Thymic tolerance to only one viral protein reduces lymphocytic choriomeningitis virus-induced immunopathology and increases survival in perforin-deficient mice

Matthias Von Herrath, Bryan Coon, Dirk Homann, Tom Wolfe, Luca G. Guidotti

Research output: Contribution to journalArticle

Abstract

The outcome of viral infections is dependent on the amount of tissue destruction caused either by direct lysis of infected cells and/or by immunopathology resulting from the immune response to the virus. We investigated whether induction of tolerance to only one vital protein could reduce immunopathology caused by nonlytic lymphocytic choriomeningitis virus (LCMV) in perforin-deficient hosts. Earlier studies had shown that LCMV infection results in aplastic anemia and death in most of these mice and that this is associated with bone marrow infiltration by antiviral cytotoxic T lymphocytes (CTL) that secrete inflammatory cytokines. We report here that perforin-deficient mice exhibit severe immunopathology in multiple organs that is characterized by infiltration of anti-LCMV CTL that secrete large amounts of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF- α). Importantly, this immunopathology is significantly reduced and long- term survival of LCMV infection is increased in perforin-deficient mice expressing LCMV nucleoprotein (NP) in the thymus (and therefore deleting most of their LCMV-NP CTL) compared to the situation in thymus nonexpressors. This is due to the selective reduction of NP-specific CTL responses and their inflammatory-cytokine (IFN-γ and TNF-γ) secretion and to a lack of pathogenetically relevant compensatory responses to other viral proteins. Thus, 'selective reduction' of the antiviral immune response to only one viral protein can significantly reduce inflammatory immunopathology and might be a therapeutic possibility for certain nonlytic infections.

Original languageEnglish
Pages (from-to)5918-5925
Number of pages8
JournalJournal of Virology
Volume73
Issue number7
Publication statusPublished - 1999

ASJC Scopus subject areas

  • Immunology

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