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Production by CD8+ T Cells Depends on NFAT1 Transcription Factor and Regulates Th Differentiation1
* Division of Cellular Biology, Brazilian National Cancer Institute, Rio de Janeiro, Brazil; and
Laboratory of Immunopharmacology, Department of Physiology and Pharmacodynamics, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
CD8+ T lymphocytes are excellent sources of IFN-
; however, the molecular mechanisms that dictate IFN- 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- gene expression in murine CD8+ T cells and its relevance during Th differentiation. We show that CD8+, but not CD4+, T cells, represent the very first source of IFN- upon primary T cell activation, and also that the IFN- produced by naive CD8+ T cells may enhance CD4+ Th1 differentiation in vitro. TCR stimulation rapidly induced IFN- expression in CD8+ T lymphocytes in a cyclosporin A-sensitive manner. Evaluation of CD8+ T cells showed that calcium influx alone was sufficient to activate NFAT1 protein, transactivate IFN- gene promoter, and induce IFN- production. In fact, NFAT1-deficient mice demonstrated highly impaired IFN- production by naive CD8+ T lymphocytes, which were totally rescued after retroviral transduction with NFAT1-encoding vectors. Moreover, NFAT1-dependent IFN- production by the CD8+ T cell compartment was crucial to control a Th2-related response in vivo, such as allergic inflammation. Consistently, CD8
- as well as IFN--deficient mice did not mount a Th1 immune response and also developed in vivo allergic inflammation. Our results clearly indicate that IFN- production by CD8+ T cells is dependent of NFAT1 transcription factor and may be an essential regulator of Th immune responses in vivo.
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