PMID- 31974305 OWN - NLM STAT- MEDLINE DCOM- 20200511 LR - 20200723 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 117 IP - 6 DP - 2020 Feb 11 TI - A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease. PG - 3063-3073 LID - 10.1073/pnas.1914308117 [doi] AB - The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4(+) T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22alpha and HLA-DQ2.2-Phe22alpha) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance. FAU - Ting, Yi Tian AU - Ting YT AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. FAU - Dahal-Koirala, Shiva AU - Dahal-Koirala S AUID- ORCID: 0000-0002-0165-5098 AD - Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway. AD - K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway. FAU - Kim, Hui Shi Keshia AU - Kim HSK AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. FAU - Qiao, Shuo-Wang AU - Qiao SW AUID- ORCID: 0000-0002-0935-8397 AD - Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway. AD - K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway. FAU - Neumann, Ralf S AU - Neumann RS AD - Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway. AD - K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway. FAU - Lundin, Knut E A AU - Lundin KEA AD - Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway. AD - K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway. AD - Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway. FAU - Petersen, Jan AU - Petersen J AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. FAU - Reid, Hugh H AU - Reid HH AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. FAU - Sollid, Ludvig M AU - Sollid LM AUID- ORCID: 0000-0001-8860-704X AD - Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; l.m.sollid@medisin.uio.no jamie.rossjohn@monash.edu. AD - K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; l.m.sollid@medisin.uio.no jamie.rossjohn@monash.edu. AD - The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, CF14 4XN Cardiff, United Kingdom. LA - eng SI - PDB/6PX6 SI - PDB/6PY2 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200123 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-DQ Antigens) RN - 0 (HLA-DQ2 antigen) RN - 0 (Receptors, Antigen, T-Cell) RN - 8002-80-0 (Glutens) SB - IM MH - CD4-Positive T-Lymphocytes/chemistry/metabolism MH - *Celiac Disease/genetics/immunology/metabolism MH - Cell Line MH - Crystallography, X-Ray MH - Epitopes, T-Lymphocyte/chemistry/genetics/metabolism MH - Glutens/chemistry/immunology/metabolism MH - *HLA-DQ Antigens/chemistry/genetics/metabolism MH - Humans MH - Models, Molecular MH - Protein Binding MH - *Receptors, Antigen, T-Cell/chemistry/genetics/metabolism PMC - PMC7022145 OTO - NOTNLM OT - T cell receptor OT - X-ray crystallography OT - celiac disease OT - human leukocyte antigen COIS- The authors declare no competing interest. EDAT- 2020/01/25 06:00 MHDA- 2020/05/12 06:00 PMCR- 2020/07/23 CRDT- 2020/01/25 06:00 PHST- 2020/01/25 06:00 [pubmed] PHST- 2020/05/12 06:00 [medline] PHST- 2020/01/25 06:00 [entrez] PHST- 2020/07/23 00:00 [pmc-release] AID - 1914308117 [pii] AID - 201914308 [pii] AID - 10.1073/pnas.1914308117 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3063-3073. doi: 10.1073/pnas.1914308117. Epub 2020 Jan 23.