One of the earliest steps in the signal transduction after T-cell receptor (TCR)/CD3 engagement is the phosphorylation of the tyrosine residues within the three immunoreceptor tyrosine-based activation motifs (ITAMs) of the ^-chain
From: Methods in Molecular Medicine, Vol. 102: Autoimmunity: Methods and Protocols Edited by: A. Perl © Humana Press Inc., Totowa, NJ
by Lck and Fyn leading to the association and activation of ^-chain-associated protein-70 (ZAP-70) (1-4). Once activated, Fyn, Lck, Syk, and ZAP-70 cooperate in the tyrosine phosphorylation, activation, and juxtaposition of downstream signal transducers that contribute to the initiation of mitogen-activated protein (MAP) kinase cascades, phosphatidyl inositol 3 (PI3)-kinase activation, and Ca2+ flux. Increase in the intracellular Ca2+ after T-cell activation gives rise to sequential activation of sets of genes that in turn initiate proliferation, differentiation, and effector functions.
Basically, in addition to the complete investigation of the expression of various signaling molecules, T-lymphocyte signaling is analyzed at four stages to compare the signaling (1) early (1, 2, and 3 min) tyrosine phosphorylation of the cellular proteins, (2) intracellular calcium response, (3) expression of cytokines, and (4) cell proliferation. In normal T cells, the intensity of the T-cell signaling directly correlates with the level of expression of the critical T-cell signaling molecule, such as TCR ^-chain. TCR ^-chain is the limiting factor in T-cell receptor assembly, transport, and surface expression and receptor function (5,6). However, in autoimmune disorders, the cell signaling remains abnormal and appears to correlate inversely with the level of TCR ^-chain. The exact nature of the mechanism that triggers the inverse correlation has become a topic of intense interest to many researchers.
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