Journal article

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

Yi Tian Ting, Shiva Dahal-Koirala, Hui Shi Keshia Kim, Shuo-Wang Qiao, Ralf S Neumann, Knut EA Lundin, Jan Petersen, Hugh H Reid, Ludvig M Sollid, Jamie Rossjohn

Proceedings of the National Academy of Sciences | NATL ACAD SCIENCES | Published : 2020

Abstract

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,..

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University of Melbourne Researchers

Grants

Awarded by South-Eastern Norway Regional Health Authority Projects


Awarded by Research Council of Norway through the Centre of Excellence


Awarded by Stiftelsen Kristian Gerhard Jebsen Project



Funding Acknowledgements

This research was supported by the National Health and Medical Research Council (Australia) and Australian Research Council (ARC) (J.R.); by the South-Eastern Norway Regional Health Authority Projects 2011050 and 2015009; Research Council of Norway Project 179573/V40 through the Centre of Excellence funding scheme, and Project 233885; and the Stiftelsen Kristian Gerhard Jebsen Project SKGJ-MED-017 (to L.M.S.). J.R. is supported by an ARC Australian Laureate Fellowship. We thank Khai Lee Loh, Mai Tran, and Bjorg Simonsen for their excellent technical assistance. The protein crystal X-ray diffraction data were collected on MX2 beamline at the Australian Synchrotron facility, Melbourne, Australia.