Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection
The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self...
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00179/full |
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| author | Bernhard Loll Christine Rückert Barbara Uchanska-Ziegler Barbara Uchanska-Ziegler Andreas Ziegler |
| author_facet | Bernhard Loll Christine Rückert Barbara Uchanska-Ziegler Barbara Uchanska-Ziegler Andreas Ziegler |
| author_sort | Bernhard Loll |
| collection | DOAJ |
| description | The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus. |
| first_indexed | 2024-12-13T10:48:57Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T10:48:57Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-38509f8a5ee84513b1f5556c8831c2b12022-12-21T23:49:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00179513523Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell SelectionBernhard Loll0Christine Rückert1Barbara Uchanska-Ziegler2Barbara Uchanska-Ziegler3Andreas Ziegler4Institut für Chemie und Biochemie, Abteilung Strukturbiochemie, Freie Universität Berlin, Berlin, GermanyInstitut für Immungenetik, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, GermanyInstitut für Immungenetik, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, GermanyZiegler Biosolutions, Waldshut-Tiengen, GermanyZiegler Biosolutions, Waldshut-Tiengen, GermanyThe development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.https://www.frontiersin.org/article/10.3389/fimmu.2020.00179/fullHLA-B27X-ray structurepeptide binding modesconformational flexibilityT cell selectioncentral tolerance |
| spellingShingle | Bernhard Loll Christine Rückert Barbara Uchanska-Ziegler Barbara Uchanska-Ziegler Andreas Ziegler Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection Frontiers in Immunology HLA-B27 X-ray structure peptide binding modes conformational flexibility T cell selection central tolerance |
| title | Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection |
| title_full | Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection |
| title_fullStr | Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection |
| title_full_unstemmed | Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection |
| title_short | Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection |
| title_sort | conformational plasticity of hla b27 molecules correlates inversely with efficiency of negative t cell selection |
| topic | HLA-B27 X-ray structure peptide binding modes conformational flexibility T cell selection central tolerance |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00179/full |
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