Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion

Zernich, Danielle; Purcell, Anthony W.; Macdonald, W.A.; Kjer‐Nielsen, Lars; Ely, Lauren Kate; Laham, Nihay; Crockford, Tanya L.; Mifsud, Nicole A.; Bharadwaj, Mandvi; Chang, Linus; Tait, Brian D.; Holdsworth, Rhonda; Brööks, Andrëw G.; Bottomley, Stephen P.; Beddoe, Travis; Peh, Chen Au; Rossjohn, Jamie; McCluskey, James

doi:10.1084/jem.20031680

Cited by 149 publications

(183 citation statements)

References 63 publications

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“…A possible explanation for the escape of these peptides is that they might bind to certain HLA class I molecules that dissociate more quickly from the peptide-loading complex (57)(58)(59)(60)(61)(62). In this regard, it is interesting to note that two of the HLA-B35 molecules studied (HLA-B*3501 and HLA-B*3508) were not associated with N-terminal-extended peptides.…”

Section: Discussionmentioning

confidence: 98%

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Escobar

Crockett

Reyes-Vargas

et al. 2008

The Journal of Immunology

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The majority of >2000 HLA class I molecules can be clustered according to overlapping peptide binding specificities or motifs recognized by CD8 ؉ T cells. HLA class I motifs are classified based on the specificity of residues located in the P2 and the C-terminal positions of the peptide. However, it has been suggested that other positions might be relevant for peptide binding to HLA class I molecules and therefore be used for further characterization of HLA class I motifs. In this study we performed large-scale sequencing of endogenous peptides eluted from K562 cells (HLA class I null) made to express a single HLA molecule from HLA-B*3501, -B*3502, -B*3503, -B*3504, -B*3506, or -B*3508. Using sequence data from >1,000 peptides, we characterized novel peptide motifs that include dominant anchor residues extending to all positions in the peptide. The length distribution of HLA-B35-bound peptides included peptides of up to 15 residues. Remarkably, we determined that some peptides longer than 11 residues represented N-terminal-extended peptides containing an appropriate HLA-B35 peptide motif. These results provide evidence for the occurrence of endogenous N-terminal-extended peptide-HLA class I configurations. In addition, these results expand the knowledge about the identity of anchor positions in HLA class I-associated peptides that can be used for characterization of HLA class I motifs.

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Section: Discussionmentioning

confidence: 98%

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Escobar

Crockett

Reyes-Vargas

et al. 2008

The Journal of Immunology

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show abstract

“…4), which may yield elevated dissociation rates and a compromised overall stability of the complex. This point is particularly apparent for Tyr116, an amino acid conserved in many MHC class I alleles, essential for tapasin-independent peptide loading (28,29) and influencing MHC I-T-cell receptor interactions (30). Ensemble refinements calculated on the basis of X-ray diffraction data, where local low resolution essentially corresponds to higher local dynamics, indicate that mobility of Tyr116 is markedly restricted by larger than typical peptide anchors (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Garstka¹,

Fish

Celie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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).

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“…47 The preferential usage of a distinct set of MHC class I alleles may be associated with epitope selection and the responding T-cell repertoire. Recent data suggest that antigen presentation and susceptibility to viral evasion of immune surveillance are associated with certain MHC class I alleles 48 and that the magnitude of an antiviral MHC class I-restricted immune response is related to the individual HLA-A and -B allele 49 and the nature of the antigen. 19 Several ways to identify MHC class I-restricted and antigenspecific immune responses have been explored; most of the experimental approaches relied on reverse immunology, i.e., testing if T cells raised against an MHC-binding synthetic peptide would be able to recognize tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

Oerke¹,

Höhn²,

Zehbe³

et al. 2005

Intl Journal of Cancer

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Several major histocompatibility complex (MHC) alleles have been reported to present peptides derived from the HPV16 E7 oncoprotein to T cells. We describe an overrepresentation of the HLA-B8 allele (28.44%) in cervical cancer patients as compared to the MHC class I allele frequency in a local healthy control population (18.80%) and the identification of an HLA-B8-binding peptide TLHEYMLDL (HPV16 E7 7-15 ), which is able to drive HPV16 E7-specific and MHC class I-restricted T-cell responses in peripheral blood lymphocytes from healthy individuals. TLHEYMLDLspecific T cells recognize the naturally processed and presented peptide on HPV16؉ cervical cancer cells transfected with the HLA-B8 gene defined by IFN-␥ production. This peptide epitope is also recognized by freshly harvested tumor-infiltrating T cells or T cells from tumor-draining lymph nodes from patients with cervical cancer determined by flow cytometry as well as by tetramer in situ staining. HLA-B8-restricted HPV E7 7-15 -specific T cells reside predominantly in the CD8 ؉ CD45RA ؉ CCR7 ؉ precursor or in the differentiated CD8 ؉ CD45RA ؉ CCR7 ؊ T-cell population.

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Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion

Cited by 149 publications

References 63 publications

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

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

Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

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