title: IFN-alpha is not sufficient to drive Th1 development due to lack of stable T-bet expression.
abstract: During inflammatory immune responses, the innate cytokine IL-12 promotes CD4+ Th-1 development through the activation of the second messenger STAT4 and the subsequent expression of T-bet. In addition, type I IFN (IFN-alphabeta), secreted primarily during viral and intracellular bacterial infections, can promote STAT4 activation in human CD4+ T cells. However, the role of IFN-alphabeta in regulating Th1 development is controversial, and previous studies have suggested a species-specific pathway leading to Th1 development in human but not mouse CD4+ T cells. In this study, we found that although both IFN-alpha and IL-12 can promote STAT4 activation, IFN-alpha failed to promote Th1 commitment in human CD4+ T cells. The difference between these innate signaling pathways lies with the ability of IL-12 to promote sustained STAT4 tyrosine phosphorylation, which correlated with stable T-bet expression in committed Th1 cells. IFN-alpha did not promote Th1 development in human CD4+ T cells because of attenuated STAT4 phosphorylation, which was insufficient to induce stable expression of T-bet. Further, the defect in IFN-alpha-driven Th1 development was corrected by ectopic expression of T-bet within primary naive human CD4+ T cells. These results indicate that IL-12 remains unique in its ability to drive Th1 development in human CD4+ T cells and that IFN-alpha lacks this activity due to its inability to promote sustained T-bet expression.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Hilario J
authors.initials: HJ
authors.lastname: Ramos
authors.forename: Ann M
authors.initials: AM
authors.lastname: Davis
authors.forename: Thaddeus C
authors.initials: TC
authors.lastname: George
authors.forename: J David
authors.initials: JD
authors.lastname: Farrar
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000378:metabolism; D013045:Species Specificity; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor