The first step of peptide selection in antigen presentation by MHC class I molecules

Abstract

MHC class I molecules present a variable but limited repertoire of antigenic peptides for T-cell recognition. Understanding how peptide selection is achieved requires mechanistic insights into the interactions between the MHC I and candidate peptides. We find that, at first encounter, MHC I H-2K b considers a wide range of peptides, including those with expanded N termini and unfitting anchor residues. Discrimination occurs in the second step, when noncanonical peptides dissociate with faster exchange rates. This second step exhibits remarkable temperature sensitivity, as illustrated by numerous noncanonical peptides presented by H-2K b in cells cultured at 26°C relative to 37°C. Crystallographic analyses of H-2K b -peptide complexes suggest that a conformational adaptation of H-2K b drives the decisive step in peptide selection. We propose that MHC class I molecules consider initially a large peptide pool, subsequently refined by a temperature-sensitive induced-fit mechanism to retain the canonical peptide repertoire.antigen presentation | peptide binding | anchor residues | dynamics | entropy M HC class I molecules present a wide array of peptides to cytotoxic T lymphocytes, allowing the immune system to scan for intracellular pathogens and mutated proteins. These peptides are not chosen at random, but rather are selected for their ability to bind to the polymorphic MHC class I peptidebinding groove. Antigenic peptide precursors are produced by the proteasome and further trimmed by cytosolic aminopeptidases. They are translocated into the endoplasmic reticulum (ER) lumen by the peptide transporter TAP that has broad peptide specificity. Peptides can be further trimmed in the ER lumen by ER aminopeptidases before selection by a defined MHC class I allele (reviewed in ref. 1). Only few peptides from a broad peptidome are presented by a given MHC class I allele. How a defined MHC I allele selects the correct peptides for presentation out of a large and diverse peptide pool is unclear.In principle, MHC class I molecules could consider only "optimal" peptides and ignore the remainder of the TAPtranslocated peptidome. Alternatively, MHC class I could bind all available peptides followed by a selection step for the optimal candidates for presentation. To discriminate between these scenarios, we studied peptide association (on-rates) and dissociation (off-rates) from the mouse MHC class I molecule H-2K b . To characterize the biophysical basis of discrimination between candidate peptides we complemented the kinetic data with five crystal structures of H-2K b with peptide variants. A comprehensive analysis of our in vitro data indicated that discrimination against suboptimal peptides by MHC class I may exhibit a strong temperature dependency, as illustrated by the H-2K b peptidome from cells cultured at 26°C versus 37°C. We thus arrive at a two-step model for peptide selection by MHC class I molecules, which explains how not so "empty MHC class I molecules come out in the cold" (2).

Surface expression, peptide repertoire, and thermostability of chicken class I molecules correlate with peptide transporter specificity

“…Similar data were also reported for the B4 haplotype (21). Such a phenomenon has recently been reported for a mouse class I molecule (25), with H-2K b initially binding a wide range of anchor residues that are then self-edited in a temperature-dependent step. We find no enormous temperature-dependent effect with the chicken molecule BF2*1501, consistent with the restriction of peptides by TAP translocation.…”

Present Yourself! By MHC Class I and MHC Class II Molecules

“…These empty MHC I molecules are held in a peptide-receptive state by the chaperone tapasin and tapasin also promotes MHC I-binding of peptides with a slow-off rate, thereby helping to shape the repertoire of presented peptides[25]. In this reaction, MHC-I molecules test the binding of many peptides and subsequently release most of these until a proper (low off-rate) peptide is bound[26]. These are usually peptides of a very specific length of 8–10 amino acids with appropriate anchor residues.…”

Gene conversion of the major histocompatibility complex class I Caja‐G in common marmosets (Callithrix jacchus)

“…Crucial for antigen interaction are six binding pockets located in the α 1 and α 2 chains and transcribed by exons 2 and 3. For binding and anchoring of antigen fragments, the B pocket, located in the α 1 domain, and the F pocket, located in α 1 and α 2, are most important . Comparison of amino acid substitutions in exon 2 and exon 3 revealed abundant polymorphisms not only in positions relevant for the B and F pockets (Fig.…”

“…The N‐terminal residues are bound by the A pocket, whereas the C‐terminal anchor side chains are accepted by the F pocket, formed by 10 amino acids in the α 1 and α 2 domains. Also crucial for the specificity of peptide‐binding is the B pocket, which is located on the α 1 domain of the MHC molecules . In humans, the classical human leucocyte antigens HLA‐A, HLA‐B and HLA‐C are highly polymorphic, whereas the non‐classical HLA‐E, HLA‐F and HLA‐G show lower levels of polymorphism and their expression is limited to some tissues .…”