Abstract
CD8+ 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+ T cells and its relevance during Th differentiation. We show that CD8+, but not CD4+, 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+ T cells may enhance CD4+ Th1 differentiation in vitro. TCR stimulation rapidly induced IFN-gamma 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-gamma gene promoter, and induce IFN-gamma production. In fact, NFAT1-deficient mice demonstrated highly impaired IFN-gamma production by naive CD8+ T lymphocytes, which were totally rescued after retroviral transduction with NFAT1-encoding vectors. Moreover, NFAT1-dependent IFN-gamma production by the CD8+ T cell compartment was crucial to control a Th2-related response in vivo, such as allergic inflammation. Consistently, CD8alpha- 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+ T cells is dependent of NFAT1 transcription factor and may be an essential regulator of Th immune responses in vivo.
Highlights
Why The JI? Submit online. Rapid Reviews! 30 days* from submission to initial decision No Triage! Every submission reviewed by practicing scientists Fast Publication! 4 weeks from acceptance to publicatio
In this study we show that naive CD8ϩ T cells do produce high levels of IFN-␥ upon TCR triggering during the primary response, which is dependent on NFAT1 transcription factor
We demonstrate that IFN-␥ production by the CD8ϩ T cell compartment enhances CD4ϩ Th1 differentiation in vitro and is crucial to control allergic inflammation, which has been related to a Th1/ Th2 immune response deregulation
Summary
CsA, cyclosporin A; EGFP, enhanced GFP; Eomes, eomesodermin; IRES, internal ribosomal entry sequence. We addressed the involvement of NFAT1 transcription factor in the regulation of IFN-␥ production in CD8ϩ T cells and its influence on Th1/Th2 immune responses using in vitro and in vivo models of Th differentiation. In this study we show that naive CD8ϩ T cells do produce high levels of IFN-␥ upon TCR triggering during the primary response, which is dependent on NFAT1 transcription factor. We demonstrate that IFN-␥ production by the CD8ϩ T cell compartment enhances CD4ϩ Th1 differentiation in vitro and is crucial to control allergic inflammation, which has been related to a Th1/ Th2 immune response deregulation. Our results suggest that NFAT1 protein plays a positive regulatory role in IFN-␥ production in CD8ϩ T cells, which may modulate Th immune response in vivo
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
