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Exposure during Human Dendritic Cell Maturation and Naive Th Cell Stimulation Has Contrasting Effects on Th1 Subset Generation: A Role for IFN--Mediated Regulation of IL-12 Family Cytokines and IL-18 in Naive Th Cell Differentiation1
* 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; and
Laboratory of Molecular Immunology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
Type I IFNs, IFN-
and IFN-
, 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- to inhibit autoimmune Th1 responses is thought to account for some of the beneficial effects of IFN- therapy in the treatment of relapsing remitting multiple sclerosis. To understand the basis of the paradoxical effects of IFN- 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- on the generation of Th1 cells. In this model we found that the timing of IFN- exposure determines whether IFN- will have a positive or a negative effect on naive Th cell differentiation into Th1 cells. Specifically, the presence of IFN- during TNF--induced DC maturation strongly augments the capacity of DC to promote the generation of IFN-
-secreting Th1 cells. In contrast, exposure to IFN- 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- 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.
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