scholarly journals Astrocytes promote a protective immune response to brain Toxoplasma gondii infection via IL-33-ST2 signaling

2018 ◽  
Author(s):  
Katherine M. Still ◽  
Samantha J. Batista ◽  
Carleigh O’Brien ◽  
Oyebola O. Oyesola ◽  
Simon P. Früh ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Brain Tissue ◽  
Immune Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Parasite Burden ◽  
Beneficial Effects ◽  
The Brain

SUMMARYUnderstanding how invading pathogens are sensed within the brain is necessary to uncover how effective immune response are mounted in immunoprivileged sites. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts and initiates robust immune cell recruitment, but little is known about innate recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment of peripheral anti-parasitic immune cells, including IFN-γ-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33R-deficient astrocytes fail to promote an adaptive immune response in the CNS and control parasite burden, demonstrating that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released and sensed locally, to engage the peripheral immune system in controlling a neurotropic pathogen.

scholarly journals Astrocytes promote a protective immune response to brain Toxoplasma gondii infection via IL-33-ST2 signaling

2020 ◽  
Vol 16 (10) ◽  
pp. e1009027
Author(s):  
Katherine M. Still ◽  
Samantha J. Batista ◽  
Carleigh A. O’Brien ◽  
Oyebola O. Oyesola ◽  
Simon P. Früh ◽  
...  
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Toxoplasma Gondii ◽  
Brain Tissue ◽  
Immune Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Parasite Burden ◽  
The Brain

It is of great interest to understand how invading pathogens are sensed within the brain, a tissue with unique challenges to mounting an immune response. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts, and initiates robust immune cell recruitment, but little is known about pattern recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but, like many other pattern recognition pathways, IL-33 can signal peripherally, and the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released locally into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment and/or maintenance of blood-derived anti-parasitic immune cells, including proliferating, IFN-γ-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33 receptor-deficient astrocytes fail to mount an adequate adaptive immune response in the CNS to control parasite burden–demonstrating, genetically, that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released locally, and sensed locally, to engage the peripheral immune system in controlling a pathogen.

scholarly journals Transcriptomic Analysis of the Effects of Chemokine Receptor CXCR3 Deficiency on Immune Responses in the Mouse Brain during Toxoplasma gondii Infection

2021 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Kousuke Umeda ◽  
Youta Goto ◽  
Kenichi Watanabe ◽  
Nanako Ushio ◽  
Ragab M. Fereig ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mouse Brain ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Expression Patterns ◽  
Parasite Burden ◽  
Cxc Chemokine ◽  
Immune Related Genes ◽  
The Brain

The obligate intracellular parasite Toxoplasma gondii infects warm-blooded animals, including humans. We previously revealed through a whole-brain transcriptome analysis that infection with T. gondii in mice causes immune response-associated genes to be upregulated, for instance, chemokines and chemokine receptors such as CXC chemokine receptor 3 (CXCR3) and its ligand CXC chemokine ligand 10 (CXCL10). Here, we describe the effect of CXCR3 on responses against T. gondii infection in the mouse brain. In vivo assays using CXCR3-deficient mice showed that the absence of CXCR3 delayed the normal recovery of body weight and increased the brain parasite burden, suggesting that CXCR3 plays a role in the control of pathology in the brain, the site where chronic infection occurs. Therefore, to further analyze the function of CXCR3 in the brain, we profiled the gene expression patterns of primary astrocytes and microglia by RNA sequencing and subsequent analyses. CXCR3 deficiency impaired the normal upregulation of immune-related genes during T. gondii infection, in astrocytes and microglia alike. Collectively, our results suggest that the immune-related genes upregulated by CXCR3 perform a particular role in controlling pathology when the host is chronically infected with T. gondii in the brain.

scholarly journals Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3431-3438 ◽  
Author(s):  
Roch Houot ◽  
Matthew J. Goldstein ◽  
Holbrook E. Kohrt ◽  
June H. Myklebust ◽  
Ash A. Alizadeh ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Antitumor Immunity ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Adaptive Immune Response ◽  
Primary Lymphoma ◽  
Treg Depletion

Abstract Despite the success of passive immunotherapy with monoclonal antibodies (mAbs), many lymphoma patients eventually relapse. Induction of an adaptive immune response may elicit active and long-lasting antitumor immunity, thereby preventing or delaying recurrence. Immunomodulating mAbs directed against immune cell targets can be used to enhance the immune response to achieve efficient antitumor immunity. Anti-CD137 agonistic mAb has demonstrated antitumor efficacy in various tumor models and has now entered clinical trials for the treatment of solid tumors. Here, we investigate the therapeutic potential of anti-CD137 mAb in lymphoma. We found that human primary lymphoma tumors are infiltrated with CD137+ T cells. We therefore hypothesized that lymphoma would be susceptible to treatment with anti-CD137 agonistic mAb. Using a mouse model, we demonstrate that anti-CD137 therapy has potent antilymphoma activity in vivo. The antitumor effect of anti-CD137 therapy was mediated by both natural killer (NK) and CD8 T cells and induced long-lasting immunity. Moreover, the antitumor activity of anti-CD137 mAb could be further enhanced by depletion of regulatory T cell (Tregs). These results support the evaluation of anti-CD137 therapy in clinical trials for patients with lymphoma.

scholarly journals Hypoxia/HIF Modulates Immune Responses

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 260
Author(s):  
Yuling Chen ◽  
Timo Gaber
Keyword(s):  
Immune Response ◽  
Cancer Progression ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Oxygen Availability ◽  
The Body ◽  
Low Oxygen ◽  
Adaptive Immune

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

scholarly journals Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Xu ◽  
Jianping Jia
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Immune Repertoire ◽  
Adaptive Immune ◽  
Peripheral Immune Cells

The peripheral immune system is thought to affect the pathology of the central nervous system in Alzheimer’s disease (AD). However, current knowledge is inadequate for understanding the characteristics of peripheral immune cells in AD. This study aimed to explore the molecular basis of peripheral immune cells and the features of adaptive immune repertoire at a single cell level. We profiled 36,849 peripheral blood mononuclear cells from AD patients with amyloid-positive status and normal controls with amyloid-negative status by 5’ single-cell transcriptome and immune repertoire sequencing using the cell ranger standard analysis procedure. We revealed five immune cell subsets: CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes–macrophages cells, and disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. Thirty-one cell type-specific key genes, comprising abundant human leukocyte antigen genes, and multiple immune-related pathways were identified by protein–protein interaction network and pathway enrichment analysis. We also found high-frequency amplification clonotypes in T and B cells and decreased diversity in T cells in AD. As clone amplification suggested the activation of an adaptive immune response against specific antigens, we speculated that the peripheral adaptive immune response, especially mediated by T cells, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and the development of immune-related biomarkers or therapy.

scholarly journals Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

2021 ◽  
Vol 9 (11) ◽  
pp. e002970
Author(s):  
Yu-Chao Zhu ◽  
Hany M Elsheikha ◽  
Jian-Hua Wang ◽  
Shuai Fang ◽  
Jun-Jun He ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Complete Regression ◽  
Type I

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We examined the synergetic therapeutic activity of attenuated T. gondii RH ΔGRA17 strain and programmed death ligand-1 (PD-L1) treatment on both targeted and distal tumors in mice.MethodsThe effects of administration of T. gondii RH ΔGRA17 strain on the tumor volume and survival rate of mice bearing flank B16-F10, MC38, or LLC tumors were studied. We characterized the effects of ΔGRA17 on tumor biomarkers’ expression, PD-L1 expression, immune cells infiltrating the tumors, and expression of immune-related genes by using immunohistochemistry, immunofluorescence, flow cytometry, NanoString platform, and real-time quantitative PCR, respectively. The role of immune cells in the efficacy of ΔGRA17 plus PD-L1 blockade therapy was determined via depletion of immune cell subtypes.ResultsTreatment with T. gondii ΔGRA17 tachyzoites and anti-PD-L1 therapy significantly extended the survival of mice and suppressed tumor growth in preclinical mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma. Attenuation of the tumor growth was detected in the injected and distant tumors, which was associated with upregulation of innate and adaptive immune pathways. Complete regression of tumors was underpinned by late interferon-gamma-producing CD8+ cytotoxic T cells.ConclusionThe results from these models indicate that intratumoral injection of ΔGRA17 induced a systemic effect, improved mouse immune response, and sensitized immunologically ‘cold’ tumors and rendered them sensitive to immune checkpoint blockade therapy.

scholarly journals A Dynamic in vitro BBB Model for the Study of Immune Cell Trafficking into the Central Nervous System

2010 ◽  
Vol 31 (2) ◽  
pp. 767-777 ◽  
Author(s):  
Luca Cucullo ◽  
Nicola Marchi ◽  
Mohammed Hossain ◽  
Damir Janigro
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Cell Trafficking ◽  
In Vitro System ◽  
Immune Cell Trafficking ◽  
The Central Nervous System ◽  
In Vitro Bbb Model ◽  
The Brain

Although there is significant evidence correlating overreacting or perhaps misguided immune cells and the blood–brain barrier (BBB) with the pathogenesis of neuroinflammatory diseases, the mechanisms by which they enter the brain are largely unknown. For this purpose, we revised our humanized dynamic in vitro BBB model (DIV-BBBr) to incorporate modified hollow fibers that now feature transmural microholes (2 to 4 μm Ø) allowing for the transendothelial trafficking of immune cells. As with the original model, this new DIV-BBBr reproduces most of the physiological characteristics of the BBB in vivo. Measurements of transendothelial electrical resistance (TEER), sucrose permeability, and BBB integrity during reversible osmotic disruption with mannitol (1.6 mol/L) showed that the microholes do not hamper the formation of a tight functional barrier. The in vivo rank permeability order of sucrose, phenytoin, and diazepam was successfully reproduced in vitro. Flow cessation followed by reperfusion (Fc/Rp) in the presence of circulating monocytes caused a biphasic BBB opening paralleled by a significant increase of proinflammatory cytokines and activated matrix metalloproteinases. We also observed abluminal extravasation of monocytes but only when the BBB was breached. In conclusion, the DIV-BBBr represents the most realistic in vitro system to study the immune cell trafficking across the BBB.

scholarly journals Modulation of Adaptive Immunity and Viral Infections by Ion Channels

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen Bohmwald ◽  
Nicolás M. S. Gálvez ◽  
Catalina A. Andrade ◽  
Valentina P. Mora ◽  
José T. Muñoz ◽  
...  
Keyword(s):  
Immune Response ◽  
Ion Channels ◽  
Immune Cells ◽  
Viral Infections ◽  
Immune Cell ◽  
Ion Homeostasis ◽  
Adaptive Immune Response ◽  
Ionic Channels ◽  
Cellular Functions ◽  
Adaptive Immune

Most cellular functions require of ion homeostasis and ion movement. Among others, ion channels play a crucial role in controlling the homeostasis of anions and cations concentration between the extracellular and intracellular compartments. Calcium (Ca2+) is one of the most relevant ions involved in regulating critical functions of immune cells, allowing the appropriate development of immune cell responses against pathogens and tumor cells. Due to the importance of Ca2+ in inducing the immune response, some viruses have evolved mechanisms to modulate intracellular Ca2+ concentrations and the mobilization of this cation through Ca2+ channels to increase their infectivity and to evade the immune system using different mechanisms. For instance, some viral infections require the influx of Ca2+ through ionic channels as a first step to enter the cell, as well as their replication and budding. Moreover, through the expression of viral proteins on the surface of infected cells, Ca2+ channels function can be altered, enhancing the pathogen evasion of the adaptive immune response. In this article, we review those ion channels and ion transporters that are essential for the function of immune cells. Specifically, cation channels and Ca2+ channels in the context of viral infections and their contribution to the modulation of adaptive immune responses.

scholarly journals Measuring host immune response status by simultaneous quantitative measurement of activity of signal transduction pathways that coordinate functional activity of immune cells from innate and adaptive immune system

2021 ◽  
Author(s):  
Wilbert Bouwman ◽  
Wim Verhaegh ◽  
Arie van Doorn ◽  
Anja van de Stolpe
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Functional Activity ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Cell Types ◽  
Activity Profile ◽  
Pathway Activity ◽  
Adaptive Immune

Abstract For many diseases, including cancer, viral infections such as COVID-19, bacterial infections, and auto-immune diseases, the immune response is a major determinant of progression, response to therapy, and clinical outcome. Innate and adaptive immune response are controlled by coordinated activity of multiple immune cell types. The functional activity state of immune cells is determined by cellular signal transduction pathways (STPs). A novel mRNA-based signaling pathway assay platform has been developed to quantitatively measure relevant STP activities in all types of immune cells and mixed immune cell samples for experimental and diagnostic purposes. We generated a STP activity profile, termed Immune-Pathway Activity Profile (I-PAP), for a variety of immune cell types in resting and activated state, and provide a first example for use in patient samples. Methods. The technology to measure STP activity has been described for androgen and estrogen receptor, PI3K, MAPK, TGFB;, Notch, NFkB, JAK-STAT1/2, and JAK-STAT3 pathways. STP activity was measured on Affymetrix expression microarray data from preclinical studies containing public data from different types of immune cells, resting/naive or immune-activated in vitro, to establish I-PAPs. Subsequently data from a clinical study on rheumatoid arthritis were analyzed. Results. I-PAPs of naive/resting and immune-activated CD4+ and CD8+ T cells, T helper cells, B cells, NK cells, monocytes, macrophages, and dendritic cells were established and in agreement with known experimental immunobiology. In whole blood samples of rheumatoid arthritis patients TGFβ pathway activity was increased; JAK-STAT3 pathway activity was selectively increased in female patients. In naive CD4+ Tregs TGFB; pathway activity was increased, while in memory T effector cells JAK-STAT3 pathway activity tended to increase, suggesting that these immune cell types contributed to whole blood analysis results. Conclusion. STP assay technology (currently being converted to qPCR-based assays) makes it possible to directly measure functional activity of cells of the innate and adaptive immune response enabling quantitative assessment of the immune response of an individual patient. Envisioned utility lies in (1) prediction and monitoring of response to immunomodulatory treatments for a variety of immune-mediated diseases, including RA; (2) uncovering novel treatment targets; (3) improvement and standardization of in vitro immunology research and drug development.

scholarly journals ITGBL1 is a new immunomodulator that favors development of melanoma tumors by inhibiting natural killer cells cytotoxicity

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yann Cheli ◽  
Meri K. Tulic ◽  
Najla El Hachem ◽  
Nicolas Nottet ◽  
Arnaud Jacquel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune Cells ◽  
Immune Cell ◽  
Melanoma Cells ◽  
Secreted Protein ◽  
Cell Cytotoxicity ◽  
Mesenchymal Phenotype ◽  
Beneficial Effects

AbstractResistances to immunotherapies remains a major hurdle towards a cure for melanoma in numerous patients. An increase in the mesenchymal phenotype and a loss of differentiation have been clearly associated with resistance to targeted therapies. Similar phenotypes have been more recently also linked to resistance to immune checkpoint therapies. We demonstrated here that the loss of MIcrophthalmia associated Transcription Factor (MITF), a pivotal player in melanocyte differentiation, favors the escape of melanoma cells from the immune system. We identified Integrin beta-like protein 1 (ITGBL1), a secreted protein, upregulated in anti-PD1 resistant patients and in MITFlow melanoma cells, as the key immunomodulator. ITGBL1 inhibited immune cell cytotoxicity against melanoma cells by inhibiting NK cells cytotoxicity and counteracting beneficial effects of anti-PD1 treatment, both in vitro and in vivo. Mechanistically, MITF inhibited RUNX2, an activator of ITGBL1 transcription. Interestingly, VitaminD3, an inhibitor of RUNX2, improved melanoma cells to death by immune cells. In conclusion, our data suggest that inhibition of ITGBL1 might improve melanoma response to immunotherapies.

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