Cutting Edge: Pulmonary Immunopathology Mediated by Antigen-Specific Expression of TNF-α by Antiviral CD8+ T Cells

Xu, Lumei; Yoon, Heesik; Zhao, Min; Li, Jun; Ramana, Chilakamarti V.; Enelow, Richard I.

doi:10.4049/jimmunol.173.2.721

Cited by 114 publications

(125 citation statements)

References 27 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…28 The opposing conclusions regarding the role of TNF-␣ in influenza immunopathology drawn from this study and our current study are likely because the former used an adoptive transgenic T-cell transfer approach and a transgenic mouse model in which the bronchial epithelial cells overexpress hemagglutinin. 28 Two other studies have shown a decrease in disease severity in TNFR1 knockout mice infected with highly virulent H5N1 avian or a reconstructed 1918 pandemic influenza virus. In agreement with our study, these studies report the lack of involvement of TNFR1 in influenza viral clearance.…”

Section: Discussionmentioning

confidence: 60%

See 1 more Smart Citation

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Damjanovic

Divangahi

Kugathasan

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Lung immunopathology is the main cause of influenzamediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-␣ (TNF-␣) is traditionally considered a proinflammatory cytokine, its role in influenza immunopathology is unresolved. We have investigated this issue by using a model of acute H1N1 influenza infection established in wild-type and TNF-␣-deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Whereas TNF-␣ was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-␣ deficiency led not only to a greater extent of illness but also to heightened lung immunopathology and tissue remodeling. The severe lung immunopathology was associated with increased inflammatory cell infiltration, anti-influenza adaptive immune responses, and expression of cytokines such as monocyte chemoattractant protein-1 (MCP-1) and fibrotic growth factor, TGF-␤1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-␤1 production following influenza infection in these hosts. On the other hand, in vivo transgenic expression of MCP-1 worsened lung immunopathology following influenza infection in wild-type hosts. Thus, TNF-␣ is dispensable for influenza clearance; however, different from the traditional belief, this cytokine is critically required for negatively regulating the extent of lung immunopathology during acute influenza infection.

show abstract

Section: Discussionmentioning

confidence: 60%

“…[23][24][25][26][27] In this regard, the limited data also suggest that production of TNF-␣ by influenza-specific CD8 T cells may contribute to lung immunopathology. 28,29 The immune-activating role of TNF-␣ was also shown in the models of other viral infections. 30,31 However, recent emerging evidence has suggested an immune regulatory nature of TNF-␣.…”

mentioning

confidence: 92%

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Damjanovic

Divangahi

Kugathasan

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…þ T-cell bulk lines and clones were activated in vitro prior to adoptive transfer (43), and injected via the tail vein. Weight loss was monitored daily, and lungs were harvested at appropriate times for histology or chemokine analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The enhanced inflammatory response and leukocyte recruitment occurring after infection with highly pathogenic strains of influenza has been suggested to be dependent on TNF-and i-NOS-producing dendritic cells, as well as the CCR2 receptor (1,23). Epithelial CCL2 is rapidly induced in response to CD8 þ T-cell recognition in vitro and in vivo (32,43,45), and appears to require both TNF receptors, TNF-R1 and TNF-R2 (24).…”

mentioning

confidence: 99%

Interference with Intraepithelial TNF-α Signaling Inhibits CD8⁺T-Cell-Mediated Lung Injury in Influenza Infection

Srikiatkhachorn

Chintapalli

et al. 2010

Viral Immunology

Self Cite

View full text Add to dashboard Cite

CD8þ T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-a expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8 þ T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-a signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8 þ T-cell recognition, or to TNF-a. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-kB activity, which was independent of Ik-Ba degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3b, and the p65 subunit of NF-kB, as well as recruitment of NF-kB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-kB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection.

show abstract

“…The initial inflammatory infiltrate helps control viral replication until the virus is cleared by a viral-specific, CTL-mediated response [4,5]. However, the inflammatory response to a respiratory infection may sometimes be detrimental to the host, causing augmented lung pathology [6,7]. Identifying factors involved in the recruitment of proinflammatory leukocytes will further our understanding of the inflammatory response and immunopathology associated with respiratory viral infections.…”

Section: Introductionmentioning

confidence: 99%

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice

Wareing

Lyon

Inglis

et al. 2006

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Influenza virus infections induce chemokines and cytokines, which regulate the immune response. The chemokine receptor CCR2 plays an important role in macrophage recruitment and in the development of T1 immunity. In the present study, we addressed the role of CCR2 in influenza A virus infection. CCR2 knockout (؊/؊) mice are protected against influenza A virus infection, despite delayed recruitment of macrophages. We show that low-dose influenza infection of CCR2؊/؊ mice leads to increased neutrophilia between Days 5 and 10 after infection and decreased monocyte/macrophage and CD4 ؉ T cell recruitment to the lungs between Days 5 and 7 after infection. These changes in leukocyte recruitment did not result from or cause increased viral titers or delayed viral clearance. Neutrophilia in the lungs correlated with increased keratinocyte-derived chemokine (KC) and/or MIP-2 expression in CCR2؊/؊ mice between Days 5 to 10 after infection, although the kinetics of neutrophil recruitment was not altered. MIP-2 mRNA and protein expression was increased three-to fivefold, and KC protein levels were increased two-to threefold in CCR2؊/؊ compared with CCR2 wild-type mice at Day 5 after infection. This preceded the peak neutrophil influx, which occurred 7 days after infection. In vitro studies confirmed that MIP-2 and KC accounted for neutrophil chemotactic activity in the bronchoalveolar lavage. CCR2 deficiency also resulted in increased MIP-1␣, MIP-1␤, MCP-1, and IFN-inducible protein 10 and decreased RANTES mRNA expression. Furthermore, IL-6 and TNF-␣ cytokine production were elevated after infection. These studies suggest that CCR2 plays a multifactorial role in the development of the immune response to influenza. J. Leukoc. Biol. 81: 793-801; 2007.

show abstract

Cutting Edge: Pulmonary Immunopathology Mediated by Antigen-Specific Expression of TNF-α by Antiviral CD8+ T Cells

Cited by 114 publications

References 27 publications

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Interference with Intraepithelial TNF-α Signaling Inhibits CD8⁺T-Cell-Mediated Lung Injury in Influenza Infection

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice

Contact Info

Product

Resources

About

Cutting Edge: Pulmonary Immunopathology Mediated by Antigen-Specific Expression of TNF-α by Antiviral CD8+ T Cells

Cited by 114 publications

References 27 publications

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Interference with Intraepithelial TNF-α Signaling Inhibits CD8+T-Cell-Mediated Lung Injury in Influenza Infection

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice

Contact Info

Product

Resources

About

Interference with Intraepithelial TNF-α Signaling Inhibits CD8⁺T-Cell-Mediated Lung Injury in Influenza Infection