The specificity of T-cell recognition involves both the peptide and its presenting MHC molecule. Kinetic analysis of T-cell receptor binding to peptide:MHC ligands suggests that the interactions with MHC molecules might predominate at the start of the contact, but that subsequent interactions with the peptide as well as the MHC molecule dictate the final outcome—binding or dissociation. As with antibody–antigen interactions, only a few amino acids at the interface might provide the essential contacts that determine the specificity and strength of binding. Simply changing a leucine to isoleucine in the peptide, for example, is sufficient to alter a T-cell response from strong killing to no response at all. Mutations of single residues in the presenting MHC molecules can have the same effect. This dual specificity for T-cell recognition of antigen underlies the MHC restriction of T-cell responses, a phenomenon that was observed long before the peptide-binding properties of MHC molecules were known. Another consequence of this dual specificity is a need for T-cell receptors to exhibit some inherent specificity for MHC molecules in order to be able to interact appropriately with the antigen-presenting surface of MHC
Fig. 4.25 The T-cell receptor interacts with MHC class I and MHC class II molecules in a similar fashion. Shown is the structure of a T-cell receptor, specific for a peptide derived from chicken cytochrome c, bound to an Mhc class ii molecule. This T-cell receptor’s binding is at a site and orientation similar to that of the T-cell receptor bound to the Mhc class i molecule shown in fig. 4.24. The α and β chains of the T-cell receptor are colored in light and dark blue, respectively. The cytochrome c peptide is light orange. The T-cell receptor sits in a shallow saddle formed between the α-helical regions of the Mhc class ii α (brown) and β (yellow) chains at roughly 90° to the long axis of the Mhc class ii molecule and the bound peptide. Structure derived from PDB 3QiB. courtesy of K.c. garcia.
molecules. We will return to these issues in Chapter 6, where we recount the discovery of MHC restriction in the context of T-cell recognition and MHC polymorphisms, and in Chapter 8, where we discuss the impact of these phenomena on T-cell development in the thymus.
4-18 The CD4 and CD8 cell-surface proteins of T cells directly contact MHC molecules and are required to make an effective response to antigen.
As we introduced in Section 1-21, T cells fall into two major classes distinguished by the expression of the cell-surface proteins CD4 and CD8. CD8 is expressed by cytotoxic T cells, while CD4 is expressed by T cells whose function is to activate other cells. CD4 and CD8 were known as markers for these functional sets for some time before it became clear that the distinction was based on the ability of T cells to recognize different classes of MHC molecules. We now know that CD8 recognizes MHC class I molecules and CD4 recognizes MHC class II. During antigen recognition, CD4 or CD8 (depending on the type of T cell) associates with the T-cell receptor on the T-cell surface and binds to invariant sites on the MHC portion of the composite peptide:MHC ligand, away from the peptide-binding site. This binding contributes to the overall effectiveness of the T-cell response, and so CD4 and CD8 are called co-receptors.
CD4 is a single-chain protein composed of four Ig-like domains (Fig. 4.26). The first two domains (D1 and D2) are packed tightly together to form a rigid