Inhibition of TCR/CD3-mediated signaling by a mutant of the hematopoietically expressed G16 GTP-binding protein.
EUR J IMMUNOL
1645 - 1655.
We have investigated the role of the hematopoietically expressed G16 GTP-binding protein on T cell activation. We constructed transfectants of Jurkat T cells that express a function-deficient mutant of G alpha 16 predicted to prevent activation of this G protein. Upon stimulation with anti-CD3 epsilon antibodies, mutant G alpha 16 transfectants display a profound defect in the production of IL-2 and IL-10, as well as in the expression of CD69. In contrast, the phorbol 12-myristate 13-acetate (PMA)-induced IL-10 production and CD69 expression, and the ionomycin plus PMA-induced IL-2 production are not affected. Consistent with the reduction in cytokine production is the inhibition of early signaling events in the mutant G alpha 16-expressing cells. There are significant reductions in anti-epsilon-induced tyrosine phosphorylation of zeta, epsilon, ZAP-70, and phospholipase C gamma 1, as well as in intracellular Ca2+; mobilization. In accordance with the effects on tyrosine phosphorylation is the reduction of TCR/CD3-mediated Fyn and Lck activities in G alpha 16 mutant cells. Even though the mechanism through which the G alpha 16 mutant mediates inhibition of T cell activation is not known, the data suggest a model where G proteins become activated upon TCR/CD3 engagement and regulate the activation of tyrosine kinases and subsequent downstream signaling events that lead to the activation of cytokine genes.
|Title:||Inhibition of TCR/CD3-mediated signaling by a mutant of the hematopoietically expressed G16 GTP-binding protein|
|Keywords:||G protein, TCR/CD3, T cell, signal transduction, CELL ANTIGEN RECEPTOR, CYTOPLASMIC FREE CALCIUM, TYROSINE KINASES, INOSITOL TRISPHOSPHATE, MEDIATED ACTIVATION, ALPHA-SUBUNIT, T-CELLS, PHOSPHORYLATION, TRANSDUCTION, STIMULATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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