title: B cell-derived IL-15 enhances CD8 T cell cytotoxicity and is increased in multiple sclerosis patients.
abstract: Multiple lines of evidence suggest that CD8 T cells contribute to the pathogenesis of multiple sclerosis (MS). However, the sources and involvement of cytokines such as IL-15 in activating these cells is still unresolved. To investigate the role of IL-15 in enhancing the activation of CD8 T cells in the context of MS, we determined cell types expressing the bioactive surface IL-15 in the peripheral blood of patients and evaluated the impact of this cytokine on CD8 T cell cytotoxicity and migration. Flow cytometric analysis showed a significantly greater proportion of B cells and monocytes from MS patients expressing IL-15 relative to controls. We established that CD40L activation of B cells from healthy donors increased their IL-15 levels, reaching those of MS patients. We also demonstrated an enhanced cytotoxic profile in CD8 T cells from MS patients upon stimulation with IL-15. Furthermore, we showed that IL-15 expressed by B cells and monocytes is sufficient and functional, enhancing granzyme B production by CD8 T cells upon coculture. Exposure of CD8 T cells to this cytokine enhanced their ability to kill glial cells as well as to migrate across an in vitro inflamed human blood-brain barrier. The elevated levels of IL-15 in patients relative to controls, the greater susceptibility of CD8 T cells from patients to IL-15, in addition to the enhanced cytotoxic responses by IL-15-exposed CD8 T cells, stresses the potential of therapeutic strategies to reduce peripheral sources of IL-15 in MS.
authors.affiliation: Département de Médecine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2L 4M1, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Schneider
authors.forename: Alma Nazlie
authors.initials: AN
authors.lastname: Mohebiany
authors.forename: Igal
authors.initials: I
authors.lastname: Ifergan
authors.forename: Diane
authors.initials: D
authors.lastname: Beauseigle
authors.forename: Pierre
authors.initials: P
authors.lastname: Duquette
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Arbour
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D019409:Interleukin-15