IFN- gamma Production by CD8 super(+) T Cells Depends on NFAT1 Transcription Factor and Regulates Th Differentiation

CD8 super(+) T lymphocytes are excellent sources of IFN- gamma ; however, the molecular mechanisms that dictate IFN- gamma expression upon TCR stimulation in these cells are not completely understood. In this study, we evaluated the involvement of NFAT1 in the regulation of IFN- gamma gene expressio...

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Published in:The Journal of immunology (1950) 2005-11, Vol.175 (9), p.5931-5939
Main Authors: Teixeira, Leonardo K, Fonseca, Bruna PF, Vieira-de-Abreu, Adriana, Barboza, Bianca A, Robbs, Bruno K, Bozza, Patricia T, Viola, Joao PB
Format: Article
Language:English
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Summary:CD8 super(+) T lymphocytes are excellent sources of IFN- gamma ; however, the molecular mechanisms that dictate IFN- gamma expression upon TCR stimulation in these cells are not completely understood. In this study, we evaluated the involvement of NFAT1 in the regulation of IFN- gamma gene expression in murine CD8 super(+) T cells and its relevance during Th differentiation. We show that CD8 super(+), but not CD4 super(+), T cells, represent the very first source of IFN- gamma upon primary T cell activation, and also that the IFN- gamma produced by naive CD8 super(+) T cells may enhance CD4 super(+) Th1 differentiation in vitro. TCR stimulation rapidly induced IFN- gamma expression in CD8 super(+) T lymphocytes in a cyclosporin A-sensitive manner. Evaluation of CD8 super(+) T cells showed that calcium influx alone was sufficient to activate NFAT1 protein, transactivate IFN- gamma gene promoter, and induce IFN- gamma production. In fact, NFAT1-deficient mice demonstrated highly impaired IFN- gamma production by naive CD8 super(+) T lymphocytes, which were totally rescued after retroviral transduction with NFAT1-encoding vectors. Moreover, NFAT1-dependent IFN- gamma production by the CD8 super(+) T cell compartment was crucial to control a Th2-related response in vivo, such as allergic inflammation. Consistently, CD8 alpha - as well as IFN- gamma -deficient mice did not mount a Th1 immune response and also developed in vivo allergic inflammation. Our results clearly indicate that IFN- gamma production by CD8 super(+) T cells is dependent of NFAT1 transcription factor and may be an essential regulator of Th immune responses in vivo.
ISSN:0022-1767