogenesis and may serve as a basis for development of recommendations related to diagnosis and treatment of diseases of the cattle immune system. The morphofunctional state of organs and tissues of the immune system in cattle was first studied with regard to the age dynamics. Based on the immunohistological studies, this article described the distribution and topography of immunocompetent cells (T lymphocytes, B lymphocytes and macrophages) and proliferative activity of lymphoid cells in the lymphoid organs and tissues in cattle.

Rapid Inflammation in Mice Lacking Both SOCS1 and SOCS3 in Hematopoietic Cells.

The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFNγ and gamma-common (γc) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and SOCS3 show significant sequence homology and are the only SOCS proteins to possess a KIR domain. The possibility of overlapping or redundant functions was investigated in inflammatory disease via generation of mice lacking both SOCS1 and SOCS3 in hematopoietic cells. Loss of SOCS3 significantly accelerated the pathology and inflammatory disease characteristic of SOCS1 deficiency. We propose a model in which SOCS1 and SOCS3 operate independently to control specific cytokine responses and together modulate the proliferation and activation of lymphoid and myeloid cells to prevent rapid inflammatory disease.

Vitamin A Deficiency Promotes Inflammation by Induction of Type 2 Cytokines in Experimental Ovalbumin-Induced Asthma Murine Model.

Vitamin A (VA) deficiency is one of the most common malnutrition conditions. Recent reports showed that VA plays an important role in the immune balance; lack of VA could result in enhanced type 2 immune response characterized by increased type 2 cytokine production and type 2 innate lymphoid cell infiltration and activation. Type 2 immune response plays protective role in anti-infection but plays pathological role in asthmatic disease. In order to investigate the role of VA in the asthmatic disease, we used ovalbumin-induced asthma murine model and observed the pathological changes between mouse-received VA-deficient and VA-sufficient diets. We also measured the type 2 cytokine expressions to reveal the potential mechanism. Our results showed that VA deficiency exacerbates ovalbumin-induced lung inflammation and type 2 cytokine productions. Thus, VA deficiency, or malnutrition in further extent, may contribute to the increasing prevalence of asthma.

MTOR Regulation of Lymphoid Cells in Immunity to Pathogens.

Immunity to pathogens exists as a fine balance between promoting activation and expansion of effector cells, while simultaneously limiting normal and aberrant responses. These seemingly opposing functions are kept in check by immune regulators. The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that senses nutrient availability and, in turn, regulates cell metabolism, growth, and survival accordingly. mTOR plays a pivotal role in facilitating immune defense against invading pathogens by regulating the differentiation, activation, and effector functions of lymphoid cells. Here, we focus on the emerging and sometimes contradictory roles of mTOR in orchestrating lymphoid cell-mediated host immune responses to pathogens. A thorough understanding of how mTOR impacts lymphoid cells in pathogen defense will provide the necessary base for developing therapeutic interventions for infectious diseases.

C-Kit inhibitors prevent respiratory viral infection-induced acute asthma via the blockade of innate lymphoid cell activation

Abstract Asthma is a major public health problem that affects nearly 10% of the general population and is thought to be mediated by allergen-specific Th2 cells, adaptive immunity and allergic inflammation. Current treatments for asthma generally focus on minimizing the Th2-driven eosinophilic inflammation with the use of anti-inflammatory therapies such as corticosteroids. However, this approach, targeting the adaptive Th2 cell immunity with corticosteroids, has not reduced the high rates of hospitalizations for acute asthma, most often caused by acute viral infection, including influenza. Recently, type 2 innate lymphoid cells (ILC2) expressing c-Kit have been shown to expand during influenza infection and directly caused airway hyper reactivity (AHR), a cardinal feature of asthma. We now show that the treatment of influenza-infected mice with c-Kit kinase inhibitors blocked the development of AHR and airway inflammation and greatly reduced the number and function of ILC2 cells, whereas the treatment with corticosteroids, commonly used to treat acute asthma, failed to prevent the influenza-induced AHR. We also demonstrated that c-Kit function is required for normal ILC2 cell function and for influenza-induced AHR, and that c-Kit kinase inhibitor inhibits murine lung ILC2 cell proliferation and cytokine productions in vitro and in vivo. Furthermore, the treatment of c-Kit inhibitor did not affect in vivo viral clearance. Our study demonstrated the crucial role of c-Kit in modulating the ILC2 activation in the lungs, particularly in respiratory viral infection induced acute asthma.

Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

AbstractSince its discovery in the late 1990s, Pten has turned out to be one of the most important tumor suppressor genes. Pten loss results in increased activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which is associated with increased proliferation, survival, and neoplastic growth. Here, we have addressed the effects of conditional deletion of Pten in hematopoietic cells by crossing Pten conditional knockout mice with a knock-in mouse expressing the Cre recombinase in the CD45 locus. CD45 is also known as leukocyte common antigen, and it is expressed in virtually all white cells and in hematopoietic stem cells. Using a reporter mouse, we demonstrate that CD45:Cre mouse displays recombinase activity in both myeloid and lymphoid cells. However, deletion of Pten in CD45-expressing cells induces development of T-cell acute lymphoblastic leukemia and lymphoma, but not other hematologic malignancies.

The histone deacetylase inhibitor trichostatin A suppresses murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation

BackgroundGroup 2 innate lymphoid cells (ILC2) are an important source of the type 2 cytokines interleukin (IL)-5 and IL-13 that are critical to the allergic airway phenotype. Previous studies reported...

The Histone Deacetylase Inhibitor Trichostatin a (TSA) Suppresses Alternaria Extract-Induced Murine Innate Allergic Inflammation By Blocking Group 2 Innate Lymphoid Cell (ILC2) Activation

The Histone Deacetylase Inhibitor Trichostatin a (TSA) Suppresses Alternaria Extract-Induced Murine Innate Allergic Inflammation By Blocking Group 2 Innate Lymphoid Cell (ILC2) Activation

Telomerase reverse transcriptase acts in a feedback loop with NF-κB pathway to regulate macrophage polarization in alcoholic liver disease.

Activation of Kupffer cells (KCs) plays a central role in the pathogenesis of alcoholic liver disease (ALD). C57BL/6 mice fed EtOH-containing diet showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Since telomerase activation occurs at critical stages of myeloid and lymphoid cell activation, we herein investigated the role of telomerase reverse transcriptase (TERT), the determining factor of telomerase, in macrophage activation during ALD. In our study, TERT expression and telomerase activity (TA) were remarkably increased in liver tissue of EtOH-fed mice. Moreover, EtOH significantly up-regulated TERT in isolated KCs and RAW 264.7 cells and LPS induced TERT production in vitro. These data indicate that up-regulation of TERT may play a critical role in macrophages during ALD. Furthermore, loss- and gain-of-function studies suggested that TERT switched macrophages towards M1 phenotype by regulating NF-κB signaling, but had limited effect on M2 macrophages polarization in vitro. Additionally, PDTC, a chemical inhibitor of NF-κB, could dramatically down-regulate TERT expression and the hallmarks of M1 macrophages. Therefore, our study unveils the role of TERT in macrophage polarization and the cross-talk between TERT and p65, which may provide a possible explanation for the ethanol-mediated hepatic proinflammatory response and M1 macrophage polarization.

Expression of CD200R1 and its Ligand CD200 on T-helper Lymphocytes of Pediatric Patients with Ulcerative Colitis and Crohn's Disease.

CD200 and its receptor CD200R are both type I membrane glycoproteins that modulate the activity of myeloid and lymphoid cells, and their interaction is functionally important in the suppression of effector T-cell responses by regulatory T-cells. We aimed to investigate the extent of expression of CD200 and CD200R1 on CD4+ T-cells in blood of children with ulcerative colitis (UC) and Crohn's disease (CD) and to explore their correlations with effector T cell subsets, regulatory T cells (Treg), and routine clinical and serological markers. The frequencies of blood CD4+ expressing CD200 and CD200R1 as well as T-helper CD4+CD25+Foxp3+ Treg, CD4+ IL-17+ (Th17), CD4+ IFN-γ + (Th1), and CD4+IL-4+ (Th2) were estimated by flow cytometry in 23 patients with CD, 14 with UC, and 14 healthy volunteers (HCs). The clinical and inflammatory markers were also investigated. IBD patients showed decreased CD4+CD200R1+ T-cells, whereas, CD4+CD200+ T-cells were significantly higher in patient groups compared with healthy controls. Treg cells were found significantly decreased in the patients with UC and CD compared with healthy controls (both at p < 0.01). The percentage of Th17 was found significantly increased in CD (p < 0.05) compared with UC patients and healthy subjects (p = 0.014). CD200+CD4+ T-cells showed significant positive correlations with ESR, Th1, and Th17 (r = 0.438, p < 0.05; r = 0.411, p < 0.05; r = 0.492, p < 0.01, respectively). CD200R1+CD4+ T-cells correlated positively with Th2 and Treg (r = 0.482, p < 0.01, and r = 0.457, p < 0.01, respectively) and negatively with ESR (r = -0.387, p < 0.01). Our study demonstrates an aberrant expression of CD200/CD200R1 on CD4+ T-cells in IBD patients and these data may have potent pathological significance in IBD pathophysiology.

Immune Mechanisms of Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is a common inflammatory disease that results in a significant decrease in patient quality of life and a large economic burden. However, the lack of population-based epidemiologic studies and robust model systems has made it difficult to fully elucidate the key inflammatory pathways that drive the chronic inflammatory responses observed in CRS. This review will highlight the wide variety of factors that likely contribute to CRS disease pathogenesis. Defects in the innate immune function of the airway epithelium, including decreases in barrier function, mucociliary clearance, and production of antimicrobial peptides, all likely play a role in the initial inflammatory response. Subsequent recruitment and activation of eosinophils, mast cells, and innate lymphoid cells (ILCs) further contributes to the chronic inflammatory response and directly activates adaptive immune cells, including T and B cells. However, development of new tools and model systems is still needed to further understand the chronicity of this inflammatory response and which specific factors are necessary or sufficient to drive CRS pathogenesis. Such studies will be critical for the development of improved therapeutic strategies aimed at treating this highly prevalent and costly disease.

Pandemic influenza virus, pH1N1, induces asthmatic symptoms via activation of innate lymphoid cells.

The pandemic strain of the influenza A virus (pH1N1) in 2009 caused many complications in patients. In this study, we introduce asthmatic symptoms as a complication of pH1N1 infection in children, not having a relationship with asthma history. The aim of this study was to quantify asthmatic symptoms in pH1N1-infected children and elucidate the underlying mechanisms of airway hyper-responsiveness (AHR) induced in a murine model of pH1N1 infection. As a retrospective study, pH1N1-infected children who were hospitalized with moderate to severe acute asthmatic symptoms were enrolled and administered a methacholine challenge test (MCT) at 3 months post-discharge. Additionally, the induction of AHR by pH1N1 infection was measured by MCT in wild-type and Rag1(-/-) mice. The effect of the innate immune response on the development of AHR following pH1N1 infection was investigated. More than 70% of the pH1N1-infected children without a pre-infection diagnosis of asthma had a negative response on the MCT. None of these children had recurrent wheezing or asthma during the 3 years following pH1N1 infection. The development of AHR in pH1N1-infected mice was associated with an elevation in IL-33 and innate lymphoid cells 2 (ILC2). This study demonstrates that pH1N1 infection directly induces transient asthmatic symptoms in patients regardless of their medical history. pH1N1 infection was shown to stimulate the rapid development of AHR and Th2-type cytokine secretion in mice via the activation of ILC2; it may be activated independently of adaptive immunity.

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.

ICOS promotes group 2 innate lymphoid cell activation in lungs

Group 2 innate lymphoid cells (ILC2s) are newly identified, potent producers of type 2 cytokines, such as IL-5 and IL-13, and contribute to the development of allergic lung inflammation induced by cysteine proteases. Although it has been shown that inducible costimulator (ICOS), a costimulatory molecule, is expressed on ILC2s, the role of ICOS in ILC2 responses is largely unknown. In the present study, we investigated whether the interaction of ICOS with its ligand B7-related protein-1 (B7RP-1) can promote ILC2 activation. Cytokine production in ILC2s purified from mouse lungs was significantly increased by coculture with B7RP-1-transfected cells, and increased cytokine production was inhibited by monoclonal antibody-mediated blocking of the ICOS/B7RP-1 interaction. ILC2 expansion and eosinophil influx induced by papain, a cysteine protease antigen, in mouse lungs were significantly abrogated by blocking the ICOS/B7RP-1 interaction. Dendritic cells (DCs) in the lungs expressed B7RP-1 and the number of DCs markedly increased with papain administration. B7RP-1 expression on lung DCs was reduced after papain administration. This downregulation of B7RP-1 expression may be an indication of ICOS/B7RP-1 binding. These results indicate that ILC2s might interact with B7RP-1-expressing DCs in allergic inflammatory lung, and ICOS signaling can positively regulate the protease allergen-induced ILC2 activation followed by eosinophil infiltration into the lungs.

Suppression of OVA-alum induced allergy by Heligmosomoides polygyrus products is MyD88-, TRIF-, regulatory T- and B cell-independent, but is associated with reduced innate lymphoid cell activation

The murine intestinal nematode Heligmosomoides polygyrus exerts multiple immunomodulatory effects in the host, including the suppression of allergic inflammation in mice sensitized to allergen presented with alum adjuvant. Similar suppression is attained by co-administration of H. polygyrus excretory/secretory products (HES) with the sensitizing dose of ovalbumin (OVA) in alum. We investigated the mechanism of suppression by HES in this model, and found it was maintained in MyD88xTRIF-deficient mice, implying no role for helminth- or host-derived TLR ligands, or IL-1 family cytokines that signal in a MyD88- or TRIF-dependent manner. We also found suppression was unchanged in µMT mice, which lack B2 B cells, and that suppression was not abrogated when regulatory T cells were depleted in Foxp3.LuciDTR-4 mice. However, reduced IL-5 production was seen in the first 12 h after injection of OVA-alum when HES was co-administered, associated with reduced activation of IL-5+ and IL-13+ group 2 innate lymphoid cells. Thus, the suppressive effects of HES on alum-mediated OVA sensitization are reflected in the very earliest innate response to allergen exposure in vivo.