Response to influenza infection in mice with a targeted disruption in the interferon gamma gene.

Graham, Mary Beth; Dalton, Dyana K.; Giltinan, David M.; Braciale, Vivian L.; Stewart, Timothy A.; Braciale, Thomas J.

doi:10.1084/jem.178.5.1725

Cited by 220 publications

(196 citation statements)

References 36 publications

(43 reference statements)

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“…5). In agreement with others, we found that IFN-␥ is not required for the generation of cytolytic effector cells during virus infection (30,58,59). Indeed, vaccinia-specific CTL responses were slightly elevated in IFN-␥ Ϫ/Ϫ mice, which may be due to enhanced proliferation of T cells in the absence of IFN-␥ (45,59).…”

Section: Ctl Responses Are Abrogated In Il-12 ϫ/ϫ Mice But Not In Ifnsupporting

confidence: 79%

IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

Broek¹,

Bachmann²,

Köhler

et al. 2000

The Journal of Immunology

126

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Resistance or susceptibility to most infectious diseases is strongly determined by the balance of type 1 vs type 2 cytokines produced during infection. However, for viruses, this scheme may be applicable only to infections with some cytopathic viruses, where IFN-γ is considered as mandatory for host defense with little if any participation of type 2 responses. We studied the role of signature Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-10) cytokines for immune responses against vaccinia virus (VV). IL-12−/− mice were far more susceptible than IFN-γ−/− mice, and primary CTL responses against VV were absent in IL-12−/− mice but remained intact in IFN-γ−/− mice. Both CD4+ and CD8+ T cells from IL-12−/− mice were unimpaired in IFN-γ production, although CD4+ T cells showed elevated Th2 cytokine responses. Virus replication was impaired in IL-4−/− mice and, even more strikingly, in IL-10−/− mice, which both produced elevated levels of the proinflammatory cytokines IL-1α and IL-6. Thus, IL-4 produced by Th2 cells and IL-10 produced by Th2 cells and probably also by macrophages counteract efficient anti-viral host defense. Surprisingly, NO production, which is considered as a major type 1 effector pathway inhibited by type 2 cytokines, appears to play a limited role against VV, because NO sythetase 2-deficient mice did not show increased viral replication. Thus, our results identify a new role for IL-12 in defense beyond the induction of IFN-γ and show that IL-4 and IL-10 modulate host protective responses to VV.

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Section: Ctl Responses Are Abrogated In Il-12 ϫ/ϫ Mice But Not In Ifnsupporting

confidence: 79%

IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

Broek¹,

Bachmann²,

Köhler

et al. 2000

The Journal of Immunology

126

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“…However, cytotoxic T cell responses in these mice were comparable to wildtype controls. Interestingly, CD4 cell clones isolated from IFN-γ −/− mice and restimulated in vitro could protect against lethal challenge with influenza via a cytolytic mechanism [50]. It has also been demonstrated that virally infected class-I-deficient mice have CD4 cells capable of lysing Sendai or LCMV-infected targets [11], suggesting that CD4 cells can compensate for the lack of IFN-γ or CD8 cells by becoming killers themselves.…”

Section: Cd4 Effector Mechanisms and Protectionmentioning

confidence: 95%

“…Infection of mice with a targeted disruption of the IFN-γ gene demonstrated increases in type 2 cytokine production and increases in influenza-specific IgG1 antibody secretion [50]. However, cytotoxic T cell responses in these mice were comparable to wildtype controls.…”

Section: Cd4 Effector Mechanisms and Protectionmentioning

confidence: 99%

“…The importance of cytolytic CD4 cells in the response to influenza remains controversial since experiments using bone marrow chimeras with class II −/− epithelial cells demonstrated that CD4 cells did not have to directly recognize infected epithelium in order to exert effector function [11]. In contrast, CD4 cell clones isolated from wildtype [51] or IFN-γ-deficient mice [50] could protect against a lethal inoculation with influenza that depended not on their cytokine profile, but their ability to lyse virally infected targets.…”

Section: Cd4 Effector Mechanisms and Protectionmentioning

confidence: 99%

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CD4 T cell responses to influenza infection

Brown

Román

Swain

2004

Seminars in Immunology

153

121

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“…There is accumulating evidence that IFN-c is ineffectual against influenza A virus [3]. In fact, IFN-c is not necessary for recovery from primary infection with influenza A virus [30]. IFN-a/b and IFN-c pathways do not contribute to the development of immunity to influenza A virus and protection or recovery from influenza A virus infection [31].…”

mentioning

confidence: 99%

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

et al. 2008

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The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-c is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-c as evidenced by studies using anti-IFN-c Ab and IFN-c -/-mice. Thus, we hypothesized that IFN-c is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-c. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-c to detect IFN-c-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-c-induced up-regulation of HLA-DRa mRNA and the IFN-c induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1a upon IFN-c stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1a. Thus, influenza A virus subverts antiviral host defense mediated by IFN-c through effects on the intracellular signaling pathways. IntroductionInfluenza A viruses are negative-strand RNA viruses that have a segmented genome with a coding capacity for 11 polypeptides. The virus genome is composed of eight different RNA segments, which are tightly associated with the viral nucleoprotein and polymerases in ribonucleoprotein complexes [1]. Influenza A viruses, causing acute infections, continuously escape from recognition by virus neutralizing Ab as a result of accumulation of mutations in their surface glycoproteins hemagglutinin and neuraminidase (antigenic drift) or by introduction of new subtypes of these glycoproteins (antigenic shift) [2,3]. Recent outbreaks of highly pathogenic avian influenza A virus infections in poultry and in humans have raised concerns that a new influenza pandemic will occur in the near future [4]. Thus, prediction of the severity of continuously emerging human influenza virus strains remains a high public health priority, but it is limited by our incomplete understanding of the molecular determinants of pathogenicity in this disease. Although factors dictating the severity of virus disease are complex, interaction between inherent viral properties and host cellular response ultimately determines disease outcome. The first site of viral contact with the host and main target of infection and inflammation is the airway mucosal epithelium. Epithelial cells at the airway mucosal surface have a variety of inflammatory and immune defense mechanisms to deal with virus, including Eur. J. Immunol. 2008. 38: 1559-1573 Immunity to infection expression of cytokines with chemoattractant and proinflammatory functions [5], intercellular adhesion molecule-1 (ICAM-1) [6], IFN regulatory factor 1 (IRF-1) [7], nitric oxide synthase 2 (NOS2) [8], and MHC ...

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Response to influenza infection in mice with a targeted disruption in the interferon gamma gene.

Cited by 220 publications

References 36 publications

IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

CD4 T cell responses to influenza infection

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

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