T cell activation

Studies have shown that CD8 may function as a coreceptor with the oJ\3 TCR in recognition of adjacent epitopes on the same class I molecule. These findings support the concept that T cell activation involves formation of a ternary complex composed of CD8 and TCR on the T cell and class I MHC molecules on the target cell. Indeed, ligation of CD8 with the TCR complex elicits much more vigorous T cell responses than ligation of either receptor molecule alone, indicating that CD8 plays a decisive role in augmenting TCR-dependent activation, either by increasing the avidity of binding to MHC class I or a —i—■-1-|-1-n— tew»

by amplification of signal transduction. High-avidity interaction between T cells and antigen-presenting cells is heavily dependent on CD8 expression, which is more important for primary proliferative responses than for CTL activity. While stimulation of T cells by anti-TCR antibodies results in coordinate localization of TCR and CD8, it is not yet clear whether the TCR a/[3 chain directly contacts the CD8 molecule in the lipid bilayer of a cell membrane. However, the ability of the two cell surface molecules to interact with distinct but adjacent regions of class I MHC products places CD8 and the TCR in close proximity to one another.

A potential molecular basis for the role of CD8 in T cell activation comes from studies showing that CD8 is closely associated with the tyrosine kinase p56lck, an src-related tyrosine kinase expressed mainly in T lymphocytes. p56kk is a cytoplasmic protein that, unlike other growth factor receptors, is found on the inner leaflet of the plasma membrane where it associates with a highly conserved cytoplasmic domain of CD8. Site-directed mutagenesis of CD8 defines a motif of CD8<* which may bind to the N-terminal region of p56lck: +-+-x-cys-x-cys-(pro) where x denotes a nonconserved residue and + a basic residue. It is currently thought that engagement of CD8 leads to enhanced activity of the associated p56lck enzyme which phosphorylates the f chain of the CD3 complex leading to signal transduction. In mature T cells, CD4 and CD8 may associate with equal amounts of p56lck; however, kinase activity after cross-linking of CD8 is much lower than after cross-linking of CD4. On the other hand, protein kinase C appears to be activated much more strongly after ligation of CD8 than after ligation of CD4. The cytoplasmic segment of CD8a also has two serine residues which are likely to be phosphorylated in signaling. T cells with targeted mutations of the cytoplasmic serine residues are insignificantly impaired in their response to antigen, whereas cells with substitutions in both cytoplasmic cysteine residues display deficient responses. Surprisingly, transgenic mice whose CD8 lacks the p56kk binding site show no impairment of T cell function.

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