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Active Ca²⁺/Calmodulin-Dependent Protein Kinase IIB Impairs Positive Selection of T Cells by Modulating TCR Signaling¹

Maureen A. McGargill^*, Leslie L. Sharp^*, Jack D. Bui, Stephen M. Hedrick^* and Sébastien Calbo^2,*

^* Department of Biology and Cancer Center, University of California, San Diego, La Jolla, CA 92093; and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

T cell development is regulated at two critical checkpoints that involve signaling events through the TCR. These signals are propagated by kinases of the Src and Syk families, which activate several adaptor molecules to trigger Ca²⁺ release and, in turn, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation. In this study, we show that a constitutively active form of CaMKII antagonizes TCR signaling and impairs positive selection of thymocytes in mice. Following TCR engagement, active CaMKII decreases TCR-mediated CD3 chain phosphorylation and ZAP70 recruitment, preventing further downstream events. Therefore, we propose that CaMKII belongs to a negative-feedback loop that modulates the strength of the TCR signal through the tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP-2).

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