title: Type I interferon signaling enhances CD8+ T cell effector function and differentiation during murine gammaherpesvirus 68 infection.
abstract: CD8(+) T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8(+) T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1(-/-) mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8(+) T cell response. To test this, IFNAR1(-/-) mice were infected with MHV68 and the CD8(+) T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8(+) T cells, and MHV68-specific CD8(+) T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-α), gamma IFN (IFN-γ), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8(+) T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1(-/-) mice failed to improve CD8(+) T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8(+) T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8(+) T cell response.
  
  
  OBJECTIVE
  The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8(+) T cells as well as type I interferon signaling. Type I IFNs have been shown to critically support the antiviral CD8(+) T cell response in other virus models. Here, we identify an indirect role for type I IFN signaling in enhancing gammaherpesvirus-specific CD8(+) T cell cytokine production. Further, this function of type I IFN signaling can be partially rescued by suppressing viral replication during early MHV68 infection. Our data suggest that type I IFN signaling on non-T cells can enhance CD8(+) T cell function during gammaherpesvirus infection, potentially through suppression of MHV68 replication.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Jennings
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Grayson
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA ebarton@wakehealth.edu.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Barton
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D006566:Herpesviridae Infections / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D018144:Rhadinovirus / Q000276:immunology*; D015398:Signal Transduction; D014412:Tumor Virus Infections / Q000276:immunology*
chemical_list: D016207:Cytokines; D007370:Interferon Type I; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor