Roles of IFN-gamma and IFN-alpha in IL-12-induced T helper cell-1 development.
IL-12 and IL-4 direct T cell development toward Th1 and Th2 phenotypes, respectively. While IFN-gamma and IFN-alpha have been reported to regulate Th1 development as well, the mechanism and cellular locus of their effects are unclear. In this study, we use a TCR-transgenic system to examine the actions of these cytokines on CD4+ T cell phenotype development. We find that neither IFN-gamma nor IFN-alpha can induce Th1 development alone. However, IFN-gamma can significantly augment IL-12 priming for subsequent IFN-gamma production by T cells. Interestingly, lymphocyte endothelial cell adhesion molecule-1bright (naive) T cells require IFN-gamma during primary activation for maximal IL-12-induced Th1 development, whereas lymphocyte endothelial cell adhesion molecule-1dull (memory) T cells do not. IFN-alpha only partially substitutes for IFN-gamma in promoting IL-12-induced Th1 development. When the endogenous IFN-gamma present in primary T cell cultures is neutralized, IFN-alpha treatment augments IL-12-induced effects on inhibition of subsequent IL-4 production, but fails to significantly enhance IL-12 priming for subsequent IFN-gamma production. Thus, our data suggest that IFN-gamma provides a direct costimulatory signal to T cells to up-regulate IL-12-induced Th1 development and may operate by inducing IL-12 responsiveness in naive T cells.
Wenner
C A
CA
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Güler
M L
ML
Macatonia
S E
SE
O'Garra
A
A
Murphy
K M
KM
D000818:Animals; D005260:Female; D016898:Interferon-alpha / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D019041:L-Selectin / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
D016898:Interferon-alpha; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D019041:L-Selectin; D018664:Interleukin-12; D007371:Interferon-gamma