In rare cases, processing of a protein does not generate any peptides with a suitable sequence motif for binding to any of the MHC molecules expressed by an individual. This individual fails to respond to the antigen. Such failures in responsiveness to simple antigens were first reported in inbred animals and were called immune response (Ir) gene defects. These defects were mapped to genes within the MHC long before the structure or function of MHC molecules was understood, and they were the first clue to the antigen-presenting function of MHC molecules. We now understand that Ir gene defects are common in inbred strains of mice because the mice are homozygous at all their MHC gene loci, which limits the range of peptides they can present to T cells. Ordinarily, MHC polymorphism guarantees a sufficient number of different MHC molecules in a single individual to make this type of nonresponsiveness unlikely, even to relatively simple antigens such as small toxins.
Initially, the only evidence linking Ir gene defects to the MHC was genetic— mice of one MHC genotype could make antibody in response to a particular antigen, whereas mice of a different MHC genotype, but otherwise genetically identical, could not. The MHC genotype was somehow controlling the ability
Fig. 6.22 Different allelic variants of an MHC class I molecule bind different peptides. Shown are cutaway views of (a) ovalbumin peptide bound to the mouse H2-Kb MHC class I molecule and (b) influenza nucleoprotein (NP) peptide bound to the H2-Kd MHC class I molecule. The solvent-accessible surface of the MHC molecules is shown as a blue dotted surface. Class I MHC molecules typically have six pockets in the peptide-binding groove, which are conventionally called A–F. The bound peptides, shown as space-filling models, fit into the peptide-binding groove, with side chains from the anchor residues extending to fill the pockets. H2-Kb is binding SIINFEKL (single-letter amino acid code), a peptide of eight residues (P1–8) from ovalbumin, and H2-Kd is binding TYQRTRALV, a peptide of nine residues (P1–9) from the influenza nucleoprotein (NP). Anchor residues (shown in yellow) may be primary or secondary in their influence on peptide binding. For H2-Kb, the sequence motif is determined by two primary anchors, P5 and P8; the C pocket binds the P5 side chain of the peptide [a tyrosine (Y) or a phenylalanine (F)], and the F pocket binds the P8 residue [a non-aromatic hydrophobic side chain from leucine (L), isoleucine (I), methionine (M), or valine (V)]. The B pocket binds P2, a secondary anchor residue in H-2Kb. For H2-Kd, the sequence motif is primarily determined by the two primary anchors, P2 and P9. The B pocket accommodates a tyrosine side chain. The F pocket binds leucine, isoleucine, or valine. Beneath the structures are shown sequence motifs from peptides that are known to bind to the MHC molecule. CSP, circumsporozoite antigen; ERK4, extracellular signal-related kinase 4; HBV, hepatitis B virus; JAK1, Janus-associated kinase 1; LCMV, lymphocytic choriomeningitis virus; NS2, NS2 protein; P198, modified tumor-cell antigen; P. berghei, Plasmodium berghei; P. yoelii, Plasmodium yoelii; VSV, vesicular stomatitis virus. An extensive collection of motifs can be found at http://www. syfpeithi.de. Structures courtesy of V.E. Mitaksov and D. Fremont.
of the immune system to detect or respond to specific antigens, but it was not clear at the time that direct recognition of MHC molecules was involved.