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Down-Regulation of IL-2 Production in T Lymphocytes by Phosphorylated Protein Kinase A-RII¹

Michael R. Elliott^*, Ryan A. Shanks, Islam U. Khan, James W. Brooks, Pamela J. Burkett, Brandy J. Nelson, Vasileios Kyttaris, Yuang-Taung Juang, George C. Tsokos and Gary M. Kammer^2,*,

^* Department of Microbiology and Immunology and Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157; BD Biosciences, Lexington, KY 40511; and Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910

The isoform of the type II regulatory subunit (RII) of protein kinase A suppresses CREB transcriptional activity and c-Fos production in T cells following activation via the TCR. Because CREB is an integral nuclear transcription factor for IL-2 production by T cells, we tested the hypothesis that RII down-regulates IL-2 expression and IL-2 production in T cells. Stable transfection of RII in Jurkat T cells led to an 90% reduction in IL-2 mRNA and IL-2 protein following T cell activation. The inhibition of IL-2 production was associated with phosphorylation of the RII subunit at serine 114 (pRII) and localization of pRII in intranuclear clusters. A serine 114 phosphorylation-defective mutant, RII^S114A, did not form these intranuclear clusters as well as wild-type RII, and did not inhibit IL-2 mRNA and protein synthesis, indicating that serine 114 phosphorylation is required for both nuclear localization and down-regulation of IL-2 production by RII. In contrast to its effect on IL-2, RII induced constitutive up-regulation of CD154 mRNA and cell surface expression. Thus, pRII differentially regulates gene expression following T cell activation. Unexpectedly, we also found that stable overexpression of another protein kinase A regulatory subunit, RI, had the opposite effect on IL-2 expression, causing a 3- to 4-fold increase in IL-2 production following stimulation. In summary, our data demonstrate a novel mechanism by which serine 114 phosphorylation and nuclear localization of RII controls the regulation of gene expression in T cells.

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