scholarly journals Tissue-Resident Innate and Innate-Like Lymphocyte Responses to Viral Infection

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 272
Author(s):  
Andrew Hildreth ◽  
Timothy O’Sullivan
Keyword(s):  
Viral Infection ◽  
Cytokine Production ◽  
Lymphocyte Subsets ◽  
Current Knowledge ◽  
Critical Role ◽  
Lymphoid Cells ◽  
T Cell Subsets ◽  
Antiviral Responses ◽  
Host Protection ◽  
Lymphocyte Responses

Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Recent discoveries have demonstrated that tissue-resident lymphocyte subsets, comprised of innate lymphoid cells (ILCs) and unconventional T cells, have vital roles in the initiation of primary antiviral responses. Via direct and indirect mechanisms, ILCs and unconventional T cell subsets play a critical role in the ability of the immune system to mount an effective antiviral response through potent early cytokine production. In this review, we will summarize the current knowledge of tissue-resident lymphocytes during initial viral infection and evaluate their redundant or nonredundant contributions to host protection or virus-induced pathology.

scholarly journals Mechanistic Insights into the Inhibition of T Regulatory Cells By Dasatinib May Predict Immunostimulatory Effects in CML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1635-1635
Author(s):  
Patrick Harrington ◽  
Richard Dillon ◽  
Philippe Rousselot ◽  
Deepti Radia ◽  
Yvonne Francis ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cell ◽  
Research Funding ◽  
Cytokine Production ◽  
Critical Role ◽  
T Cell Subsets ◽  
Healthy Controls ◽  
Cd4 Cells ◽  
The Mean ◽  
And Function

Background Dasatinib potently inhibits the Src family kinase Lck at therapeutic concentrations. Lck plays a critical role in signalling from the T cell receptor with immediate downstream targets including ZAP70 and LAT. The cell surface scaffolding protein LAT has been previously shown to play a central role in normal Treg development. STAT5, the downstream target of IL-2, also plays a critical role in Treg differentiation and maintenance of FOXP3 expression through its binding of the promoter region of the FOXP3 gene. The proportion of Tregs has been shown to inversely correlate with improved molecular response in patients on dasatinib and a subset of patients taking dasatinib will develop a large granular lymphocytosis (LGL) which is associated with inflammatory toxicity and improved outcome (Mustjoki et al. Leukaemia 2009). We hypothesised that a reduction in Treg frequency and function would correlate with the expansion of a clonal LGL population in certain patients taking dasatinib. To investigate this, we performed ex-vivo analysis of the phosphorylation of key cell signalling proteins and intracellular cytokine production in Tregs and T effectors from CML patients and healthy controls. Methods We first performed phosphoflow cytometry in Tregs and T effectors to assess the effect of dasatinib on signalling downstream from the TCR, including activated/phosphorylated ZAP70 (pZAP70), LAT (pLAT) and STAT5 (pSTAT5). 11-colour flow cytometry was performed after cells were activated with H2O2 for 15 minutes, due to its activity as a potent phosphatase inhibitor. A gating strategy of CD3+/CD4+/CD25+/FOXP3+/CD127lo cells was used for identification of Tregs. We then performed 10-colour intracellular flow cytometry assessing the impact of dasatinib on cellular cytokine production including TNF, IFN gamma, IL-2, IL-4 and IL-10 after stimulation with OKT3. Results 8 patients with CML and 2 healthy controls were recruited. Of the CML patients 5 were taking dasatinib, 100mg daily, two were taking imatinib and one nilotinib. Patients on dasatinib had lower proportion of Tregs compared with the non dasatinib group with a mean proportion of CD3+ cells of 1.4 vs 2.1. Patients on dasatinib had significantly reduced phosphorylation of ZAP70 compared with the non dasatinib group in CD3+ cells, CD4+ cells and Tregs, following H2O2 stimulation. The mean increase in median fluorescence intensity (MFI) of pZAP70 was 1.7 vs 3.6 in CD3+ cells, 1.4 vs 3.5 in CD4+ cells and 1.5 vs 2.8 in Tregs (p=0.006, p=0.004, p=0.045). Similarly, pLAT showed a lower increase in phosphorylation in the dasatinib group in all T cell subsets evaluated, with mean increase in MFI of 4.3 vs 11.9 in CD3+ cells, 4 vs 12.3 in CD4+ cells and 4.3 vs 8.2 in Tregs. STAT5 also showed reduced phosphorylation in the dasatinib group with a mean increase in MFI of 6.4 vs 21.2 in CD3+ cells, 5.7 vs 20.3 in CD4+ cells and 5.9 vs 19.7 in Tregs (p=0.007, p=0.003, p=0.01). Two patients on dasatinib had reversal of normal CD4:CD8 ratio, with one of these also having absolute lymphocytosis, in keeping with likely development of clonal LGL populations. These patients had lower increase in MFI of pZAP70, pLAT and pSTAT5 following stimulation within isolated Tregs compared to patients on dasatinib with normal CD4:CD8 (Figure 1A). Within CD4+ cells the mean proportional increase in IL-2 production was lower in the dasatinib group at 0.4 vs 5 (p=0.003). Using an additional panel, a single patient was also evaluated and shown to have strikingly reduced production of TNF within isolated Tregs and Il-2 within CD4+cells compared to control (Figure 1B). Conclusion Dasatinib inhibits phosphorylation of ZAP70, LAT and STAT5 within T cell subsets including Tregs, with the strongest effect seen against STAT5. In addition, dasatinib causes a reduction in pro-inflammatory cytokine production within CD4+ cells, with the most significant inhibitory effect seen against IL-2. Tregs have abundant expression of the IL-2 receptor on the cell surface and binding leads to STAT5 signalling resulting in transcription of FOXP3. A more pronounced inhibition of phosphorylation of ZAP70, LAT and STAT5 is seen in two patients on dasatinib with reversal of CD4:CD8 when compared with other patients on dasatinib, suggestive of a more potent reduction of Treg function. Reduction in number and function of Tregs might explain the immunostimulatory effects seen in patients who develop a monoclonal LGL population. Disclosures Harrington: Bristol-Myers Squibb: Research Funding. Dillon:TEVA: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Rousselot:Incyte: Research Funding; Pfizer: Research Funding. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. Harrison:Promedior: Honoraria; Gilead: Speakers Bureau; Sierra Oncology: Honoraria; Roche: Honoraria; Celgene: Honoraria, Speakers Bureau; CTI: Speakers Bureau; Shire: Speakers Bureau; AOP: Honoraria; Janssen: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Kordasti:Celgene: Research Funding; Novartis: Research Funding; Boston Biomed: Consultancy; API: Consultancy. De Lavallade:Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.

scholarly journals Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

2014 ◽  
Vol 211 (9) ◽  
pp. 1723-1731 ◽  
Author(s):  
Theresa L. Geiger ◽  
Michael C. Abt ◽  
Georg Gasteiger ◽  
Matthew A. Firth ◽  
Margaret H. O’Connor ◽  
...  
Keyword(s):  
Critical Role ◽  
Innate Lymphoid Cells ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Bzip Transcription Factor ◽  
Host Protection ◽  
Intestinal Pathogens ◽  
And Function ◽  
Type 3 ◽  
Deficient Mice

The bZIP transcription factor Nfil3 (also known as E4BP4) is required for the development of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). We find that Nfil3 plays a critical role in the development of other mucosal tissue-associated innate lymphocytes. Type 3 ILCs (ILC3s), including lymphoid tissue inducer (LTi)–like cells, are severely diminished in both numbers and function in Nfil3-deficient mice. Using mixed bone marrow chimeric mice, we demonstrate that Nfil3 is critical for normal development of gut-associated ILC3s in a cell-intrinsic manner. Furthermore, Nfil3 deficiency severely compromises intestinal innate immune defense against acute bacterial infection with Citrobacter rodentium and Clostridium difficile. Nfil3 deficiency resulted in a loss of the recently identified ILC precursor, yet conditional ablation of Nfil3 in the NKp46+ ILC3 subset did not perturb ILC3 numbers, suggesting that Nfil3 is required early during ILC3 development but not for lineage maintenance. Lastly, a marked defect in type 2 ILCs (ILC2s) was also observed in the lungs and visceral adipose tissue of Nfil3-deficient mice, revealing a general requirement for Nfil3 in the development of all ILC lineages.

scholarly journals MicroRNAs and Oxidative Stress: An Intriguing Crosstalk to Be Exploited in the Management of Type 2 Diabetes

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 802
Author(s):  
Teresa Vezza ◽  
Aranzazu M. de Marañón ◽  
Francisco Canet ◽  
Pedro Díaz-Pozo ◽  
Miguel Marti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Signaling Pathways ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Dysfunction ◽  
Non Coding Rnas ◽  
And Oxidative Stress ◽  
Molecular Crosstalk

Type 2 diabetes is a chronic disease widespread throughout the world, with significant human, social, and economic costs. Its multifactorial etiology leads to persistent hyperglycemia, impaired carbohydrate and fat metabolism, chronic inflammation, and defects in insulin secretion or insulin action, or both. Emerging evidence reveals that oxidative stress has a critical role in the development of type 2 diabetes. Overproduction of reactive oxygen species can promote an imbalance between the production and neutralization of antioxidant defence systems, thus favoring lipid accumulation, cellular stress, and the activation of cytosolic signaling pathways, and inducing β-cell dysfunction, insulin resistance, and tissue inflammation. Over the last few years, microRNAs (miRNAs) have attracted growing attention as important mediators of diverse aspects of oxidative stress. These small endogenous non-coding RNAs of 19–24 nucleotides act as negative regulators of gene expression, including the modulation of redox signaling pathways. The present review aims to provide an overview of the current knowledge concerning the molecular crosstalk that takes place between oxidative stress and microRNAs in the physiopathology of type 2 diabetes, with a special emphasis on its potential as a therapeutic target.

scholarly journals A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes

2021 ◽  
Author(s):  
Andrea Guennoun ◽  
Salim Bougarn ◽  
Taushif Khan ◽  
Rafah Mackeh ◽  
Mahbuba Rahman ◽  
...  
Keyword(s):  
T Cell ◽  
Bacterial Infections ◽  
Genetic Disorder ◽  
Lymphoid Cells ◽  
T Cell Immunity ◽  
T Cell Subsets ◽  
Transcriptional Responses ◽  
Barr Virus ◽  
Cell Immunity ◽  
Gene And Protein Expression

Abstract Purpose Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls. Methods The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing. Results The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein–Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens. Conclusion Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages

2021 ◽  
Vol 22 (15) ◽  
pp. 7856
Author(s):  
Sang Min Lee ◽  
Kyung-No Son ◽  
Dhara Shah ◽  
Marwan Ali ◽  
Arun Balasubramaniam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Mapk Signaling ◽  
Response To Treatment ◽  
No Production ◽  
Inflammatory Signaling ◽  
Raw264.7 Macrophages ◽  
Inflammatory Mediator Production

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.

scholarly journals Hydrogen production from water electrolysis: role of catalysts

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Shan Wang ◽  
Aolin Lu ◽  
Chuan-Jian Zhong
Keyword(s):  
Hydrogen Production ◽  
Water Splitting ◽  
Noble Metal ◽  
Active Sites ◽  
Current Knowledge ◽  
Low Cost ◽  
Critical Role ◽  
Water Electrolysis ◽  
Efficient Production ◽  
Production Of Hydrogen

AbstractAs a promising substitute for fossil fuels, hydrogen has emerged as a clean and renewable energy. A key challenge is the efficient production of hydrogen to meet the commercial-scale demand of hydrogen. Water splitting electrolysis is a promising pathway to achieve the efficient hydrogen production in terms of energy conversion and storage in which catalysis or electrocatalysis plays a critical role. The development of active, stable, and low-cost catalysts or electrocatalysts is an essential prerequisite for achieving the desired electrocatalytic hydrogen production from water splitting for practical use, which constitutes the central focus of this review. It will start with an introduction of the water splitting performance evaluation of various electrocatalysts in terms of activity, stability, and efficiency. This will be followed by outlining current knowledge on the two half-cell reactions, hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), in terms of reaction mechanisms in alkaline and acidic media. Recent advances in the design and preparation of nanostructured noble-metal and non-noble metal-based electrocatalysts will be discussed. New strategies and insights in exploring the synergistic structure, morphology, composition, and active sites of the nanostructured electrocatalysts for increasing the electrocatalytic activity and stability in HER and OER will be highlighted. Finally, future challenges and perspectives in the design of active and robust electrocatalysts for HER and OER towards efficient production of hydrogen from water splitting electrolysis will also be outlined.

scholarly journals Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

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