Innate immunity modulates autoimmunity: type 1 interferon-beta treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation.
Type 1 interferon-beta (T1IFN-beta) is an innate cytokine and the first-choice therapy for multiple sclerosis (MS). It is still unclear how T1IFN-beta, whose main function is to promote innate immunity during infections, plays a beneficial role in autoimmune disease. Here we show that T1IFN-beta promoted the expansion and function of invariant natural killer (iNKT) cells, an innate T-cell subset with strong immune regulatory properties that is able to prevent autoimmune disease in pre-clinical models of MS and type 1 diabetes. Specifically, we observed that T1IFN-beta treatment significantly increased the percentages of Valpha24(+) NKT cells in peripheral blood mononuclear cells of MS patients. Furthermore, iNKT cells of T1IFN-beta-treated individuals showed a dramatically improved secretion of cytokines (interleukins 4 and 5 and interferon-gamma) in response to antigenic stimulation compared to iNKT cells isolated from the same patients before T1IFN-beta treatment. The effect of T1IFN-beta on iNKT cells was mediated through the modulation of myeloid dendritic cells (DCs). In fact, DCs modulated in vivo or in vitro by T1IFN-beta were more efficient antigen-presenting cells for iNKT cells. Such a modulatory effect of T1IFN-beta was associated with up-regulation on DCs of key costimulatory molecules for iNKT (i.e. CD80, CD40 and CD1d). Our data identified the iNKT cell/DC pathway as a new target for the immune regulatory effect of T1IFNs in autoimmune diseases and provide a possible mechanism to explain the clinical efficacy of T1IFN-beta in MS.
Gigli
Gianluigi
G
Immunology of Diabetes Unit, San Raffaele Scientific Institute, Milan, Italy.
Caielli
Simone
S
Cutuli
Daniela
D
Falcone
Marika
M
D000328:Adult; D017951:Antigen Presentation / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D016130:Immunophenotyping; D016899:Interferon-beta / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D016899:Interferon-beta