IFN-gamma production by CD8+ T cells depends on NFAT1 transcription factor and regulates Th differentiation.
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.
Teixeira
Leonardo K
LK
Division of Cellular Biology, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
Fonseca
Bruna P F
BP
Vieira-de-Abreu
Adriana
A
Barboza
Bianca A
BA
Robbs
Bruno K
BK
Bozza
Patrícia T
PT
Viola
João P B
JP
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018417:Th1 Cells / Q000166:cytology*
D050778:NFATC Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma