Dynamics of proximal signaling events after TCR/CD8-mediated induction of proliferation or apoptosis in mature CD8+ T cells.

Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany.
Engagement of the TCR can induce different functional outcomes such as activation, proliferation, survival, or apoptosis. How the TCR-mediated signaling cascades generating these distinct cellular responses are organized on the molecular level is so far not completely understood. To obtain insight into this question, we analyzed TCR/CD8-mediated signaling events in mature OT-I TCR transgenic T cells under conditions of stimulation that lead to either proliferation or apoptosis. These experiments revealed major differences in the phosphorylation dynamics of LAT, ZAP70, protein kinase B, phospholipase C-gamma1, protein kinase D1, and ERK1/2. Moreover, input signals leading to apoptosis induced a strong, but transient activation of ERK1/2 mainly at sites of TCR-engagement. In contrast, stimuli promoting survival/proliferation generated a low and sustained activation of ERK1/2, which colocalizes with Ras in recycling endosomal vesicles. The transient activation of ERK1/2 under pro-apoptotic conditions of stimulation is at least partially due to the rapid polyubiquitination and subsequent degradation of ZAP70, whereas the sustained activation of ERK1/2 under survival promoting conditions is paralleled by the induction/phosphorylation of anti-apoptotic molecules such as protein kinase B and Bcl-x(L). Collectively, our data provide signaling signatures that are associated with proliferation or apoptosis of T cells.
Mesh Terms:
Animals, Antigens, CD8, Apoptosis, Blotting, Western, CD8-Positive T-Lymphocytes, Cell Proliferation, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Gene Expression, Gene Expression Regulation, Humans, Immunoprecipitation, Lymphocyte Activation, Mice, Mice, Transgenic, Microscopy, Confocal, Phosphorylation, Receptors, Antigen, T-Cell, Signal Transduction, Ubiquitination, ZAP-70 Protein-Tyrosine Kinase
J. Immunol. May. 15, 2008; 180(10);6703-12 [PUBMED:18453590]
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