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Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition
The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T cell activ...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582474/ https://www.ncbi.nlm.nih.gov/pubmed/32992915 http://dx.doi.org/10.3390/ijms21197081 |
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author | Szeto, Christopher Bloom, Joseph I. Sloane, Hannah Lobos, Christian A. Fodor, James Jayasinghe, Dhilshan Chatzileontiadou, Demetra S. M. Grant, Emma J. Buckle, Ashley M. Gras, Stephanie |
author_facet | Szeto, Christopher Bloom, Joseph I. Sloane, Hannah Lobos, Christian A. Fodor, James Jayasinghe, Dhilshan Chatzileontiadou, Demetra S. M. Grant, Emma J. Buckle, Ashley M. Gras, Stephanie |
author_sort | Szeto, Christopher |
collection | PubMed |
description | The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T cell activation. These structures represent a static “snapshot”, yet the nature of pHLAs and their interactions with TCRs are highly dynamic. This has been demonstrated for HLA class I molecules with in silico techniques showing that some interactions, thought to stabilise pHLA-I, are only transient and prone to high flexibility. Here, we investigated the dynamics of HLA class II molecules by focusing on three allomorphs (HLA-DR1, -DR11 and -DR15) that are able to present the same epitope and activate CD4+ T cells. A single TCR (F24) has been shown to recognise all three HLA-DR molecules, albeit with different affinities. Using molecular dynamics and crystallographic ensemble refinement, we investigate the molecular basis of these different affinities and uncover hidden roles for HLA polymorphic residues. These polymorphisms were responsible for the widening of the antigen binding cleft and disruption of pHLA-TCR interactions, underpinning the hierarchy of F24 TCR binding affinity, and ultimately T cell activation. We expanded this approach to all available pHLA-DR structures and discovered that all HLA-DR molecules were inherently rigid. Together with in vitro protein stability and peptide affinity measurements, our results suggest that HLA-DR1 possesses inherently high protein stability, and low HLA-DM susceptibility. |
format | Online Article Text |
id | pubmed-7582474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75824742020-10-29 Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition Szeto, Christopher Bloom, Joseph I. Sloane, Hannah Lobos, Christian A. Fodor, James Jayasinghe, Dhilshan Chatzileontiadou, Demetra S. M. Grant, Emma J. Buckle, Ashley M. Gras, Stephanie Int J Mol Sci Article The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T cell activation. These structures represent a static “snapshot”, yet the nature of pHLAs and their interactions with TCRs are highly dynamic. This has been demonstrated for HLA class I molecules with in silico techniques showing that some interactions, thought to stabilise pHLA-I, are only transient and prone to high flexibility. Here, we investigated the dynamics of HLA class II molecules by focusing on three allomorphs (HLA-DR1, -DR11 and -DR15) that are able to present the same epitope and activate CD4+ T cells. A single TCR (F24) has been shown to recognise all three HLA-DR molecules, albeit with different affinities. Using molecular dynamics and crystallographic ensemble refinement, we investigate the molecular basis of these different affinities and uncover hidden roles for HLA polymorphic residues. These polymorphisms were responsible for the widening of the antigen binding cleft and disruption of pHLA-TCR interactions, underpinning the hierarchy of F24 TCR binding affinity, and ultimately T cell activation. We expanded this approach to all available pHLA-DR structures and discovered that all HLA-DR molecules were inherently rigid. Together with in vitro protein stability and peptide affinity measurements, our results suggest that HLA-DR1 possesses inherently high protein stability, and low HLA-DM susceptibility. MDPI 2020-09-25 /pmc/articles/PMC7582474/ /pubmed/32992915 http://dx.doi.org/10.3390/ijms21197081 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Szeto, Christopher Bloom, Joseph I. Sloane, Hannah Lobos, Christian A. Fodor, James Jayasinghe, Dhilshan Chatzileontiadou, Demetra S. M. Grant, Emma J. Buckle, Ashley M. Gras, Stephanie Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition |
title | Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition |
title_full | Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition |
title_fullStr | Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition |
title_full_unstemmed | Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition |
title_short | Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition |
title_sort | impact of hla-dr antigen binding cleft rigidity on t cell recognition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582474/ https://www.ncbi.nlm.nih.gov/pubmed/32992915 http://dx.doi.org/10.3390/ijms21197081 |
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