The binding sites for cD4 and cD8 on the Mhc class ii and class i molecules, respectively, lie in the ig-like domains nearest to the membrane and distant from the peptide-binding cleft. The binding of cD4 to an Mhc class ii molecule is shown as a ribbon structure in panel a and schematically in panel c. The α chain of the Mhc class ii molecule is shown in pink, and the β chain in white, while cD4 is in gold. only the D1 and D2 domains of the cD4 molecule are shown in panel a. The binding site for cD4 lies at the base of the β2 domain of an Mhc class ii molecule, in the hydrophobic crevice between the β2 and α2 domains. The binding of cD8αβ to an Mhc class i molecule is shown in panel b and schematically in panel d. The class i heavy chain and β2-microglobulin are shown in white and pink, respectively, and the two chains of the cD8 dimer are shown in light (cD8β) and dark (cD8α) purple. The binding site for cD8 on the Mhc class i molecule lies in a similar position to that of cD4 in the Mhc class ii molecule, but cD8 binding also involves the base of the α1 and α2 domains, and thus the binding of cD8 to Mhc class i is not completely equivalent to the binding of cD4 to Mhc class ii. Structures derived from PDB 3S4S (cD4/ Mhc class ii) and PDB 3DMM (cD8αβ/ Mhc class i). courtesy of K.c. garcia.
Fig. 4.27 The binding sites for CD4 and CD8 on MHC class II and class I molecules lie in the Ig-like domains.
is extensively glycosylated, which is thought to maintain it in an extended conformation and protect it from cleavage by proteases. CD8α chains can form homodimers, although these are usually not found when CD8β is expressed. Naive T cells express CD8αβ, but the CD8αα homodimer can be expressed by highly activated effector and memory T cells. CD8αα is also expressed by a population of intraepithelial lymphocytes known as mucosal associated invariant T cells (MAIT cells); these cells recognize metabolites of folic acid that are produced by bacteria in association with the nonclassical MHC class I molecule MR1, which we will describe in Chapter 6.
CD8αβ binds weakly to an invariant site in the α3 domain of an MHC class I molecule (see Fig. 4.27b). The CD8β chain interacts with residues in the base of the α2 domain of the MHC class I molecule, while the αchain is in a lower position interacting with the α3 domain of the MHC class I molecule. The strength of binding of CD8 to the MHC class I molecule is influenced by the glycosylation state of the CD8 molecule; increasing the number of sialic acid residues on CD8 carbohydrate structures decreases the strength of the interaction. The pattern of sialylation of CD8 changes during the maturation of T cells and also on activation, and this likely has a role in modulating antigen recognition.
Like the interactions with MHC class II molecules, the T-cell receptor and CD8 can interact simultaneously with one MHC class I molecule (Fig. 4.29). Like CD4, CD8 binds Lck through the cytoplasmic tail of the α chain, and CD8αβ increases the sensitivity of T cells to antigen presented by MHC class I molecules about 100-fold. Although the molecular details are unclear, the CD8αα homodimer appears to function less efficiently than CD8αβ as a co-receptor, and may negatively regulate activation. In contrast to CD8, CD4 is not thought to dimerize.