Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1

Hennecke, Jens; Carfı́, Andrea; Wiley, Don C.

doi:10.1093/emboj/19.21.5611

Cited by 255 publications

(267 citation statements)

References 74 publications

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“…25 For orientation purposes, MHC II residues interacting with peptide as well as certain T-cell receptor (TCR) contact residues are shown as evidenced from two human MHC class IIpeptide-TCR complexes, where the same TCR molecule interacts with an identical microbial peptide in identical registers in two slightly different human MHC class II molecules (DR1 and DR4). 26,27 All DQA1*0301-bearing molecules (that is, DQ8cis and DQ2trans) have an intensely positively charged region in the vicinity of a48-54, with three Arg residues on the surface (Arg49, Arg50 and Arg53) and another one (Arg52) at the bottom of pocket 1. It is apparent that these three arginines on the surface of pocket 1 would contribute vastly to the attraction of a negatively charged p1 acidic residue that HLA-DQ8 homozygosity and heterozygosity in type 1 diabetes P Eerligh et al would eventually be anchored and detained tightly via these interactions.…”

Section: Resultsmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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Section: Resultsmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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“…The structure of the 3K peptide bound to IA b reveals five upwardly pointing amino acids as potential candidates for recognition by the ␣␤ T cell antigen receptors (TCR): the p-1Glu, p2Gln, p3Lys, p5Lys, and p8Lys. The side chains of these amino acids are at least partially exposed on the molecule surface and fall within the footprints seen of the ␣␤TCRs on other MHCII͞peptide complexes (51,52). To test whether these are indeed important for recognition, we synthesized a set of mutant peptides in which each of these amino acids was mutated to Ala.…”

Section: Resultsmentioning

confidence: 99%

Alternate interactions define the binding of peptides to the MHC molecule IA^b

Liu

Dai

Crawford

et al. 2002

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

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T he crystal structures of a variety of MHCI (1-9) and MHCII (10-23) molecules have revealed their features that lead to stable peptide binding. Conserved amino acids of MHCI interact with the N terminus and C terminus of the peptide in virtually all isotypes and alleles. Between these termini, the peptide can vary in length and in the path it takes through the binding groove, often bulging out of the groove in the middle. In MHCII, the N and C termini of the peptide generally extend beyond the binding groove and do not interact with the MHCII molecule. Rather, H-bonding interactions between the peptide backbone and conserved amino acids of the MHCII ␣-helices force the peptide to take a similar, extended path through the groove of all MHCII isotypes and alleles.The unique interactions that determine the allelic specificity of peptide binding seem to be controlled by the character of pockets within the interior of the binding groove that preferentially accept particular amino acid side chains. Because the MHC amino acids that line these pockets are among the most genetically variable, their depth, shape, and chemistry vary considerably among MHC alleles and isotypes, and they appear to be the most important factor in the specificity of peptide binding.In the current study we have solved the crystal structure of the mouse MHCII molecule IA b with a bound immunogenic peptide variant of a dominant peptide derived from the MHCII E␣ protein that is found in IA b in some strains of mice (24). Despite the high stability and immunogenicity of this complex, the four usual p1, p4, p6, and p9 peptide side chain binding pockets of IA b are largely unfilled, because alanines occur in the peptide at these positions. Rather, the stability of this peptide͞MHCII complex can be attributed to the combination of the conserved interactions with the peptide backbone as well as extensive unique interactions of the IA b molecule with other peptide amino acids particularly at the N-terminal end and the p7 position of the peptide. These results suggest that IA b can achieve stable peptide binding in more than one way and may account for the previous difficulty in defining the IA b peptidebinding motif. Materials and MethodsPreparation of Soluble IA b . The production of soluble IA b containing a peptide attached to the ␤-chain N terminus via a flexible peptide linker has been described (25). In the original constructions, peptides included both the E␣-derived peptide, ASFEAQGALANIAVDKA (pE␣), which occupies about 10% of natural IA b , and an immunogenic variant, ASFEAQKAK-ANKAVDKA (p3K), in which three positions in the peptide (underlined) had lysines substituted for the E␣ peptide amino acids. For crystallization, the construct was altered to use a shortened form of p3K, FEAKGAKANKAVD, and to shorten the IA b ␣ and ␤ chains to the predicted ends of the ␣2 and ␤2 domains. The construct was cloned into a previously described dual promoter baculovirus transfer vector (26, 27) and introduced into BacVector 3000 version of AcNPV baculovirus ...

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“…As shown in Table III, MK20.2 had the same V␤3.1 usage as did HA1.7, and it was reported that V␤3.1 was predominantly expressed in HA 306 -318 -specific TCRs which preferred P8K of HA 306 -318 (42). Molecular modeling (Fig.…”

Section: Discussionmentioning

confidence: 77%

“…Although the two TCRs represented a distinct specificity at relative positions 3, 5, 7, or 8 of the peptides, SA32.5 TCR and MK20.2 TCR represented similar preferences for certain amino acids at some positions. For example, at relative position 1, both TCR tolerate phenylalanine, methionine, leucine, isoleucine, valine, and cysteine; at relative position 4 they tolerate leucine, methionine, glutamine, (42), interactions between residues that provide TCR-DR binding sites between ␣-helical structure of the DR␣ chain and the CDR2 region of HA1.7 TCR are lined with dotted doublet lines. Electrostatic interactions between P8K of HA (peptides 306 -318) and the CDR region of HA1.7 are indicated by solid doublet lines.…”

Section: Discussionmentioning

confidence: 99%

Systematic Analysis of the Combinatorial Nature of Epitopes Recognized by TCR Leads to Identification of Mimicry Epitopes for Glutamic Acid Decarboxylase 65-Specific TCRs

Uemura

Senju

Maenaka

et al. 2003

The Journal of Immunology

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Accumulating evidence indicates that recognition by TCRs is far more degenerate than formerly presumed. Cross-recognition of microbial Ags by autoreactive T cells is implicated in the development of autoimmunity, and elucidating the recognition nature of TCRs has great significance for revelation of the disease process. A major drawback of currently used means, including positional scanning synthetic combinatorial peptide libraries, to analyze diversity of epitopes recognized by certain TCRs is that the systematic detection of cross-recognized epitopes considering the combinatorial effect of amino acids within the epitope is difficult. We devised a novel method to resolve this issue and used it to analyze cross-recognition profiles of two glutamic acid decarboxylase 65-autoreactive CD4+ T cell clones, established from type I diabetes patients. We generated a DNA-based randomized epitope library based on the original glutamic acid decarboxylase epitope using class II-associated invariant chain peptide-substituted invariant chains. The epitope library was composed of seven sublibraries, in which three successive residues within the epitope were randomized simultaneously. Analysis of agonistic epitopes indicates that recognition by both TCRs was significantly affected by combinations of amino acids in the antigenic peptide, although the degree of combinatorial effect differed between the two TCRs. Protein database searching based on the TCR recognition profile proved successful in identifying several microbial and self-protein-derived mimicry epitopes. Some of the identified mimicry epitopes were actually produced from recombinant microbial proteins by APCs to stimulate T cell clones. Our data demonstrate the importance of the combinatorial nature of amino acid residues of epitopes in molecular mimicry.

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Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1

Cited by 255 publications

References 74 publications

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Alternate interactions define the binding of peptides to the MHC molecule IA^b

Systematic Analysis of the Combinatorial Nature of Epitopes Recognized by TCR Leads to Identification of Mimicry Epitopes for Glutamic Acid Decarboxylase 65-Specific TCRs

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Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1

Cited by 255 publications

References 74 publications

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Alternate interactions define the binding of peptides to the MHC molecule IAb

Systematic Analysis of the Combinatorial Nature of Epitopes Recognized by TCR Leads to Identification of Mimicry Epitopes for Glutamic Acid Decarboxylase 65-Specific TCRs

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Alternate interactions define the binding of peptides to the MHC molecule IA^b