Contribution of astrocyte-derived IL-15 to CD8 T cell effector functions in multiple sclerosis

The contribution of local factors to the activation of immune cells infiltrating the CNS of patients with multiple sclerosis (MS) remains to be defined. The cytokine IL-15 is pivotal in the maintenance and activation of CD8 T lymphocytes, a prominent lymphocyte population found in MS lesions. We inv...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2010-11, Vol.185 (10), p.5693-5703
Main Authors: Saikali, Philippe, Antel, Jack P, Pittet, Camille L, Newcombe, Jia, Arbour, Nathalie
Format: Article
Language:English
Subjects:
Astrocytes - immunology
Astrocytes - metabolism
Brain - immunology
Brain - metabolism
Brain - pathology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cell Line
Cell Separation
Coculture Techniques
Cytokines - immunology
Cytokines - metabolism
Cytokines - pharmacology
Cytotoxicity, Immunologic - immunology
Flow Cytometry
Humans
Immunohistochemistry
Interleukin-15 - biosynthesis
Interleukin-15 - immunology
Lymphocyte Activation - immunology
Multiple Sclerosis - immunology
Multiple Sclerosis - metabolism
Multiple Sclerosis - pathology
Reverse Transcriptase Polymerase Chain Reaction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The contribution of local factors to the activation of immune cells infiltrating the CNS of patients with multiple sclerosis (MS) remains to be defined. The cytokine IL-15 is pivotal in the maintenance and activation of CD8 T lymphocytes, a prominent lymphocyte population found in MS lesions. We investigated whether astrocytes are a functional source of IL-15 sufficient to enhance CD8 T lymphocyte responses and whether they provide IL-15 in the inflamed CNS of patients with MS. We observed that human astrocytes in primary cultures increased surface IL-15 levels upon activation with combinations of proinflammatory cytokines. Expanded human myelin autoreactive CD8 T lymphocytes cultured with such activated astrocytes displayed elevated lytic enzyme content, NKG2D expression, and Ag-specific cytotoxicity. These functional enhancements were abrogated by anti-IL-15-blocking Abs. Immunohistochemical analysis of brain tissue sections obtained from patients with MS demonstrated colocalization for IL-15 and the astrocyte marker glial fibrillary acidic protein within white matter lesions. The majority of astrocytes (80-90%) present in demyelinating MS lesions expressed IL-15, whereas few astrocytes in normal control brain sections had detectable IL-15. IL-15 could be detected in the majority of Iba-1-expressing microglia in the control sections, albeit in lower numbers when compared with microglia/macrophages in MS lesions. Furthermore, infiltrating CD8 T lymphocytes in MS lesions were in close proximity to IL-15-expressing cells. Astrocyte production of IL-15 resulting in the activation of CD8 T lymphocytes ascribes a role for these cells as contributors to the exacerbation of tissue damage during MS pathogenesis.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1002188