J Immunol. 2003 Nov 15;171(10):5233-5243
Nagai T, Devergne O, Mueller TF, Perkins DL, Van Seventer JM, Van Seventer GA.
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118. Tsukiyono Hospital, Gunma, Japan. Centre National de la Recherche Scientifique, Paris V University, Paris, France. Laboratory of Molecular Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Type I IFNs, IFN-alpha and IFN-beta, are early effectors of innate immune responses against microbes that can also regulate subsequent adaptive immunity by promoting antimicrobial Th1-type responses.
In contrast, the ability of IFN-beta to inhibit autoimmune Th1 responses is thought to account for some of the beneficial effects of IFN-beta therapy in the treatment of relapsing remitting multiple sclerosis.
To understand the basis of the paradoxical effects of IFN-beta on the expression of Th1-type immune responses, we developed an in vitro model of monocyte-derived dendritic cell (DC)-dependent, human naive Th cell differentiation, in which one can observe both positive and negative effects of IFN-beta on the generation of Th1 cells.
In this model we found that the timing of IFN-beta exposure determines whether IFN-beta will have a positive or a negative effect on naive Th cell differentiation into Th1 cells.
Specifically, the presence of IFN-beta during TNF-alpha-induced DC maturation strongly augments the capacity of DC to promote the generation of IFN-gamma-secreting Th1 cells.
In contrast, exposure to IFN-beta during mature DC-mediated primary stimulation of naive Th cells has the opposite effect, in that it inhibits Th1 cell polarization and promotes the generation of an IL-10-secreting T cell subset.
Studies with blocking mAbs and recombinant cytokines indicate that the mechanism by which IFN-beta mediates these contrasting effects on Th1 cell generation is at least in part by differentially regulating DC expression of IL-12 family cytokines (IL-12 and/or IL-23, and IL-27) and IL-18.