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IFN- Is Not Sufficient to Drive Th1 Development Due to Lack of Stable T-bet Expression¹

Hilario J. Ramos^2,*, Ann M. Davis^2,*, Thaddeus C. George and J. David Farrar^3,*,

^* Department of Immunology and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and Amnis Corporation, Seattle, WA 98121

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by a grant from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (AI56222) awarded to J.D.F. H.J.R. was supported by a predoctoral fellowship from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (AI68622) and A.M.D. was supported by a training grant from the National Institutes of Health (GM00820317).

² H.J.R. and A.M.D. contributed equally to the present work.

³ Address correspondence and reprint requests to Dr. J. David Farrar, Department of Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9093. E-mail address: David.Farrar{at}UTSouthwestern.edu

⁴ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; cIMDM, complete IMDM; GFPRV, retrovirus vector expressing GFP; h, human (prefix); IFNAR, IFN- receptor; LCMV, lymphocytic choriomeningitis virus; P-Y, tyrosine phosphorylated; qPCR, quantitative real-time PCR; rh, recombinant human (prefix); SOCS, suppressor of cytokine signaling.

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