Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation. (February 2016)

• Record Type: Journal Article
• Authors: Shaabani, Namir; Khairnar, Vishal; Duhan, Vikas; Zhou, Fan; Tur, Rita Ferrer; Häussinger, Dieter; Recher, Mike; Tumanov, Alexei V.; Hardt, Cornelia; Pinschewer, Daniel; Christen, Urs; Lang, Philipp A.; Honke, Nadine; Lang, Karl S.
• Is Part Of: Journal of autoimmunity. Volume 67(2016)
• Page Start: 82
• Page End: 89
• Publication Date: 2016-02
• Subjects: Immunopathology -- Lymphocytic choriomeningitis virus (LCMV) -- Enforced viral replication; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.10.004
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18 -dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8 + T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell–derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8 + T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system. Highlights: Viral replication is essential for activation of CD8 + T cells. Viral distribution along marginal zone is necessary for systemic induction of IFN-I. Viral replication is Usp18 dependent while viral distribution is LT dependent