title: CD161(high)CD8+T cells bear pathogenetic potential in multiple sclerosis.
abstract: To identify differentially expressed genes in multiple sclerosis, microarrays were used in a stringent experimental setting-leukapheresis from disease-discordant monozygotic twins and gene expression profiling in CD4(+) and CD8(+) T-cell subsets. Disease-related differences emerged only in the CD8(+) T-cell subset. The five differentially expressed genes identified included killer cell lectin-like receptor subfamily B, member 1, also known as natural killer receptor protein 1a/CD161, presented by the International Multiple Sclerosis Genetics Consortium as one of the non-MHC candidate loci. Flow cytometric analysis on peripheral blood of healthy donors and patients with multiple sclerosis and rheumatoid arthritis confirmed an upregulation of CD161 at the protein level, showing also a significant excess of CD161(high)CD8(+) T cells in multiple sclerosis. This subset prevalently included chemokine (C-C motif) receptor 6(+), cytokine-producing, effector-memory T cells with proinflammatory profiles. It also included all circulating interleukin-17(+)CD8(+) T cells. In the CD161(high)CD8(+) subset, interleukin-12 facilitated proliferation and interferon-γ production, with CD161 acting as a co-stimulatory receptor. CD161(+)CD8(+)CD3(+) T cells producing interferon-γ were part of intralesional immune infiltrates and ectopic B cell follicles in autopsy multiple sclerosis brains. Variations of CD161 expression on CD8(+) T cells identify a subset of lymphocytes with proinflammatory characteristics that have not been previously reported in multiple sclerosis and are likely to contribute to disease immunopathology.
authors.affiliation: Neurology and Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital Site, Sapienza University of Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Annibali
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ristori
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Angelini
authors.forename: Barbara
authors.initials: B
authors.lastname: Serafini
authors.forename: Rosella
authors.initials: R
authors.lastname: Mechelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Cannoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Romano
authors.forename: Andrea
authors.initials: A
authors.lastname: Paolillo
authors.forename: Hadi
authors.initials: H
authors.lastname: Abderrahim
authors.forename: Adamo
authors.initials: A
authors.lastname: Diamantini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.forename: Francesca
authors.initials: F
authors.lastname: Aloisi
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Marco
authors.initials: M
authors.lastname: Salvetti
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D014430:Twins, Monozygotic / Q000276:immunology; D015854:Up-Regulation
chemical_list: C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018664:Interleukin-12; D007371:Interferon-gamma