IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis.
T regulatory cells type 1 (Tr1 cells) are excellent candidates for cell therapy in multiple sclerosis (MS). The aim of our study was to assess the functional state of Tr1 cells and IL-10R signaling in patients with MS. Tr1 cells were induced in vitro by activation with anti-CD46 antibodies in controls and patients with MS. Cells were phenotyped by cytometry and suppression assays, and the expression of cytokines and transcription factors was evaluated by real-time PCR, ELISA, cytometry and Western blotting. We found that the activity of Tr1 cells and IL-10R signaling is impaired in MS patients since Tr1 cells isolated from MS patients produced less IL-10 than those obtained from controls. Indeed, the supernatants from Tr1 cells from controls did not suppress the proliferation of stimulated CD4(+) cells from patients with MS. Furthermore, the IL-10R signaling pathway was not fully active in CD4(+) cells from MS patients and these cells had higher baseline levels of SOCS3 transcripts than controls. Indeed, after in vitro IL-10 stimulation, the expression levels of the STAT1, STAT3 and IL-10RA genes were higher in MS patients than in controls. Moreover, Stat-3 phosphorylation was lower in controls than in patients after IL-10 stimulation. These results indicate that IL-10 regulatory function is impaired in patients with MS.
Martinez-Forero
Ivan
I
Department of Neurology, University of Navarra, Pamplona, Spain.
Garcia-Munoz
Ricardo
R
Martinez-Pasamar
Sara
S
Inoges
Susana
S
Lopez-Diaz de Cerio
Ascensión
A
Palacios
Ricardo
R
Sepulcre
Jorge
J
Moreno
Beatriz
B
Gonzalez
Zaira
Z
Fernandez-Diez
Begoña
B
Melero
Ignacio
I
Bendandi
Maurizio
M
Villoslada
Pablo
P
D000328:Adult; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
D053701:Receptors, Interleukin-10; D016753:Interleukin-10