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Nature Publishing Group press statement
The crystal structures of four different T immune cell receptors (TCRs) in complex with two gluten peptides that play an important role in celiac disease are reported this week in Nature Structural & Molecular Biology. These findings help explain why particular TCRs appear more frequently in celiac patients.
Celiac disease is an inflammatory disorder triggered by gluten ingestion and leads to damage in the small intestine tissue. The disease affects around one percent of the population in Western countries, and the only available treatment is removing gluten from the diet.
Jamie Rossjohn, Frits Koning, Hugh Reid and colleagues isolated four different TCRs from celiac disease individuals and captured their structure during the central event in the disease: recognition of gluten peptides presented by HLA-DQ2, the variant of the peptide-presenting molecule that is associated with 90-95% of celiac cases.
In an accompanying News and Views article, Bana Jabri, Xi Chen and Ludvig M Sollid say that the workadvances our understanding of how immunodominant gluten peptides are recognized by selected TCRs in celiac disease and could provide insight into other autoimmune conditions.
T-cell receptor recognition of HLA-DQ2–gliadin complexes associated with celiac disease
Jan Petersen1,8, Veronica Monserrat-Perez28, Jorge R Mujico2, Khai Lee Loh1, Dennis X Beringer1, Menno van Lummel2, Allan Thompson2, M Luisa Mearin3, Joachim Schweizer3, Yvonne Kooy-Winkelaar2, Jeroen van Bergen2, Jan W Drijfhout2, Wan-Ting Kan4, Nicole L La Gruta4, Robert P Anderson5, Hugh H Reid1,9, Frits Koning2,9 & Jamie Rossjohn1,6,7,9
Celiac disease is a T cell–mediated disease induced by dietary gluten. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin (a component of gluten), DQ2.5-glia-a1a and DQ2.5-glia-a2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-a2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non–germline encoded arginine residue within the CDR3b loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-a1a and DQ2.5-glia-a2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
1Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. 2Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. 3Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands. 4Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. 5ImmusanT, Inc., Cambridge, Massachusetts, USA. 6Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK. 7Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. 8These authors contributed equally to this work. 9These authors jointly directed this work. Correspondence should be addressed to H.H.R. (email@example.com), F.K. (firstname.lastname@example.org) or J.R. (email@example.com).
Received 12 February; accepted 28 March; published online 28 April 2014; doi:10.1038/nsmb.2817
Full paper available (paywalled) at: http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2817.html
This work was supported by the Australian Research Council, the National Health and Medical Research Council (NHMRC) of Australia, the Celiac Disease Consortium and an Innovative Cluster approved by The Netherlands Genomics Initiative and was funded in part by the Dutch government (grant BSIK03009). We thank J. Tye-Din for assistance. J.R. is supported by an Australia Fellowship from the NHMRC.
The ARC Centre of Excellence in Advanced Molecular Imaging
The ARC Centre of Excellence in Advanced Molecular Imaging integrates physics, chemistry and biology to unravel the complex molecular interactions that define immunity. The Centre will develop new imaging methods to visualize atomic, molecular and cellular details of how immune proteins interact and effect immune responses. It will enable Australia to be an international leader in biological imaging, train the next generation of interdisciplinary scientists, and provide new insights into combating common diseases that afflict society.
The Australian Synchrotron
The Australian Synchrotron is a source of highly intense light ranging from infrared to hard X-rays used for a wide variety of research purposes. The intense light it produces is filtered and adjusted to travel into experimental workstations, where the light reveals the innermost, sub-microscopic secrets of materials under investigation, from human tissue to plants to metals and more. With the new knowledge that synchrotron science provides about the molecular structure of materials, researchers can invent ways to tackle diseases, make plants more productive and metals more resilient. Officially opened in July 2007, the Australian Synchrotron is one of fewer than 40 similar facilities around the world.