A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.

Autor:	Ting YT; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Dahal-Koirala S; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.; K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway., Kim HSK; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Qiao SW; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.; K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway., Neumann RS; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.; K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway., Lundin KEA; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.; K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway.; Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway., Petersen J; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia., Reid HH; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia., Sollid LM; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; l.m.sollid@medisin.uio.no jamie.rossjohn@monash.edu.; K. G. Jebsen Centre for Coeliac Disease Research, University of Oslo, 0372 Oslo, Norway., Rossjohn J; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; l.m.sollid@medisin.uio.no jamie.rossjohn@monash.edu.; The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, CF14 4XN Cardiff, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Feb 11; Vol. 117 (6), pp. 3063-3073. Date of Electronic Publication: 2020 Jan 23.
DOI:	10.1073/pnas.1914308117
Abstrakt:	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-Tyr22α and HLA-DQ2.2-Phe22α) 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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu