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LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation¹

Jin Gene Wang^*, Mark Collinge^*, Vinod Ramgolam^*, Oran Ayalon^2,*, Xinhao Cynthia Fan^3,, Ruggero Pardi and Jeffrey R. Bender^4,*

^* Sections of Cardiovascular Medicine and Immunobiology, Vascular Biology and Transplant Program, Boyer Center for Molecular Medicine, Raymond and Beverly Sackler Foundation Cardiovascular Laboratory and Department of Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536; and Department of Molecular Pathology, Università Vita-Salute School of Medicine, San Raffaele Scientific Institute, Milan, Italy

Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the ₂ integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-, GM-CSF, and IL-3 mRNA, as well as a chimeric -globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA 3'-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF- ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF- or IFN- transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.

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