B cell-derived IL-15 enhances CD8 T cell cytotoxicity and is increased in multiple sclerosis patients

• Published in: The Journal of immunology (1950) 2011-10, Vol.187 (8), p.4119-4128
• Main Authors: Schneider, Raphael, Mohebiany, Alma Nazlie, Ifergan, Igal, Beauseigle, Diane, Duquette, Pierre, Prat, Alexandre, Arbour, Nathalie
• Format: Article
• Language: English
• Subjects: Adult; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell Separation; Chemotaxis, Leukocyte - immunology; Coculture Techniques; Female; Flow Cytometry; Humans; Interleukin-15 - immunology; Interleukin-15 - metabolism; Lymphocyte Activation - immunology; Male; Middle Aged; Multiple Sclerosis - immunology; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100885

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.