Qualitatively differential regulation of T cell activation and apoptosis by T cell receptor zeta chain ITAMs and their tyrosine residues.
The issue of whether three ITAMs in the TCR zeta chain can transmit qualitatively distinct signals or redundantly amplify TCR-mediated activation signals was extensively investigated using stable hCD8-zeta Jurkat transfectants which contain stepwise deletions of each ITAM or mutations of tyrosine residues in each ITAM of TCR zeta chain. The influence of mutations of each tyrosine residue on reduction of the amount and species of tyrosine phosphorylated proteins recruited to zeta chain was quite distinctive, but they were roughly proportional to the number of functionally intact ITAMs. However, the first N-terminal ITAM had a signaling potential to trigger most intracellular signaling events for T cell activation and apoptosis similar to wild-type CD8-zeta, but this level was substantially reduced in the presence of the first and second N-terminal ITAM together. Mutations of tyrosine residues in first and second N-terminal ITAM significantly impaired most signaling events leading to T cell activation and activation-induced cell death, but phosphorylation of mitogen-activated protein kinases (MAPKs) was differentially impaired in each mutant. The mutation of the first tyrosine residue in C-terminal ITAM did not show any impairment in induction of surface antigens and cell death, but rather increased IL-2 secretion and MAPK phosphorylation. Therefore, in this study we demonstrated that the ITAMs and their tyrosine residues of TCR zeta chain can transmit qualitatively differential intracellular signals upon TCR stimulation through distinctive regulation of recruitment of tyrosine phosphorylated proteins to zeta chain and activation of various MAPKs.
Chae
Wook-Jin
WJ
Department of Biotechnology, Yonsei University, Seodaemun-Gu Shinchon-Dong 134 120-749, Republic of Korea.
Lee
Heung-Kyu
HK
Han
Jin-Hwan
JH
Kim
Sang-Won Vincent
SW
Bothwell
Alfred L M
AL
Morio
Tomohiro
T
Lee
Sang-Kyou
SK
D020816:Amino Acid Motifs; D017209:Apoptosis; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000737:chemistry* / Q000502:physiology; D053222:Fas Ligand Protein; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D014443:Tyrosine; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3