Th17 cells in multiple sclerosis express higher levels of JAK2, which increases their surface expression of IFN-γR2.
IFN-β inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.
Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, 10126 Turin, Italy.
Laura
L
Conti
Raffaele
R
De Palma
Simona
S
Rolla
Daniela
D
Boselli
Gabriella
G
Rodolico
Surinder
S
Kaur
Olli
O
Silvennoinen
Elena
E
Niccolai
Amedeo
A
Amedei
Federico
F
Ivaldi
Marinella
M
Clerico
Giulia
G
Contessa
Antonio
A
Uccelli
Luca
L
Durelli
Francesco
F
Novelli
D016022:Case-Control Studies; D049109:Cell Proliferation; D006801:Humans; D007372:Interferons; D053614:Janus Kinase 2 / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D017471:Receptors, Interferon / Q000032:analysis / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D007372:Interferons; D053614:Janus Kinase 2; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor