What are the roles of the following molecules in the signal transduction pathway leading from the T-cell receptor:

Question

(i) the CD3 complex; (ii) protein tyrosine kinase Lck; (iii) CD45; (iv) ZAP-70; (v) the ? chain; (vi) inositol trisphosphate (IP3); (vii) calcineurin?

What will be an ideal response?

Answer 1

(i) The CD3 subunits γ, δ, and ε associated with the antigen-binding T-cell receptor help transmit the signal from the T-cell receptor–peptide–MHC interaction at the cell surface into the interior of the cell through immunoreceptor tyrosine-based activation motifs (ITAMs) present on their cytoplasmic tails. These are phosphorylated by associated protein tyrosine kinases, such as Fyn, when the antigen receptor is activated, and in turn activate further molecules of the signaling pathway. (ii) Lck associates with the tails of the CD4 and CD8 co-receptors. When these participate in binding to peptide:MHC complexes, Lck is activated and phosphorylates ZAP-70, a cytoplasmic protein tyrosine kinase. (iii) CD45 is a cell-surface protein phosphatase that helps activate Lck and other kinases by removing inhibitory phosphate groups from their tails. (iv) When ZAP-70 is phosphorylated, it binds to the phosphorylated ITAMs of (v) the ζ chain, which initiates the signal transduction cascade by activating phospholipase C-γ (PLC-γ) and guanine-exchange factors. (vi) IP3, which is produced by the action of PLC-γ on membrane inositol phospholipids, causes an increase in intracellular Ca2+ levels, which leads to the activation of the protein calcineurin. (vii) Calcineurin activates the transcription factor NFAT by removing an inhibitory phosphate group. Activated NFAT enters the nucleus, and together with the transcription factors NFκB and AP-1 will initiate the transcription of genes that lead to T-cell proliferation and differentiation.