Later experiments showed that the antigen specificity of T-cell recognition was controlled by MHC molecules. The immune responses affected by the Ir genes were known to depend on T cells, and this led to a series of experiments in mice to ascertain how MHC polymorphism might control T-cell responses. The earliest of these experiments showed that T cells could be activated only by macrophages or B cells that shared MHC alleles with the mouse in which the T cells originated. This was the first evidence that antigen recognition by T cells depends on the presence of specific MHC molecules in the antigen-presenting cell—the phenomenon we now know as MHC restriction.
Fig. 6.23 T-cell recognition of antigens is MHC-restricted. The antigen-specific T-cell receptor (TCR) recognizes a complex consisting of an antigenic peptide and a self MHC molecule. One consequence of this is that a T cell specific for peptide x and an MHC molecule that is the product of a particular MHC allele, MHCa (left panel), will usually not recognize the complex of peptide x bound to a different MHC allele product, MHCb (center panel), or the complex of a different peptide, peptide y, bound to MHCa (right panel). The co-recognition of a foreign peptide and an MHC molecule is known as MHC restriction because the particular MHC allele product is said to restrict the ability of the T cell to recognize antigen. This restriction may either result from direct contact between the MHC molecule and T-cell receptor or be an indirect effect of MHC polymorphism on the peptides that bind or on their bound conformation.
We first mentioned MHC restriction in Section 4-17 in the context of the crystal structure of the T-cell receptor bound to peptide:MHC complexes. But the phenomenon of MHC restriction was discovered much earlier and is illustrated by the studies of virus-specific cytotoxic T cells carried out by Peter Doherty and Rolf Zinkernagel, for which they received the Nobel Prize in 1996. When mice are infected with a virus, they generate cytotoxic T cells that kill the virus-infected cells while sparing both uninfected cells and cells infected with unrelated viruses. The cytotoxic T cells are thus virus-specific. The additional and striking outcome of these experiments was the demonstration that the ability of cytotoxic T cells to kill virus-infected cells was also affected by the polymorphism of MHC molecules. Cytotoxic T cells induced by viral infection in mice of MHC genotype a (MHCa) would kill any MHCa cell infected with that virus. But these same T cells would not kill cells of MHC genotype b, or c, and so on, even if they were infected with the same virus. In other words, cytotoxic T cells kill cells infected by virus only if those cells express the same MHC by which the T cells were primed. Because the MHC genotype ‘restricts’ the antigen specificity of the T cells, this effect was called MHC restriction. Together with the earlier studies on both B cells and macrophages, this work showed that MHC restriction is a critical feature of antigen recognition by all functional classes of T cells.