title: IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells.
abstract: Astrocytes may serve as effectual APCs for T cell-mediated immune responses to myelin components during multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Although astrocytes have been reported not to constitutively express MHC class II molecules, expression is up-regulated during active EAE and by in vitro incubation with IFN-gamma. Previous studies have reported that cytokine-activated astrocytes are able to activate Ag-specific previously activated T cells, but not naive alloreactive T cells. In the current study, we show that a subset of primary murine astrocytes constitutively expresses B7-2 molecules, as determined by FACS and PCR analyses, and up-regulates surface expression and mRNA levels of both B7-2 and B7-1 upon IFN-gamma stimulation. In contrast to earlier reports, we found that both untreated and IFN-gamma-treated astrocytes were able to stimulate proliferation of previously activated OVA-specific Th1 cells. In contrast, only IFN-gamma-treated astrocytes activated naive, transgenic OVA-specific T cells. Astrocyte-induced activation of both OVA-specific naive T cells and activated Th1 cells was dependent primarily on B7-2-mediated costimulation, as proliferation was inhibited by CTLA4-Ig and by anti-B7-2 mAbs. These results suggest that astrocytes in an inflammatory environment have the capacity to express the required MHC class II and B7 costimulatory molecules necessary for efficient activation of naive T cells. Since we have shown that T cells specific for endogenous myelin epitopes released during acute EAE play the major pathologic effector role in subsequent disease relapses (epitope spreading), astrocytes could play a role in the local activation and expansion of these responses.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Nikcevich
authors.forename: K B
authors.initials: KB
authors.lastname: Gordon
authors.forename: L
authors.initials: L
authors.lastname: Tan
authors.forename: S D
authors.initials: SD
authors.lastname: Hurst
authors.forename: J F
authors.initials: JF
authors.lastname: Kroepfl
authors.forename: M
authors.initials: M
authors.lastname: Gardinier
authors.forename: T A
authors.initials: TA
authors.lastname: Barrett
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D000939:Epitopes / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000138:chemical synthesis; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000069594:Abatacept; D007371:Interferon-gamma; D010047:Ovalbumin