Active Ca2+/Calmodulin-Dependent Protein Kinase II B Impairs Positive Selection of T Cells by Modulating TCR Signaling

M. A. McGargill, L. L. Sharp, J. D. Bui, S. M. Hedrick, S. Calbo
2005 Journal of Immunology  
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 Ca 2؉ release and, in turn, Ca 2؉ /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,
more » ... ve 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). The Journal of Immunology, 2005, 175: 656 -664. 3 Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; SLP-76, SH2 domain-containing leukocyte protein of 76 kDa; LAT, linker for activation of T cells; PLC, phospholipase C; CaMKII, Ca 2ϩ /calmodulindependent protein kinase II; CaMKII␥B*, Ca 2ϩ -independent mutant of CaMKII␥B; SH, Src homology; SHP, SH2 domain-containing phosphatase; WT, wild type; PT-Pase, phosphatase; PP2A, protein phosphatase 2A; PTPN-2, protein tyrosine phosphatase, nonreceptor type 2; NMDA, N-methyl-D-asparate.
doi:10.4049/jimmunol.175.2.656 pmid:16002660 fatcat:3vrlrczujrdvndlhay7p4dphfa