Timing of IFN-beta exposure during human dendritic cell maturation and naive Th cell stimulation has contrasting effects on Th1 subset generation: a role for IFN-beta-mediated regulation of IL-12 family cytokines and IL-18 in naive Th cell differentiation.
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.
Nagai
Taro
T
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
Devergne
Odile
O
Mueller
Thomas F
TF
Perkins
David L
DL
van Seventer
Jean Maguire
JM
van Seventer
Gijs A
GA
D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000502:physiology; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000502:physiology; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D021122:Protein Subunits / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D006131:Growth Inhibitors; D020382:Interleukin-18; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma