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A Pivotal Role for the Multifunctional Calcium/Calmodulin-Dependent Protein Kinase II in T Cells: From Activation to Unresponsiveness¹

Meei Yun Lin^2,*, Tomasz Zal, Irene L. Ch’en^*, Nicholas R. J. Gascoigne and Stephen M. Hedrick^3,*

^* Division of Biological Sciences, The Cancer Center, and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Stimulation of the TCR leads to an oscillatory release of free calcium that activates members of the calcium/calmodulin-dependent protein kinase II (CaMKII) family. The CaMKII molecules have profound and lasting effects on cellular signaling in several cell types, yet the role of CaMKII in T cells is still poorly characterized. In this report we describe a splice variant of CaMKII, CaMKII'e, in mouse T cells. We have determined its function, along with that of CaMKII, by introducing the active and kinase-dead mutants into activated P14 TCR transgenic T cells using retroviral transduction. Active CaMKII enhanced the proliferation and cytotoxic activity of T cells while reducing their IL-2 production. Furthermore, it induced a profound state of unresponsiveness that could be overcome only by prolonged culture in IL-2. These results indicate that members of the CaMKII family play an important role in regulation of CD8 T cell proliferation, cytotoxic effector function, and the response to restimulation.

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