Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis
Version of Record online: 8 DEC 2009
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 67, Issue 5, pages 625–638, May 2010
How to Cite
Correale, J. and Villa, A. (2010), Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis. Ann Neurol., 67: 625–638. doi: 10.1002/ana.21944
- Issue online: 26 APR 2010
- Version of Record online: 8 DEC 2009
- Manuscript Accepted: 1 DEC 2009
- Manuscript Revised: 30 NOV 2009
- Manuscript Received: 11 FEB 2009
- Dr Raúl Carrea Institute for Neurological Research
The objective of this study was to investigate the role of CD8+ CD25+ FoxP3+ cells during the course of multiple sclerosis (MS).
Peripheral blood and cerebrospinal fluid (CSF) CD8+ T-cell clones (TCCs) recognizing autoreactive CD4+ T cells were isolated from 20 MS patients during exacerbations, 15 patients in remission, 15 healthy subjects, and 10 patients with other inflammatory neurological diseases. Characteristics of noncytotoxic CD8+ CD25+ regulatory T cells were studied. Cell phenotype was evaluated using flow cytometry. Cytokine production and phospho-signal transducer and activator of transcription 3 (STAT3) concentration were determined using enzyme-linked immunosorbent assay. To assess 2,3-dioxygenase (IDO) activity on dendritic cells (DCs), kynurenine concentration was measured by high-performance liquid chromatography.
Inhibition of CD4+ self-reactive T-cell proliferation, and of interferon-γ and interleukin (IL)-17 secretion, was observed after adding CD8+ CD25+ FoxP3+ cells to cultures. Suppression was abrogated by silencing FoxP3 using small interfering RNA. Cells were CD122+, CTLA-4+, GITR+, CCR7+, and CD62L+, producing IL-10 and transforming growth factor-β. CD8+ CD25+ FoxP3+ cells downregulated costimulatory molecule expression on dendritic cells through a STAT3-mediated pathway, resulting in less efficient antigen presentation, and induced IDO expression on DCs through STAT3 and cytotoxic T-lymphocyte antigen 4-dependent mechanisms. CD8+ regulatory TCC cloning frequency studied in blood and CSF was suppressed to a greater degree during exacerbations than during remission or in controls. Likewise, in CSF of MS patients during acute exacerbations, lower levels of CD8+ CD25+ FoxP3+ T cells were detected using flow cytometry.
CD8+ CD25+ FoxP3+ cells are novel regulatory cells exerting significant influence over self-reactive CD4+ T-cell regulation during the course of MS. Induction of these cells may provide new therapeutic alternatives for MS by eliminating or inhibiting self-reactive T cells. ANN NEUROL 2010;67:625–638