Although the exact stoichiometry of the complete T-cell receptor is not definitively established, it is thought that the receptor α chain interacts with one CD3δ:CD3εdimer and one ζ dimer, while the receptor β chain interacts with one CD3γ:CD3ε dimer (see Fig. 7.8). These interactions are mediated by reciprocal charge interactions between basic and acidic intramembrane amino acids of the receptor subunits. There are two positive charges in the TCRα transmembrane region and one in the TCRβ transmembrane domain. Negative charges in the CD3 and ζ transmembrane domains interact with the positive charges in αand β. Assembly of CD3 and a ζ dimer with the α:β heterodimer stabilizes the αand β dimer during its production in the endoplasmic reticulum and allows the complex to be transported to the plasma membrane. These associations ensure that all T-cell receptors present on the plasma membrane are properly assembled.
Signaling from the T-cell receptor is initiated by tyrosine phosphorylation within cytoplasmic regions called immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3ε, γ, δ, and ζ chains. CD3γ, δ, and ε each contain one ITAM, and each ζ chain contains three, giving the T-cell receptor a total of 10 ITAMs. This motif is also present in the signaling chains of the B-cell receptor and in the NK-cell receptors described in Chapter 3, as well as in the receptors for the immunoglobulin constant region (Fc receptors) that are present on mast cells, macrophages, monocytes, neutrophils, and NK cells (see Section 7-11 below).
Each ITAM contains two tyrosine residues that become phosphorylated by specific protein tyrosine kinases when the receptor binds its ligand, providing sites for the recruitment of the SH2 domains of signaling proteins as described earlier in the chapter. Two YXXL/I motifs are separated by about six to nine amino acids within each ITAM, so the canonical ITAM sequence is …YXX[L/I] X6–9YXX[L/I]…, where Y is tyrosine, L is leucine, I is isoleucine, and X represents any amino acid. The two tyrosines of the ITAM make it particularly efficient in recruiting signaling proteins that contain two tandem SH2 domains (Fig. 7.9). When both tyrosines of the ITAM are phosphorylated, tandem SH2 domain-containing proteins such as Syk or ZAP-70 are recruited. This leads to the phosphorylation of Syk or ZAP-70, an essential step in the activation of these kinases, as will be discussed further below (see Section 7-10).
The antigen-binding immunoglobulin on the B-cell surface is also associated with invariant protein chains that mediate signaling. These two polypeptides, called Igαand Igβ, are required for transport of the receptor to the surface and for B-cell receptor signaling (Fig. 7.10). Igα and Igβ are single-chain proteins composed of an extracellular immunoglobulin-like domain connected by a transmembrane domain to a cytoplasmic tail. They form a disulfide-linked heterodimer that becomes associated with immunoglobulin heavy chains and enables their transport to the cell surface. The Igα:Igβdimer associates with the B-cell receptor through hydrophilic rather than charge interactions between their transmembrane regions. The complete B-cell receptor is thought to be a complex of six chains—two identical light chains, two identical heavy chains, and one associated heterodimer of Igα and Igβ. Like CD3 and the ζ chains of the T-cell receptor, Igα and Igβ have ITAMs, but just one each, and these are essential for the ability of the B-cell receptor to signal.
7-8 Antigen recognition by the T-cell receptor and its co-receptors transduces a signal across the plasma membrane to initiate signaling.