Crystal structure of HLA-DP2 and implications for chronic beryllium disease

Dai, Shaodong; Murphy, Guinevere A.; Crawford, Frances; Mack, Douglas G.; Falta, Michael T.; Marrack, Philippa; Kappler, John W.; Fontenot, Andrew P.

doi:10.1073/pnas.1001772107

Cited by 109 publications

(158 citation statements)

References 42 publications

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“…Genetic susceptibility to CBD is closely linked to MHCII alleles that bear a glutamic acid at position 69 of the β-chain, especially the HLA-DP2 allele (29,30). We recently solved the structure of DP2, which revealed an acidic pocket on the surface of the molecule that contained the carboxylates of β69Glu as well as two other DP2 acidic amino acids (31). Mutation of any of these amino acids eliminated Be ++ presentation to Be ++ -reactive human T cells.…”

Section: Discussionmentioning

confidence: 99%

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Yin

Crawford

Marrack

et al. 2012

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

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T cell-mediated allergy to Ni++ is one of the most common forms of allergic contact dermatitis, but how the T-cell receptor (TCR) recognizes Ni ++ is unknown. We studied a TCR from an allergic patient that recognizes Ni ++ bound to the MHCII molecule DR52c containing an unknown self-peptide. We identified mimotope peptides that can replace both the self-peptide and Ni ++ in this ligand. They share a p7 lysine whose εNH 2 group is surface-exposed when bound to DR52c. Whereas the TCR uses germ-line complementary-determining region (CDR)1/2 amino acids to dock in the conventional diagonal mode on the mimotope-DR52c complex, the interface is dominated by the TCR Vβ CDR3 interaction with the p7 lysine. Mutations in the TCR CDR loops have similar effects on the T-cell response to either the mimotope or Ni ++ ligand. We suggest that the mimotope p7 lysine mimics Ni ++ in the natural TCR ligand and that MHCII β-chain flexibility in the area around the peptide p7 position forms a common site for cation binding in metal allergies.antigen presentation | hypersensitivity | peptide display library | crystal structure | metal recognition T -cell receptors (TCRs) made up of α-and β-chains have a very large number of ligands, including self-and foreign peptides, superantigens, lipids, small organic haptens, and metal ions. These ligands usually react with TCRs when they are bound to major histocompatibility complex (MHC) proteins. TCRs usually bind MHC/peptide combinations in similar orientations such that the TCR is aligned diagonally across the MHC/peptide, with the Vβ region of the TCR placed over the α1 α-helix of the MHCI heavy chain or of the MHCII α-chain and the Vα region placed over the α2 α-helix of the MHCI heavy chain or the β1 α-helix of the MHCII β-chain (1, 2). We (1, 3-5) and others (6-8) have suggested that germ line-encoded residues in the complementary-determining region (CDR)1 and CDR2 loops of the TCR variable regions are evolutionarily conserved for interaction with the MHC. These residues are also involved when natural killer T (NKT) cells recognize glycolipids bound to the nonclassical MHCI protein CD1d, and even when T cells recognize the non-MHC protein CD155 (9).It is noteworthy, however, that the presence of these evolutionarily conserved amino acids does not assure the conventional diagonal docking mode for TCRs on MHC molecules. For example, the NKT TCRs have a unique docking mode on CD1d (10, 11): Protein superantigens bridge TCRs to MHCII in a manner that prevents conventional TCR-MHCII interaction (12), and TCRs often dock to autoantigen peptides bound to MHCII in unusual orientations (13,14). Thus, in cases in which the structural details of the interaction between the TCR and its target are not known, we cannot be certain that the interaction will occur with the TCR in its usual orientation on MHC or not. Such is the case for the recognition of metal ions by TCRs (15 ++ when a particular unknown peptide(s) is bound to DR52c (18). Here, using a display library method we have previously describe...

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Section: Discussionmentioning

confidence: 99%

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Yin

Crawford

Marrack

et al. 2012

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

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“…An HLA-DP2 crystal structure revealed a unique solvent-exposed acidic pocket located between the peptide backbone and the HLA-DP2 β-chain α-helix, formed by three glutamic acid residues from the β-chain, including βGlu69 (5). Mutagenesis of any of these residues resulted in loss of the ability of HLA-DP2 to present Be to T cells (5), establishing that the HLA contribution to the development of CBD is due to the ability of βGlu69-containing HLA-DP molecules to bind and present Be to pathogenic CD4 + T cells.…”

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confidence: 99%

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

Mack¹,

Falta²,

McKee³

et al. 2014

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

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Susceptibility to chronic beryllium disease (CBD) is linked to certain HLA-DP molecules, including HLA-DP2. To elucidate the molecular basis of this association, we exposed mice transgenic (Tg) for HLA-DP2 to beryllium oxide (BeO) via oropharyngeal aspiration. As opposed to WT mice, BeO-exposed HLA-DP2 Tg mice developed mononuclear infiltrates in a peribronchovascular distribution that were composed of CD4 + T cells and included regulatory T (T reg ) cells. Beryllium-responsive, HLA-DP2-restricted CD4 + T cells expressing IFN-γ and IL-2 were present in BeO-exposed HLA-DP2 Tg mice and not in WT mice. Using Be-loaded HLA-DP2-peptide tetramers, we identified Be-specific CD4 + T cells in the mouse lung that recognize identical ligands as CD4 + T cells derived from the human lung. Importantly, a subset of HLA-DP2 tetramer-binding CD4 + T cells expressed forkhead box P3, consistent with the expansion of antigen-specific T reg cells. Depletion of T reg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation. These findings document, for the first time to our knowledge, the development of a Be-specific adaptive immune response in mice expressing HLA-DP2 and the ability of T reg cells to modulate the beryllium-induced granulomatous immune response.metal hypersensitivity | MHC presentation | genetic susceptibility

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“…[33][34][35] Originally, this position was not considered as an anchor for DP2 binding 14 but its inclusion as an anchors QM improves the predictions. Hydrophobic amino acids, such as Trp, Tyr, and Phe, are well tolerated at position p7.…”

Section: Discussionmentioning

confidence: 99%

“…14 We assumed that for this position Coul-SR energies should be more predictive than LJ-SR energies. However, the comparative study indicated that even for this position, LJ-SR is more predictive than Coul-SR (34% vs. 26% sensitivity at the top 5% cut-off).…”

Section: Energy For Scoring the Bindingmentioning

confidence: 99%

“…13 Quite recently, the X-ray structure of the HLA-DP2 (DPA*0103, DPB1*0201) in complex with a selfpeptide derived from the HLA-DR a-chain has been published. 14 Thus HLA-DP is a MHC class II locus, while HLA-DP2 is a MHC class II allele. Although the gross structure of DP2 is very similar to that of other MHC Class II proteins, a unique solventexposed acidic pocket containing three glutamic acids (Glu 26b , Glu 68b , and Glu 69b ) was revealed.…”

Section: Introductionmentioning

confidence: 99%

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HLA‐DP2 binding prediction by molecular dynamics simulations

et al. 2011

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Major histocompatibility complex (MHC) II proteins bind peptide fragments derived from pathogen antigens and present them at the cell surface for recognition by T cells. MHC proteins are divided into Class I and Class II. Human MHC Class II alleles are grouped into three loci: HLA-DP, HLA-DQ, and HLA-DR. They are involved in many autoimmune diseases. In contrast to HLA-DR and HLA-DQ proteins, the X-ray structure of the HLA-DP2 protein has been solved quite recently. In this study, we have used structure-based molecular dynamics simulation to derive a tool for rapid and accurate virtual screening for the prediction of HLA-DP2-peptide binding. A combinatorial library of 247 peptides was built using the ''single amino acid substitution'' approach and docked into the HLA-DP2 binding site. The complexes were simulated for 1 ns and the short range interaction energies (Lennard-Jones and Coulumb) were used as binding scores after normalization. The normalized values were collected into quantitative matrices (QMs) and their predictive abilities were validated on a large external test set. The validation shows that the best performing QM consisted of Lennard-Jones energies normalized over all positions for anchor residues only plus cross terms between anchor-residues.

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Crystal structure of HLA-DP2 and implications for chronic beryllium disease

Cited by 109 publications

References 42 publications

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

HLA‐DP2 binding prediction by molecular dynamics simulations

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