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The Role of Protein Kinase A Anchoring via the RII Regulatory Subunit in the Murine Immune System¹

Robynn V. Schillace^*, Sarah F. Andrews^*, Sarah G. Galligan, Kimberly A. Burton, Holly J. Starks^*,, H. G. Archie Bouwer^*,, G. Stanley McKnight, Michael P. Davey^* and Daniel W. Carr^2,*,

^* Veterans Affairs Medical Center, Department of Endocrinology, Oregon Health and Science University, Portland, OR 97239; Earle A. Chiles Research Institute, Providence Medical Center, Portland, OR 97213; and Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195

Intracellular cAMP may inhibit T cell activation and proliferation via activation of the cAMP-dependent protein kinase, PKA. PKA signaling is maintained through interactions of the regulatory subunit with A-kinase anchoring proteins (AKAPs). We demonstrated that T cells contain AKAPs and now ask whether PKA anchoring to AKAPs via the RII regulatory subunit is necessary for cAMP-mediated inhibition of T cell activation. We studied the immune systems of mice lacking the RII regulatory subunit of PKA (–/–) and the ability of cells isolated from these mice to respond to cAMP. Dissection of spleen and thymus from wild-type (WT) and –/– mice, single cell suspensions generated from these organs, and flow cytometry analysis illustrate that the gross morphology, cell numbers, and cell populations in the spleen and thymus of the –/– mice are similar to WT controls. In vitro, splenocytes from –/– mice respond to anti-CD3/anti-CD28 and PMA/ionomycin stimulation and produce IL-2 similar to WT. Cytokine analysis revealed no significant difference in Th1 or Th2 differentiation. Finally, equivalent frequencies of CD8⁺ IFN- producing effector cells were stimulated upon infection of WT or –/– mice with Listeria monocytogenes. These data represent the first study of the role of RII in the immune system in vivo and provide evidence that T cell development, homeostasis, and the generation of a cell-mediated immune response are not altered in the RII –/– mice, suggesting either that RII is not required for normal immune function or that other proteins are able to compensate for RII function.