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Reciprocal NFAT1 and NFAT2 Nuclear Localization in CD8⁺ Anergic T Cells Is Regulated by Suboptimal Calcium Signaling¹

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742

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 C 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Cancer Institute Grant K01 CA092156 (to K.A.F.).

² Address correspondence and reprint requests to Dr. Kenneth Frauwirth, University of Maryland, 2113 Microbiology Building, College Park, MD 20742. E-mail address: kfrauwir{at}umd.edu

³ Abbreviations used in this paper: PLC, phospholipase C; ER, endoplasmic reticulum.

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