The issue of whether three ITAMs in the TCR ζ chain can transmit qualitatively distinct signals or redundantly amplify TCR-mediated activation signals was extensively investigated using stable hCD8-ζ Jurkat transfectants which contain stepwise deletions of each ITAM or mutations of tyrosine residues in each ITAM of TCR ζ chain. The influence of mutations of each tyrosine residue on reduction of the amount and species of tyrosine phosphorylated proteins recruited to ζ 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-ζ, 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 ζ chain can transmit qualitatively differential intracellular signals upon TCR stimulation through distinctive regulation of recruitment of tyrosine phosphorylated proteins to ζ chain and activation of various MAPKs.
Bibliographical noteFunding Information:
This work was supported in part by grants for The Functional Proteomics Center from the Ministry of Science and Technology (M102KM010001-02K1301-01100), the Korea Science and Engineering Foundation (199-1-212-001-5) and the Biochallenge project of Ministry of Korea Science and Technology (M1031040003-03B4640-00310).
All Science Journal Classification (ASJC) codes
- Immunology and Allergy