Increased Protection from Vaccinia Virus Infection in Mice Genetically Prone to Lymphoproliferative Disorders

Abstract

Mutations in the genes that encode Fas or Fas ligand (FasL) can result in poor restraints on lymphocyte activation and in increased susceptibility to autoimmune disorders. Because these mutations portend a continuously activated immune state, we hypothesized that they might in some cases confer resistance to infection. To examine this possibility, the immune response to, morbidity caused by, and clearance of vaccinia virus (VACV) Western Reserve was examined in 5- to 7-week-old Fas mutant ( lpr ) mice, before an overt lymphoproliferative disorder was observable. On day 6 after VACV infection, C57BL/6- lpr (B6- lpr ) mice had decreased morbidity, decreased viral titers, and an increased percentage and number of CD4 + and CD8 + T cells. As early as day 2 after infection, B6- lpr mice had decreased liver and spleen viral titers and increased numbers of and increased gamma interferon (IFN-γ) production by several different effector cell populations. Depletion of individual effector cell subsets did not inhibit the resistance of B6- lpr mice. Uninfected B6- lpr mice also had increased numbers of NK cells, γδ + T cells, and CD44 + CD4 + and CD44 + CD8 + T cells compared to uninfected B6 mice. Antibody to IFN-γ resulted in increased virus load in both B6 and B6- lpr mice and eliminated the differences in viral titers between them. These results suggest that IFN-γ produced by multiple activated leukocyte populations in Fas-deficient hosts enhances resistance to some viral infections.

CD8 T Cells Use IFN-γ To Protect against the Lethal Effects of a Respiratory Poxvirus Infection

“…Previous work has demonstrated that mice that have inactivating mutations in FAS (B6-lpr) are resistant to respiratory virus infections (41, 42). Therefore to address the role of perforin and TRAIL mediated cytotoxicity, we i.n.…”

Staying Alive: Cell Death in Antiviral Immunity

“…Similarly, Fas was dispensable for control of MCMV induced retinitis (Dix et al, 2004). In fact, lpr mice were more efficient at controlling vaccinia virus replication (Seedhom et al, 2012). Hence, although cytotoxic lymphocytes can use perforin/granzyme or Fas/FasL pathways to eliminate target cells, in vivo evidence indicates that Fas-FasL pathway has a modest role in cytolysis of virus-infected cells.…”

Anatomically Restricted Synergistic Antiviral Activities of Innate and Adaptive Immune Cells in the Skin

“…VV peptides recognized by human or mouse CD8 + T cells have been identified (Moutaftsi et al, 2006; Tscharke et al, 2005; Tscharke et al, 2006), leading to definition of robust immunodominance hierarchies of CD8 + T cells responding to individual viral peptides (Flesch et al, 2010; Tscharke et al, 2005; Tscharke et al, 2006; Yewdell, 2006). Knockout mice have revealed gene products governing the strength of the VV-specific CD8 + T cell response ((Remakus and Sigal, 2011; Salek-Ardakani et al, 2009; Seedhom et al, 2012; Zhao and Croft, 2012), for examples).…”