title: Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-γ.
abstract: Murine cytomegalovirus (MCMV) brain infection stimulates microglial cell-driven proinflammatory chemokine production which precedes the presence of brain-infiltrating systemic immune cells. Here, we show that in response to MCMV brain infection, antigen-specific CD8(+) T cells migrated into the brain and persisted as long-lived memory cells. The role of these persistent T cells in the brain is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Strikingly, memory T cells isolated from the brain exhibited an effector phenotype and produced IFN-γ upon restimulation with viral peptide. Furthermore, we observed time-dependent and long-term activation of resident microglia, indicated by chronic MHC class II up-regulation and TNF-α production. The immune response in this immunologically restricted site persisted in the absence of active viral replication. Lymphocyte infiltrates were detected until 30 days post-infection (p.i.), with CD8(+) and CD4(+) T cells present at a 3:1 ratio, respectively. We then investigated the role of IFN-γ in chronic microglial activation by using IFN-γ-knockout (GKO) mice. At 30 days p.i., GKO mice demonstrated a similar phenotypic brain infiltrate when compared to wild-type mice (Wt), however, MHC class II expression on microglia isolated from these GKO mice was significantly lower compared to Wt animals. When IFN-γ producing CD8(+) T cells were reconstituted in GKO mice, MHC class II up-regulation on microglial cells was restored. Taken together, these results suggest that MCMV brain infection results in long-term persistence of antigen-specific CD8(+) T cells which produce IFN-γ and drive chronic microglial cell activation. This response was found to be dependent on IFN-γ production by viral Ag-specific T cells during the chronic phase of disease.
authors.affiliation: Neuroimmunology Laboratory, Center for Infectious Diseases and Microbiology Translational Research, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Manohar B
authors.initials: MB
authors.lastname: Mutnal
authors.forename: Shuxian
authors.initials: S
authors.lastname: Hu
authors.forename: Morgan R
authors.initials: MR
authors.lastname: Little
authors.forename: James R
authors.initials: JR
authors.lastname: Lokensgard
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000821:virology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000473:pathology*; D005260:Female; D005802:Genes, MHC Class II; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000473:pathology*; D018146:Muromegalovirus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma