Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease

SE Broughton; J Petersen; A Theodossis; SW Scally; KL Loh; A Thompson; J van Bergen; Y Kooy-Winkelaar; KN Henderson; T Beddoe; JA Tye-Din; SI Mannering; AW Purcell; J McCluskey; RP Anderson; F Koning; HH Reid; J Rossjohn

Journal article

Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease

SE Broughton, J Petersen, A Theodossis, SW Scally, KL Loh, A Thompson, J van Bergen, Y Kooy-Winkelaar, KN Henderson, T Beddoe, JA Tye-Din, SI Mannering, AW Purcell, J McCluskey, RP Anderson, F Koning, HH Reid, J Rossjohn

Immunity | Published : 2012

DOI: 10.1016/j.immuni.2012.07.013

Abstract

Celiac disease is a human leukocyte antigen (HLA)-DQ2- and/or DQ8-associated T cell-mediated disorder that is induced by dietary gluten. Although it is established how gluten peptides bind HLA-DQ8 and HLA-DQ2, it is unclear how such peptide-HLA complexes are engaged by the T cell receptor (TCR), a recognition event that triggers disease pathology. We show that biased TCR usage (TRBV9*01) underpins the recognition of HLA-DQ8-α-I-gliadin. The structure of a prototypical TRBV9*01-TCR-HLA-DQ8-α-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-α-I-gliadin, in which all complementarity-determining region-β (CDRβ) loops interact with the gliadin peptide. Mutagenesis at the TRBV9*0..

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University of Melbourne Researchers

Stephen Scally Author

Jason Tye-Din Author

Stuart Mannering Author

McCluskey James Author

Grants

Awarded by Australian Research Council

Funding Acknowledgements

This work was supported by the National Health and Medical Research Council, the Australian Research Council, an NHMRC Independent Research Institutes Infrastructure Support Scheme grant #361646, Victorian State Government Operational Infrastructure Support, the Celiac Disease Consortium, an Innovative Cluster approved by The Netherlands Genomics Initiative, and the Dutch government (grant BSIK03009). We thank the staff at the MX1 beamline of the Australian Synchrotron, Victoria, Australia for assistance with data collection. We thank J. Dromey for assistance. T.B. is supported by Pfizer Australian Research fellowship; J.A.T.-D. is supported by a NHMRC Australian Research Training Fellowship; S.E.B. is supported by an NHMRC PhD scholarship; A.W.P. is supported by an NHMRC SRF; and J.R. is supported by an Australia Fellowship from the NHMRC. J.A.T.-D. and R.P.A. are coinventors of patents pertaining to the use of gluten peptides in therapeutics, diagnostics, and nontoxic gluten. R.P.A. and J.A.T.-D. are shareholders in Nexpep Pty Ltd and R.P.A. is a shareholder in ImmusanT Inc. R.P.A. is Chief Scientific Officer of and J.A.T.-D. is a consultant to ImmusanT, Inc., a company developing a peptide-based therapy and diagnostic suitable for celiac disease.