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Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation¹

Minggui Pan^2,*, Monte M. Winslow, Lei Chen, Ann Kuo, Dean Felsher^* and Gerald R. Crabtree^2,

^* Division of Oncology, Program in Immunology, and Howard Hughes Medical Institute, Department of Developmental Biology and Department of Pathology, Stanford University, Stanford CA 94305

TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1^nuc) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1^nuc T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1^nuc T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1^nuc destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines.

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 has been supported partially by a Lymphoma Research Foundation Fellowship (to M.P.), a Stanford Graduate Fellowship (to M.M.W.), and a Howard Hughes Medical Institute Predoctoral Fellowship (to M.M.W.).

² Address correspondence and reprint requests to Dr. Minggui Pan, Division of Oncology-Hematology, Kaiser Permanente Medical Center, Santa Clara, CA 95051 or Dr. Gerald R. Crabtree, Howard Hughes Medical Institute, Stanford, CA 94305. E-mail addresses: minggui.pan{at}kp.org or crabtree{at}stanford.edu

³ Abbreviations used in this paper: GSK3, glycogen synthase kinase; DSCR-1, Down syndrome critical region 1; CD40L, CD40 ligand; HA, hemagglutinin; Tet, tetracycline; tTA, Tet transcriptional factor; WT, wild type; CsA, cyclosporin A; CHIP, direct calcineurin inhibitor.

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