title: Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells.
abstract: Multiple sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons, and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies identified CD8 T cell infiltrates and gray matter lesions in MS patients. These findings suggest that CD8 T cells and CNS Ags other than myelin proteins may be involved during the MS disease process. In this article, we show that CD8 T cells reactive to glial fibrillary acidic protein (GFAP), a protein expressed in astrocytes, can avoid tolerance mechanisms and, depending upon the T cell-triggering event, drive unique aspects of inflammatory CNS autoimmunity. In GFAP-specific CD8 TCR-transgenic (BG1) mice, tissue resident memory-like CD8 T cells spontaneously infiltrate the gray matter and white matter of the CNS, resulting in a relapsing-remitting CNS autoimmunity. The frequency, severity, and remissions from spontaneous disease are controlled by the presence of polyclonal B cells. In contrast, a viral trigger induces GFAP-specific CD8 T effector cells to exclusively target the meninges and vascular/perivascular space of the gray and white matter of the brain, causing a rapid, acute CNS disease. These findings demonstrate that the type of CD8 T cell-triggering event can determine the presentation of distinct CNS autoimmune disease pathologies.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Sasaki
authors.forename: Angela
authors.initials: A
authors.lastname: Bean
authors.forename: Shivanee
authors.initials: S
authors.lastname: Shah
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Schutten
authors.forename: Priya G
authors.initials: PG
authors.lastname: Huseby
authors.forename: Bjorn
authors.initials: B
authors.lastname: Peters
authors.forename: Zu T
authors.initials: ZT
authors.lastname: Shen
authors.forename: Vijay
authors.initials: V
authors.lastname: Vanguri
authors.forename: Denny
authors.initials: D
authors.lastname: Liggitt
authors.forename: Eric S
authors.initials: ES
authors.lastname: Huseby
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology*; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002493:Central Nervous System Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma