Self-limitation of Th1-mediated inflammation by IFN-gamma.
IFN-gamma is an effector cytokine of cell-mediated immunity that plays an essential role in both innate and adaptive phases of an immune response. Interestingly, in several Th1-dependent autoimmune models, lack of IFN-gamma is associated with an acceleration of disease. To distinguish the influence of IFN-gamma on the polarization of naive precursors from the influence on effector cells, we used an adoptive transfer model of differentiated Ag-specific Th1 cells. In this study, IFN-gamma displayed a dual function in a Th1-dependent immune reaction. In the early phase, IFN-gamma accelerated the inflammation, whereas in the late phase it mediated the process of self-limitation. We demonstrated that IFN-gamma limits the number of Th1 effector cells after Ag challenge. Studies using IFN-gammaR-/- mice as recipients showed that IFN-gamma acts indirectly via host cells to regulate the pool size of Th1 cells. NO was a downstream effector molecule. Transfer experiments of Th1 cells into IFN-gamma-/- mice revealed that Th1 cells control both themselves and the corresponding inflammation by the release of IFN-gamma. Thus, the proinflammatory cytokine IFN-gamma can act as a negative feedback regulator to control Th1-mediated immune responses.
Experimentelle Rheumatologie, Charité Universitaetsmedizin Berlin, Campus Mitte, Berlin, Germany.
Markus
M
Feuerer
Katharina
K
Eulenburg
Christoph
C
Loddenkemper
Alf
A
Hamann
Jochen
J
Huehn
D000818:Animals; D000941:Antigens / Q000276:immunology; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D000096743:Interferon gamma Receptor
D000941:Antigens; D018836:Inflammation Mediators; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor