Reciprocal NFAT1 and NFAT2 nuclear localization in CD8+ anergic T cells is regulated by suboptimal calcium signaling.
Anergy is an important mechanism of maintaining peripheral immune tolerance. T cells rendered anergic are refractory to further stimulation and are characterized by defective proliferation and IL-2 production. We used a model of in vivo anergy induction in murine CD8+ T cells to analyze the initial signaling events in anergic T cells. Tolerant T cells displayed reduced phospholipase Cgamma activation and calcium mobilization, indicating a defect in calcium signaling. This correlated with a block in nuclear localization of NFAT1 in anergic cells. However, we found that stimulation of anergic, but not naive T cells induced nuclear translocation of NFAT2. This suggested that NFAT2 is activated preferentially by reduced calcium signaling, and we confirmed this hypothesis by stimulating naive T cells under conditions of calcium limitation or partial calcineurin inhibition. Thus, our work provides new insight into how T cell stimulation conditions might dictate specific NFAT isoform activation and implicates NFAT2 involvement in the expression of anergy-related genes.
Srinivasan
Mathangi
M
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Frauwirth
Kenneth A
KA
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology; D020013:Calcium Signaling / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D019913:Nuclear Localization Signals / Q000276:immunology / Q000378:metabolism*; D017634:Self Tolerance / Q000276:immunology