IFN-α is not sufficient to drive Th1 development due to lack of stable T-bet expression

Hilario J. Ramos, Ann M. Davis, Thaddeus C. George, J. David Farrar

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32 Citations (Scopus)

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-αβ), secreted primarily during viral and intracellular bacterial infections, can promote STAT4 activation in human CD4+ T cells. However, the role of IFN-αβ 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-α and IL-12 can promote STAT4 activation, IFN-α 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-α 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-α-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-α lacks this activity due to its inability to promote sustained T-bet expression.

Original languageEnglish (US)
Pages (from-to)3792-3803
Number of pages12
JournalJournal of Immunology
Volume179
Issue number6
StatePublished - Sep 15 2007

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Interleukin-12
T-Lymphocytes
Human Development
Aptitude
Phosphorylation
Th1 Cells
Second Messenger Systems
Bacterial Infections
Innate Immunity
Tyrosine
Drive
Cytokines

ASJC Scopus subject areas

  • Immunology

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IFN-α is not sufficient to drive Th1 development due to lack of stable T-bet expression. / Ramos, Hilario J.; Davis, Ann M.; George, Thaddeus C.; Farrar, J. David.

In: Journal of Immunology, Vol. 179, No. 6, 15.09.2007, p. 3792-3803.

Research output: Contribution to journalArticle

Ramos, Hilario J. ; Davis, Ann M. ; George, Thaddeus C. ; Farrar, J. David. / IFN-α is not sufficient to drive Th1 development due to lack of stable T-bet expression. In: Journal of Immunology. 2007 ; Vol. 179, No. 6. pp. 3792-3803.
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