title: IL-15 amplifies the pathogenic properties of CD4+CD28- T cells in multiple sclerosis.
abstract: CD4(+)CD28(-) T cells arise through repeated antigenic stimulation and are present in diseased tissues of patients with various autoimmune disorders, including multiple sclerosis (MS). These cells are believed to have cytotoxic properties that contribute to the pathogenic damaging of the target organ. Endogenous cues that are increased in the diseased tissue may amplify the activity of CD4(+)CD28(-) T cells. In this study, we focused on IL-15, a cytotoxicity-promoting cytokine that is increased in the serum and cerebrospinal fluid of MS patients. Using immunohistochemistry, we demonstrate that IL-15 is mainly produced by astrocytes and infiltrating macrophages in inflammatory lesions of MS patients. Moreover, in vitro transmigration studies reveal that IL-15 selectively attracts CD4(+)CD28(-) T cells of MS patients, but not of healthy individuals. IL-15 further induces the expression of chemokine receptors and adhesion molecules on CD4(+)CD28(-) T cells, as investigated using flow cytometry, resulting in enhanced migration over a monolayer of human brain endothelial cells. Finally, flow cytometric analyses revealed that IL-15 increases the proliferation and production of GM-CSF, expression of cytotoxic molecules (NKG2D, perforin, and granzyme B), and degranulation capacity of CD4(+)CD28(-) T cells. Taken together, these findings indicate that increased peripheral and local levels of IL-15 amplify the pathogenic potential of CD4(+)CD28(-) T cells, thus contributing to tissue damage in MS brain lesions.
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium;
authors.forename: Bieke
authors.initials: B
authors.lastname: Broux
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands; and.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Mizee
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium;
authors.forename: Marjan
authors.initials: M
authors.lastname: Vanheusden
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands; and.
authors.forename: Susanne
authors.initials: S
authors.lastname: van der Pol
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium; Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands; and.
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium; Revalidatie en MS-Centrum, 3900 Overpelt, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Van Wijmeersch
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium;
authors.forename: Veerle
authors.initials: V
authors.lastname: Somers
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands; and.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium;
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.affiliation: Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium; niels.hellings@uhasselt.be.
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D054353:Perforin / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; C569274:IL15 protein, human; D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054353:Perforin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C509213:GZMB protein, human; D053804:Granzymes