scholarly journals Resolution of a chronic viral infection after interleukin-10 receptor blockade

2006 ◽  
Vol 203 (11) ◽  
pp. 2461-2472 ◽  
Author(s):  
Mette Ejrnaes ◽  
Christophe M. Filippi ◽  
Marianne M. Martinic ◽  
Eleanor M. Ling ◽  
Lisa M. Togher ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infections ◽  
Neutralizing Antibody ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Persistently Infected ◽  
Functional Inactivation ◽  
Cellular Immune

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon γ production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cell (DC) numbers declined early after infection, whereas CD8α− DC numbers were not affected. CD8α− DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10–mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.

scholarly journals Critical Role for CD4+ T Cells in Controlling Retrovirus Replication and Spread in Persistently Infected Mice

1998 ◽  
Vol 72 (8) ◽  
pp. 6559-6564 ◽  
Author(s):  
Kim J. Hasenkrug ◽  
Diane M. Brooks ◽  
Ulf Dittmer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Critical Role ◽  
Neutralizing Antibody ◽  
T Cell Subsets ◽  
Retroviral Infection ◽  
Persistently Infected ◽  
Persistent Viral Infections

ABSTRACT Reactivations of persistent viral infections pose a significant medical problem in immunocompromised cancer, transplant, and AIDS patients, yet little is known about how persistent viral infections are immunologically controlled. Here we describe a mouse model for investigating the role of the immune response in controlling a persistent retroviral infection. We demonstrate that, following recovery from acute Friend virus infection, a small number of B cells evade immunological destruction and harbor persistent virus. In vivo depletions of T-cell subsets in persistently infected mice revealed a critical role for CD4+ T cells in controlling virus replication, spread to the erythroid lineage, and induction of erythroleukemia. The CD4+ T-cell effect was independent of CD8+ T cells and in some cases was also independent of virus-neutralizing antibody responses. Thus, the CD4+ T cells may have had a direct antiviral effect. These results may have relevance for human immunodeficiency virus (HIV) infections where loss of CD4+ T cells is associated with an increase in HIV replication, reactivation of persistent viruses, and a high incidence of virus-associated cancers.

scholarly journals Antioxidant Treatment Reduces Expansion and Contraction of Antigen-Specific CD8+ T Cells during Primary but Not Secondary Viral Infection

2004 ◽  
Vol 78 (20) ◽  
pp. 11246-11257 ◽  
Author(s):  
Nathan G. Laniewski ◽  
Jason M. Grayson
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Large Scale ◽  
Viral Infections ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Response ◽  
Oxygen Intermediates ◽  
Mimetic Compound

ABSTRACT During many viral infections, antigen-specific CD8+ T cells undergo large-scale expansion. After viral clearance, the vast majority of effector CD8+ T cells undergo apoptosis. Previous studies have implicated reactive oxygen intermediates (ROI) in lymphocyte apoptosis. The purpose of the experiments presented here was to determine the role of ROI in the expansion and contraction of CD8+ T cells in vivo during a physiological response such as viral infection. Mice were infected with lymphocytic choriomeningitis virus (LCMV) and treated with Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), a metalloporphyrin-mimetic compound with superoxide dismutase activity, from days 0 to 8 postinfection. At the peak of CD8+-T-cell response, on day 8 postinfection, the numbers of antigen-specific cells were 10-fold lower in MnTBAP-treated mice than in control mice. From days 8 to 30, a contraction phase ensued where the numbers of antigen-specific CD8+ T cells declined 25-fold in vehicle-treated mice compared to a 3.5-fold decrease in MnTBAP-treated mice. Differences in contraction appeared to be due to greater proliferation in drug-treated mice. By day 38, the numbers of antigen-specific CD8+ memory T cells were equivalent for the two groups. The administration of MnTBAP during secondary viral infection had no effect on the expansion of antigen-specific CD8+ secondary effector T cells. These data suggest that ROI production is critical for the massive expansion and contraction of antigen-specific CD8+ T cells during primary, but not secondary, viral infection.

scholarly journals Regulation of contact hypersensitivity by interleukin 10.

1994 ◽  
Vol 179 (5) ◽  
pp. 1597-1604 ◽  
Author(s):  
T A Ferguson ◽  
P Dube ◽  
T S Griffith
Keyword(s):  
T Cells ◽  
Neutralizing Antibody ◽  
Inflammatory Cells ◽  
Interleukin 10 ◽  
Lymphoid Cells ◽  
Contact Hypersensitivity ◽  
Mrna Transcription ◽  
Antigenic Challenge ◽  
A Site

Contact hypersensitivity (CHS) responses require the participation of T cells, along with a variety of cytokines and adhesion molecules. In the classical CHS, antigen-specific T cells are recruited to a site of antigenic challenge, where they react with antigen, release cytokines, and attract other inflammatory cells. In the mouse model of CHS, this reaction is elicited in sensitized mice by application of the immunogen 4-7 d after immunization. The reaction peaks at 24 h, is slightly reduced by 48 h, and can return to normal by 72 h. This is in spite of the fact that some antigen is still present at the site of challenge. Here we examined the hypothesis that locally produced interleukin 10 (IL-10) regulates the duration of the response. Our data show that IL-10 protein peaked 10-14 h after antigenic challenge and returned to background by 24 h. The production of IL-10 protein corresponded with, and followed IL-10 mRNA transcription as detected by reverse transcriptase-polymerase chain reaction. During peak IL-10 production after antigenic challenge, it was not possible to transfer CHS with immune lymphoid cells, unless neutralizing antibody to IL-10 was given first. Additionally, when sensitized mice were given neutralizing anti-IL-10 antibody at the time of antigenic challenge, the duration of CHS was prolonged well beyond the natural course of the response. Finally, we demonstrate that rIL-10, when injected into the skin before antigenic challenge, prevented the elicitation of CHS in previously sensitized mice. Taken together, our data show an important role for IL-10 in the natural regulation of CHS responses in vivo.

Differential regulation of virus-specific T-cell effector functions following activation by peptide or innate cytokines

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1179-1186 ◽  
Author(s):  
Carol Beadling ◽  
Mark K. Slifka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Activated T Cells ◽  
Effector Functions

AbstractRobust CD8+ T-cell activation is vital for the recovery from many viral infections and is orchestrated via the integration of signals delivered through surface molecules, including the T-cell antigen receptors (TcRs) and cytokine receptors. Little is known about how virus-specific T cells interpret sequential or combined stimulation through these receptors, which must undoubtedly occur in vivo during antiviral immune responses. When measured in real time, peptide antigen and the cytokines, interleukin 12 (IL-12) and IL-18, independently regulate the on/off kinetics of protective (interferon γ, tumor necrosis factor α) and immunomodulatory (IL-2, CD40L) cytokine production by activated T cells and memory T cells. The remarkable differences in effector functions elicited by innate or adaptive signals (IL-12/ IL-18 or peptide, respectively) illustrate the complex and stringent regulation of cytokine expression by CD8+ T cells. Together, these results indicate how antiviral T cells incorporate multiple signals from their local microenvironment and tailor their cytokine responses accordingly.

scholarly journals Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Blood ◽  
2019 ◽  
Vol 134 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Sabrin Albeituni ◽  
Katherine C. Verbist ◽  
Paige E. Tedrick ◽  
Heather Tillman ◽  
Jennifer Picarsic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Proinflammatory Cytokines ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Dependent Manner ◽  
Ifn Γ

Abstract Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-γ (IFN-γ). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1−/−) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-γ, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-γ signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-γ–neutralizing antibody (αIFN-γ) in 2 murine HLH models. In both models, ruxolitinib and αIFN-γ reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-γ–dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-γ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1−/− mice exhibited enhanced survival compared with mice in which αIFN-γ was discontinued. This protective effect could be mimicked by transient treatment with αIFN-γ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-γ–dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.

scholarly journals Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
S. Viganò ◽  
M. Perreau ◽  
G. Pantaleo ◽  
A. Harari
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Viral Infections ◽  
Therapeutic Interventions ◽  
Cellular Immune

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences bothin vitroandin vivosuggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

scholarly journals Effects of Promyelocytic Leukemia Protein on Virus-Host Balance

2002 ◽  
Vol 76 (8) ◽  
pp. 3810-3818 ◽  
Author(s):  
Weldy V. Bonilla ◽  
Daniel D. Pinschewer ◽  
Paul Klenerman ◽  
Valentin Rousson ◽  
Mirella Gaboli ◽  
...  
Keyword(s):  
Viral Infections ◽  
Cytotoxic T Lymphocyte ◽  
Virus Production ◽  
Neutralizing Antibody ◽  
Lymphocytic Choriomeningitis ◽  
Promyelocytic Leukemia ◽  
Host Susceptibility ◽  
High Dose ◽  
Promyelocytic Leukemia Protein

ABSTRACT The cellular promyelocytic leukemia protein (PML) associates with the proteins of several viruses and in some cases reduces viral propagation in cell culture. To examine the role of PML in vivo, we compared immune responses and virus loads of PML-deficient and control mice infected with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). PML−/− mice exhibited accelerated primary footpad swelling reactions to very-low-dose LCMV, higher swelling peaks upon high-dose inoculation, and higher viral loads in the early phase of systemic LCMV infection. T-cell-mediated hepatitis and consequent mortality upon infection with a hepatotropic LCMV strain required 10- to 100-times-lower inocula despite normal cytotoxic T-lymphocyte reactivity in PML−/− mice. Furthermore, PML deficiency rendered mice 10 times more susceptible to lethal immunopathology upon intracerebral LCMV inoculation. Accordingly, 10-times-lower VSV inocula elicited specific neutralizing-antibody responses, a replication-based effect not observed with inactivated virus or after immunization with recombinant VSV glycoprotein. These in vivo observations corroborated our results showing more virus production in PML−/− fibroblasts. Thus, PML is a contributor to innate immunity, defining host susceptibility to viral infections and to immunopathology.

scholarly journals Delayed interval BNT162b2 mRNA COVID-19 vaccination provides robust immunity

2021 ◽  
Author(s):  
Victoria Hall ◽  
Victor Ferreira ◽  
Matthew Ierullo ◽  
Terrance Ku ◽  
Beata Majchrzak-Kita ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Neutralizing Antibody ◽  
Interferon Γ ◽  
Interval Group ◽  
Standard Interval ◽  
Humoral Immune ◽  
Antibody Titres ◽  
Delayed Group ◽  
Cellular Immune

Abstract Shortages of COVID-19 vaccines have results in delayed dosing intervals as a strategy to immunize a greater proportion of the population. The effect of this strategy on vaccine immunogenicity is not well studied. Humoral (anti-RBD levels and neutralization) and cellular immune responses were compared in health care workers receiving two doses of BNT162b2 (Pfizer-BioNTech) vaccines at standard (3-6 week) and delayed (8-12 week) intervals. In the delayed group, anti-RBD antibody titres were significantly enhanced compared to the standard interval group. Neutralizing antibody responses were excellent and comparable in both groups. A slight decrease in Spike-specific polyfunctional CD4+ T-cells expressing interferon-γ and IL-2 as well as monofunctional CD4+ T-cells was seen in the delayed group. Both polyfunctional and monofunctional CD8+ T-cell responses were comparable. Our data suggest that the strategy of delayed second dose mRNA vaccination is not overtly detrimental, and specifically may lead to an enhanced humoral immune response.

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