Immune Response to Mouse Mammary Tumor Virus in Mice Lacking the Alpha/Beta Interferon or the Gamma Interferon Receptor

Abstract

Mouse mammary tumor virus (MMTV) is a retrovirus which induces a strong immune response and a dramatic increase in the number of infected cells through the expression of a superantigen (SAg). Many cytokines are likely to be involved in the interaction between MMTV and the immune system. In particular, alpha/beta interferon (IFN-α/β) and gamma interferon (IFN-γ) exert many antiviral and immunomodulatory activities and play a critical role in other viral infections. In this study, we have investigated the importance of interferons during MMTV infection by using mice with a disrupted IFN-α/β or IFN-γ receptor gene. We found that the SAg response to MMTV was not modified in IFN-α/βR0/0 and IFN-γR0/0 mice. This was true both for the early expansion of B and T cells induced by the SAg and for the deletion of SAg-reactive cells at later stages of the infection. In addition, no increase in the amount of proviral DNA was detected in tissues of IFN-α/βR0/0 and IFN-γR0/0 mice, suggesting that interferons are not essential antiviral defense mechanisms during MMTV infection. In contrast, IFN-γR0/0mice had increased amounts of IL-4 mRNA and an altered usage of immunoglobulin isotypes with a reduced frequency of IgG2a- and IgG3-producing cells. This was associated with lower titers of virus-specific antibodies in serum early after infection, although efficient titers were reached later.

Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis

“…The mechanism by which IFN-g decreases cytotoxic lymphocyte generation is postulated to be due to limitation of IL-2 production, creating a negative feedback loop (Dalton et al, 1993;Hidalgo et al, 2005). Alternatively, mouse mammary tumour virus infection of Ifngr1 À/À mice results in no change in CD8 + T cell, CD4 T cell or B cell numbers in lymph nodes, nor any difference in virus titres (Maillard et al, 1998), and Ifng À/À mice show no difference in CD4 + or CD8 + T cells in the spinal cord following infection with Theiler's murine encephalomyelitis virus (Rodriguez et al, 2003). Although less extensively studied during fatal alphavirus encephalomyelitis, macrophage recruitment in response to JHMV and LCMV infection in the CNS is also affected by IFN-g signalling Lin et al, 2009;Pewe et al, 2002;Savarin & Bergmann, 2008).…”

The role of IL-12, IL-23 and IFN-γ in immunity to viruses

“…f An abnormal immune defense refers to a more severe disease or in vitro immune response in mice with impaired IFN␥-or IL-12/IL-23-mediated response; GKO: and IFN-␥R1KO mice; aG: anti-IFN␥ antibody treated-mice; 12KO: IL-12p40 and IL-12R␤1 KO mice; a12: anti-IL-12 antibody-treated mice. Infection routes: intravenous [112,117,126,131,142]; intraperitoneal [113,114,125,126,[139][140][141]; intradermal [112,125,135,136]; intracerebral [115,123,127,128]; intranasal [116,121]; milk [147]. References for each of the experimental infection are indicated.…”

“…References for each of the experimental infection are indicated. Genetic backgrounds were: IFN-␥KO mice: Balb/C [112,125,127,128,141,149]; C57BL/6 [114,116,117,123,127,128,145,147]; IFN-␥R1KO mice: 129/SV/E [112,115,122,126,[136][137][138][139][140]; Balb/C [147]; anti-IFN␥ antibody-treated mice: Balb/C [113,132,142]; C57BL/6 [112,119,135,143,144]; 129/SV/E [113]; CBA/Ht [140]; IL-12p40KO mice: C57BL/6 [118,121,145]; anti-IL-12-antibody treated mice: Balb/C [143]. and anti-IFN-␥ Ab-treated [119,130,131] mice become more susceptible or succumb to LCMV infection.…”

“…In contrast, GKO and anti-IFN-␥-treated mice were unable to maintain long-term control over FV infection [146]. No differences between wild-type and GKO mice were observed after mouse mammary tumor virus (MMTV) infection [147].…”

Biologic functions of the IFN‐γ receptors

“…In another group of studies, the response to the pathogen in mutant mice was normal, without a concomitant Th2‐mediated disorder, although abnormally high levels of Th2 cytokines and/or Ig isotypes were detected (see Table 1 for a summary of all disease models in which IFN‐γR1 (‐/‐) mice were used). For instance, the outcome of mouse mammary tumor virus (MMTV) infection is similar in mutant and control mice, but is characterized by increased IL‐4 levels in the former ( 114). In other models, IFN‐γR1 (‐/‐) mice elaborated defective Th1 responses with no associated Th2 response.…”