Fewer CTL, not enhanced NK cells, are sufficient for viral clearance from the lungs of immunocompromised mice

Neff-LaFord, Haley; Vorderstrasse, Beth A.; Lawrence, B. Paige

doi:10.1016/j.cellimm.2003.11.005

Cited by 45 publications

(40 citation statements)

References 52 publications

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“…The difference in the level of suppression in lymphoid organs and lung also suggests that regardless of the magnitude of the CD8 response in lymphoid organs, the immune system has a mechanism for insuring that the site of infection acquires the CD8 ϩ T cells that it needs to successfully eliminate the virus. In fact, we and others (55)(56)(57) have shown previously that there is no difference in the amount of virus in lungs of vehicle control and TCDD-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

Lawrence

Roberts

Neumiller

et al. 2006

The Journal of Immunology

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The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR+/+ recipients, and the generation of CD45.2AhR−/−→CD45.1AhR+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.

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Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

Lawrence

Roberts

Neumiller

et al. 2006

The Journal of Immunology

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“…In addition to these effects on pulmonary IFN-␥ levels, exposure to TCDD impairs survival following influenza virus infection (22)(23)(24). Interestingly, decreased survival does not appear to be caused by impaired viral clearance, but by elevated pulmonary inflammation (22)(23)(24)(25). These observations are of interest because the AhR is a ligand-activated transcription factor expressed in cells of the immune system and the lung (26,27).…”

mentioning

confidence: 90%

“…For instance, many studies have demonstrated that IFN-␥ production by lymphocytes is stimulated by IL-12, IL-18, IFN␣␤, and IL-2 (15)(16)(17)(18). We have previously shown that AhR activation by TCDD suppresses pulmonary IL-12 levels (22, 24) and does not alter IFN-␣␤, TNF, IL-1, or IL-18 levels in the lung during infection (25). We also observe a significant diminution in IL-2 levels in TCDD-treated, infected animals (22).…”

Section: Neither Known Ifn-␥-stimulating Cytokines Nor Direct Ahr:ahrmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation during Influenza Virus Infection Unveils a Novel Pathway of IFN-γ Production by Phagocytic Cells

Neff-LaFord

Teske

Bushnell

et al. 2007

The Journal of Immunology

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The contribution of environmental factors is important as we consider reasons that underlie differential susceptibility to influenza virus. Aryl hydrocarbon receptor (AhR) activation by the pollutant dioxin during influenza virus infection decreases survival, which correlates with a 4-fold increase in pulmonary IFN-γ levels. We report here that the majority of IFN-γ-producing cells in the lung are neutrophils and macrophages not lymphocytes, and elevated IFN-γ is associated with increased pulmonary inducible NO synthase (iNOS) levels. Moreover, we show that even in the absence of dioxin, infection with influenza virus elicits IFN-γ production by B cells, γδ T cells, CD11c+ cells, macrophages and neutrophils, as well as CD3+ and NK1.1+ cells in the lung. Bone marrow chimeric mice reveal that AhR-mediated events external to hemopoietic cells direct dioxin-enhanced IFN-γ production. We also show that AhR-mediated increases in IFN-γ are dependent upon iNOS, but elevated iNOS in lung epithelial cells is not driven by AhR-dependent signals from bone marrow-derived cells. Thus, the lung contains important targets of AhR regulation, which likely influence a novel iNOS-mediated mechanism that controls IFN-γ production by phagocytic cells. This suggests that AhR activation changes the response of lung parenchymal cells, such that regulatory pathways in the lung are cued to respond inappropriately during infection. These findings also imply that environmental factors may contribute to differential susceptibility to influenza virus and other respiratory pathogens.

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“…and tumor necrosis factor-a. These cytokines and chemokines were chosen because they stimulate leukocyte recruitment and are known to be induced during influenza A virus infection (22,26,27). In room air-exposed mice, MCP-1 levels increased within 24 hours of infection and became significantly elevated on Day 3 before declining to naive levels by Day 9 ( Figure 6A).…”

Section: Neonatal Hyperoxia Augments Pulmonary Monocyte Chemotactic Pmentioning

confidence: 99%

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

O’Reilly

Marr

Yee

et al. 2008

Am J Respir Crit Care Med

112

124

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Rationale: Lungs of adult mice exposed to hyperoxia as newborns are simplified and exhibit reduced function much like that observed in people who had bronchopulmonary dysplasia (BPD) as infants. Because survivors of BPD also show increased risk for symptomatic respiratory infections, we investigated how neonatal hyperoxia affected the response of adult mice infected with influenza A virus infection. Objectives: To determine whether neonatal hyperoxia increased the severity of influenza A virus infection in adult mice. Methods: Adult female mice exposed to room air or hyperoxia between Postnatal Days 1 and 4 were infected with a sublethal dose of influenza A virus. Measurements and Main Results: The number of macrophages, neutrophils, and lymphocytes observed in airways of infected mice that had been exposed to hyperoxia as neonates was significantly greater than in infected siblings that had been exposed to room air. Enhanced inflammation correlated with increased levels of monocyte chemotactic protein-1 (CCL2) in lavage fluid, whereas infectionassociated changes in IFN-g, IL-1b, IL-6, tumor necrosis factor-a, KC, granulocyte-macrophage colony-stimulating factor, and macrophage inflammatory protein-1a, and production of virus-specific antibodies, were largely unaffected. Increased mortality of mice exposed to neonatal hyperoxia occurred by Day 14 of infection, and was associated with persistent inflammation and fibrosis. Conclusions: These data suggest that the disruptive effect of hyperoxia on neonatal lung development also reprograms key innate immunoregulatory pathways in the lung, which may contribute to exacerbated pathology and poorer resistance to respiratory viral infections typically seen in people who had BPD.

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Fewer CTL, not enhanced NK cells, are sufficient for viral clearance from the lungs of immunocompromised mice

Cited by 45 publications

References 52 publications

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

Aryl Hydrocarbon Receptor Activation during Influenza Virus Infection Unveils a Novel Pathway of IFN-γ Production by Phagocytic Cells

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

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