The role of Stat4 in species-specific regulation of Th cell development by type I IFNs.
Type I IFNs (IFN-alpha/beta), in addition to IL-12, have been shown to play an important role in the differentiation of human, but not mouse, Th cells. We show here that IFN-alpha/beta act directly on human T cells to drive Th1 development, bypassing the need for IL-12-induced signaling, whereas IFN-alpha cannot substitute IL-12 for mouse Th1 development. The molecular basis for this species specificity is that IFN-alpha/beta activate Stat4 in differentiating human, but not mouse, Th cells. Unlike IL-12, which acts only on Th1 cells, IFN-alpha/beta can activate Stat4 not only in human Th1, but also in Th2 cells. However, restimulation of human Th2 lines and clones in the presence of IFN-alpha does not induce the production of IFN-gamma. These results suggest that activation of Stat4, which is necessary for the differentiation of naive T cells into polarized Th1 cells, is not sufficient to induce phenotype reversal of human Th2 cells.
Rogge
L
L
Roche Milano Ricerche, Milan, Italy. lars.rogge@roche.com
D'Ambrosio
D
D
Biffi
M
M
Penna
G
G
Minetti
L J
LJ
Presky
D H
DH
Adorini
L
L
Sinigaglia
F
F
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013045:Species Specificity; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12