title: Persistent gamma-herpesvirus infection induces a CD4 T cell response containing functionally distinct effector populations.
abstract: The direct effector mechanisms of CD4 T cells during gamma-herpesvirus 68 (gammaHV68)-persistent infection are less well understood than those of their CD8 T cell counterparts, although there is substantial evidence that CD4 T cells are critical for the control of persistent gamma-herpesvirus infection. Our results show that in gammaHV68-persistently infected mice, CD4 T cells are not cytokine polyfunctional, but there is a division of labor in the CD4 T cell compartment in which CD4 T cells polarize toward two distinct populations with different effector functions: IFN-gamma producers and CD107(+) cytolytic effectors. These two CD4 T cell effector populations degranulate and produce IFN-gamma during steady state without need for exogenous antigenic restimulation, which is fundamentally different from that observed with gammaHV68-specific CD8 T cells. By using anti-IFN-gamma Ab depletions and IFN-gamma-deficient mice, we show that CD4 T cell-mediated cytotoxicity in vivo is not dependent on IFN-gamma activity. In addition, our data show that purified CD4 T cells isolated from gammaHV68-latently infected mice have the capacity to inhibit gammaHV68 reactivation from latency. Our results support the concept that CD4 T cells are critical effectors for the control of gamma-herpesvirus latent infection, and they mediate this effect by two independent mechanisms: IFN-gamma production and cytotoxicity.
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Stuller
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Cush
authors.forename: Emilio
authors.initials: E
authors.lastname: Flaño
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006566:Herpesviridae Infections / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018144:Rhadinovirus / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D017735:Virus Latency / Q000276:immunology
chemical_list: D007371:Interferon-gamma