Influenza-Infected Neutrophils within the Infected Lungs Act as Antigen Presenting Cells for Anti-Viral CD8+ T Cells

Hufford, Matthew M.; Richardson, Graham M.; Zhou, Haixia; Manicassamy, Balaji; Garcı́a-Sastre, Adolfo; Enelow, Richard I.; Braciale, Thomas J.

doi:10.1371/journal.pone.0046581

Cited by 107 publications

(116 citation statements)

References 38 publications

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“…Neutrophils can both limit and contribute to inflammation during IAV infection in mice (38,47). Neutrophils can phagocytize IAV-infected cells, control virus replication and inflammation, and activate IAV-specific CD8 T cells in the lungs (33,42,43,48,49). Depletion of neutrophils prior to IAV infection results in greater morbidity and mortality as well as a lower magnitude of IAV-specific CD8 T cells in the lungs of infected mice (33,38,42,49).…”

Section: Discussionmentioning

confidence: 99%

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17β-Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs

Robinson

Hall

Nilles

et al. 2014

J Virol

156

145

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ABSTRACT17␤-Estradiol (E2) treatment limits the pathology associated with pulmonary diseases caused by pathogens, allergens, and asthma, partly by reducing the production of proinflammatory cytokines and chemokines. To test the hypothesis that E2 protects against influenza A virus (IAV) infection by altering the recruitment and activity of innate immune cells and T cells, chemokine concentrations were measured and innate and adaptive immune cells were enumerated from the lungs of E2-and placebotreated ovariectomized female C57BL/6 mice following infection. Females treated with E2 experienced less morbidity but had similar lung virus titers to placebo-treated females. Females treated with E2 had lower induction of CCL2 but higher CCL3 and CXCL1 responses in their lungs than placebo-treated females. Pulmonary recruitment of neutrophils, NK cells, macrophages, and dendritic cells was increased following infection, but only neutrophil numbers were greater in E2-treated than placebotreated females. Neutrophils enhance the responses of influenza virus-specific CD8 T cells to promote virus clearance and improve the outcome of infection. Total numbers of virus-specific CD8 T cells were not altered by treatment with E2, but the proportion of gamma interferon (IFN-␥)-and tumor necrosis factor alpha (TNF-␣)-producing, virus-specific CD8 T cells was increased. Neutrophil depletion in E2-treated females increased morbidity, reduced pulmonary production of chemoattractants for neutrophils, and reduced IFN-␥ production by virus-specific CD8 T cells. Neutrophils mediate both inflammation and tissue repair during IAV infection and are regulated by E2 to improve the outcome of influenza in females. IMPORTANCESevere influenza is associated with excessive inflammation that leads to tissue damage. We demonstrate that estradiol (E2) is a potent anti-inflammatory hormone that reduces the severity of influenza A virus infection in females. Treatment of female C57BL/6 mice with E2 does not affect virus replication but rather alters the production of chemokines, pulmonary recruitment of neutrophils, and the cytokine responses of virus-specific CD8 T cells to protect females against severe influenza.

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Section: Discussionmentioning

confidence: 99%

“…3A to C) (P Ͻ 0.05). (42,43). To establish whether E2 treatment alters T cell recruitment or function during IAV infection, we assessed the number and cytokine production from CD4 and CD8 T cells in the lungs and draining lymph nodes during IAV infection (see Fig.…”

Section: Treatment With E2 Increases Tolerance Of Iav Infection In Fementioning

confidence: 99%

17β-Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs

Robinson

Hall

Nilles

et al. 2014

J Virol

156

145

View full text Add to dashboard Cite

show abstract

“…TNF-α, CCL3 and CCL5), but the role of these cytokines in viral clearance and/or the induction of lung injury is not clear [118]. Interestingly, a substantial body of evidence suggests that the cytolytic activity and cytokine function of effector T-cells are modified by factors present in the inflammatory milieu of the IAV-infected lung [119][120][121][122]. The complexity of these interactions is highlighted by the discovery that hHigh mobility group protein B1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule released from the infected epithelium, promotes the DC-dependent activation of IAV antigen-specific CD8 + T-effector cells via an interaction with RAGE (receptor for advanced glycation endproducts) [123].…”

Section: Molecular and Cellular Interactions At The Virus-host Interfacementioning

confidence: 99%

Influenza virus-induced lung injury: pathogenesis and implications for treatment

et al. 2015

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The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy. @ERSpublications We discuss novel aspects of virus-and immune-mediated lung injury and repair after influenza infection

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“…Monocytes, macrophages, mo-DC, and DC can all present the antigen required for induction of T cell responses (4). Furthermore, during viral infection, neutrophils may also be capable of presenting to T CD8ϩ (5). Besides their well-defined role in antigen presentation, myeloid cell populations can also produce cytokines in response to viral infection.…”

mentioning

confidence: 99%

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Kaminsky

Sei

Parekh

et al. 2015

J Virol

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Viruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8␣ ؉ DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8␣ ؉ DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection. IMPORTANCEPrior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design. P rior to the induction of the adaptive immune response, cells of the innate immune system are deployed early during viral infection to control the pathogen and limit its spread from the site of infection. Effector cells of the innate immune system include myeloid cell subsets: granulocytes (neutrophils, eosinophils, and b...

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Influenza-Infected Neutrophils within the Infected Lungs Act as Antigen Presenting Cells for Anti-Viral CD8+ T Cells

Cited by 107 publications

References 38 publications

17β-Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs

17β-Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs

Influenza virus-induced lung injury: pathogenesis and implications for treatment

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

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