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Actin Cytoskeleton Regulates Calcium Dynamics and NFAT Nuclear Duration

Department of Pathology, Department of Medicine, and Ben May Institute, The University of Chicago, Chicago, Illinois 60637

Received 19 June 2003/ Returned for modification 4 August 2003/ Accepted 18 November 2003

T-cell activation by antigen-presenting cells is accompanied by actin polymerization, T-cell receptor (TCR) capping, and formation of the immunological synapse. However, whether actin-dependent events are required for T-cell function is poorly understood. Herein, we provide evidence for an unexpected negative regulatory role of the actin cytoskeleton on TCR-induced cytokine production. Disruption of actin polymerization resulted in prolonged intracellular calcium elevation in response to anti-CD3, thapsigargin, or phorbol myristate acetate plus ionomycin, leading to persistent NFAT (nuclear factor of activated T cells) nuclear duration. These events were dominant, as the net effect of actin blockade was augmented interleukin 2 promoter activity. Increased surface expression of the plasma membrane Ca²⁺ ATPase was observed upon stimulation, which was inhibited by cytochalasin D, suggesting that actin polymerization contributes to calcium export. Our results imply a novel role for the actin cytoskeleton in modulating the duration of Ca²⁺-NFAT signaling and indicate that actin dynamics regulate features of T-cell activation downstream of receptor clustering.

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