8536d_cho7161-184 8/16/02 1: 49 PM Page 170 mac100 mac 100: 12F+\tm: 8536d: Goldsby et al./ Immunology 5e- 170 PART II Generation of B-Cell and T-Cell Response TABLE 7-2 Peptide binding by class I and class II MHC molecules Class I molecules Class ll molecules Peptide-binding domain a1/1 Nature of peptide-binding cleft Closed at both end Open at both ends General size of bound peptides 8-10 amino acids 13-18 amino acids Peptide motifs involved in Anchor residues at both ends of Anchor residues distributed along binding to MHC molecule peptide; generally hydrophobe the length of the peptide carboxyl-terminal anchor Nature of bound peptide Extended structure in which both ends Extended structure that is held nteract with MHC cleft but middle at a constant elevation above arches up away from MHC molecule the floor of mhc cleft numerous different peptides, and some peptides can bind to the MHC molecules expressed on the membrane of a cell several different MHC molecules. Because of this broad speci- will be associated with a peptide of self or nonself origin. icity, the binding between a peptide and an MHC molecule is often referred to as"promiscuous Given the similarities in the structure of the peptide-bind- CLASS I MHC-PEPTIDE INTERACTION ing cleft in class I and II MHC molecules, it is not surprising Class I MHC molecules bind peptides and present them to that they exhibit some common peptide-binding features CD8+ T cells. In general, these peptides are derived from en- (Table 7-2). In both types of MHC molecules, peptide lig. dogenous intracellular proteins that are digested in the cy- ands are held in a largely extended conformation that runs toso. The peptides are then transported from the cytosol the length of the cleft. The peptide-binding cleft in class I into the cisternae of the endoplasmic reticulum, where they molecules is blocked at both ends, whereas the cleft is open in interact with class I MHC molecules. This process, known as class II molecules(Figure 7-10). As a result of this difference, the cytosolic or endogenous processing pathway, is discussed lass I molecules bind peptides that typically contain 8-10 in detail in the next chapter. amino acid residues, while the open groove of class II mole Each type of class I MHC molecule(K, D, and L in mice cules accommodates slightly longer peptides of 13-18 amIno rA, B, and C in humans) binds a unique set of peptides. In cids. Another difference, explained in more detail below, is addition, each allelic variant of a class I MHC molecule(e.g that class I binding requires that the peptide contain specific H-2K and H-2K also binds a distinct set of peptides.Be- amino acid residues near the n and C termini; there is no cause a single nucleated cell expresses about 10 copies of such requirement for class II peptide binding. each class I molecule, many different peptides will be ex- The peptide-MHC molecule association is very stable pressed simultaneously on the surface of a nucleated cell by (Kd-" )under physiologic conditions; thus, most of class I MHC molecules. (a Class I MHC (b) Class II MHC FIGURE 7-10 MHC class I and class ll molecules with bound pep. those below from a2.(b)Space-filling model of human class ll mol- tides. (a) Space-filling model of human class I molecule HLA-A2 ecules HLA-DR1 with the DRa chain shown in white and the DRB ite)with peptide(red) from HIV reverse transcriptase(amino chain in blue. The peptide(red) in the binding groove is from in- acid residues 309-317) in the binding groove. B2-microglobulin is fluenza hemagglutinin(amino acid residues 306-318) From D. A shown in blue. Residues above the peptide are from the al doma Vignali and. Strominger, 1994, The Immunologist 2: 112. 1numerous different peptides, and some peptides can bind to several different MHC molecules. Because of this broad speci￾ficity, the binding between a peptide and an MHC molecule is often referred to as “promiscuous.” Given the similarities in the structure of the peptide-bind￾ing cleft in class I and II MHC molecules, it is not surprising that they exhibit some common peptide-binding features (Table 7-2). In both types of MHC molecules, peptide lig￾ands are held in a largely extended conformation that runs the length of the cleft. The peptide-binding cleft in class I molecules is blocked at both ends, whereas the cleft is open in class II molecules (Figure 7-10). As a result of this difference, class I molecules bind peptides that typically contain 8–10 amino acid residues, while the open groove of class II mole￾cules accommodates slightly longer peptides of 13–18 amino acids. Another difference, explained in more detail below, is that class I binding requires that the peptide contain specific amino acid residues near the N and C termini; there is no such requirement for class II peptide binding. The peptide–MHC molecule association is very stable (Kd ~ 106 ) under physiologic conditions; thus, most of 170 PART II Generation of B-Cell and T-Cell Responses TABLE 7-2 Peptide binding by class I and class II MHC molecules Class I molecules Class II molecules Peptide-binding domain 1/2 1/1 Nature of peptide-binding cleft Closed at both ends Open at both ends General size of bound peptides 8–10 amino acids 13–18 amino acids Peptide motifs involved in Anchor residues at both ends of Anchor residues distributed along binding to MHC molecule peptide; generally hydrophobic the length of the peptide carboxyl-terminal anchor Nature of bound peptide Extended structure in which both ends Extended structure that is held interact with MHC cleft but middle at a constant elevation above arches up away from MHC molecule the floor of MHC cleft (a) Class I MHC (b) Class II MHC FIGURE 7-10 MHC class I and class II molecules with bound pep￾tides. (a) Space-filling model of human class I molecule HLA-A2 (white) with peptide (red) from HIV reverse transcriptase (amino acid residues 309–317) in the binding groove. 2-microglobulin is shown in blue. Residues above the peptide are from the 1 domain, those below from 2. (b) Space-filling model of human class II mol￾ecules HLA-DR1 with the DR chain shown in white and the DR chain in blue. The peptide (red) in the binding groove is from in￾fluenza hemagglutinin (amino acid residues 306–318). [From D. A. Vignali and J. Strominger, 1994, The Immunologist 2:112.] the MHC molecules expressed on the membrane of a cell will be associated with a peptide of self or nonself origin. CLASS I MHC–PEPTIDE INTERACTION Class I MHC molecules bind peptides and present them to CD8 T cells. In general, these peptides are derived from en￾dogenous intracellular proteins that are digested in the cy￾tosol. The peptides are then transported from the cytosol into the cisternae of the endoplasmic reticulum, where they interact with class I MHC molecules. This process, known as the cytosolic or endogenous processing pathway, is discussed in detail in the next chapter. Each type of class I MHC molecule (K, D, and L in mice or A, B, and C in humans) binds a unique set of peptides. In addition, each allelic variant of a class I MHC molecule (e.g., H-2Kk and H-2Kd ) also binds a distinct set of peptides. Be￾cause a single nucleated cell expresses about 105 copies of each class I molecule, many different peptides will be ex￾pressed simultaneously on the surface of a nucleated cell by class I MHC molecules. 8536d_ch07_161-184 8/16/02 1:49 PM Page 170 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: