Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease

Sophie E Broughton, Jan Petersen, Alex Theodossis, Stephen W Scally, Khai Lee Loh, Allan Thompson, Jeroen van Bergen, Yvonne Kooy-Winkelaar, Kate N Henderson, Travis C Beddoe, Jason Allan Tye-Din, Stuart I Mannering, Anthony W Purcell, James McCluskey, Robert P Anderson, Frits Koning, Hugh H Reid, Jamie Rossjohn

Research output: Contribution to journalArticleResearchpeer-review

72 Citations (Scopus)

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-alpha-I-gliadin. The structure of a prototypical TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDRbeta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the Vbeta bias. Moreover, CDR3 diversity accounts for TRBV9( *)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.
Original languageEnglish
Pages (from-to)611 - 621
Number of pages11
JournalImmunity
Volume37
Issue number4
DOIs
Publication statusPublished - 2012

Cite this

Broughton, Sophie E ; Petersen, Jan ; Theodossis, Alex ; Scally, Stephen W ; Loh, Khai Lee ; Thompson, Allan ; van Bergen, Jeroen ; Kooy-Winkelaar, Yvonne ; Henderson, Kate N ; Beddoe, Travis C ; Tye-Din, Jason Allan ; Mannering, Stuart I ; Purcell, Anthony W ; McCluskey, James ; Anderson, Robert P ; Koning, Frits ; Reid, Hugh H ; Rossjohn, Jamie. / Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. In: Immunity. 2012 ; Vol. 37, No. 4. pp. 611 - 621.
@article{e77959a3160f452cb563063779c17f61,
title = "Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease",
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-alpha-I-gliadin. The structure of a prototypical TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDRbeta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the Vbeta bias. Moreover, CDR3 diversity accounts for TRBV9( *)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.",
author = "Broughton, {Sophie E} and Jan Petersen and Alex Theodossis and Scally, {Stephen W} and Loh, {Khai Lee} and Allan Thompson and {van Bergen}, Jeroen and Yvonne Kooy-Winkelaar and Henderson, {Kate N} and Beddoe, {Travis C} and Tye-Din, {Jason Allan} and Mannering, {Stuart I} and Purcell, {Anthony W} and James McCluskey and Anderson, {Robert P} and Frits Koning and Reid, {Hugh H} and Jamie Rossjohn",
year = "2012",
doi = "10.1016/j.immuni.2012.07.013",
language = "English",
volume = "37",
pages = "611 -- 621",
journal = "Immunity",
issn = "1074-7613",
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number = "4",

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Broughton, SE, Petersen, J, Theodossis, A, Scally, SW, Loh, KL, Thompson, A, van Bergen, J, Kooy-Winkelaar, Y, Henderson, KN, Beddoe, TC, Tye-Din, JA, Mannering, SI, Purcell, AW, McCluskey, J, Anderson, RP, Koning, F, Reid, HH & Rossjohn, J 2012, 'Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease', Immunity, vol. 37, no. 4, pp. 611 - 621. https://doi.org/10.1016/j.immuni.2012.07.013

Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. / Broughton, Sophie E; Petersen, Jan; Theodossis, Alex; Scally, Stephen W; Loh, Khai Lee; Thompson, Allan; van Bergen, Jeroen; Kooy-Winkelaar, Yvonne; Henderson, Kate N; Beddoe, Travis C; Tye-Din, Jason Allan; Mannering, Stuart I; Purcell, Anthony W; McCluskey, James; Anderson, Robert P; Koning, Frits; Reid, Hugh H; Rossjohn, Jamie.

In: Immunity, Vol. 37, No. 4, 2012, p. 611 - 621.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease

AU - Broughton, Sophie E

AU - Petersen, Jan

AU - Theodossis, Alex

AU - Scally, Stephen W

AU - Loh, Khai Lee

AU - Thompson, Allan

AU - van Bergen, Jeroen

AU - Kooy-Winkelaar, Yvonne

AU - Henderson, Kate N

AU - Beddoe, Travis C

AU - Tye-Din, Jason Allan

AU - Mannering, Stuart I

AU - Purcell, Anthony W

AU - McCluskey, James

AU - Anderson, Robert P

AU - Koning, Frits

AU - Reid, Hugh H

AU - Rossjohn, Jamie

PY - 2012

Y1 - 2012

N2 - 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-alpha-I-gliadin. The structure of a prototypical TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDRbeta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the Vbeta bias. Moreover, CDR3 diversity accounts for TRBV9( *)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.

AB - 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-alpha-I-gliadin. The structure of a prototypical TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDRbeta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the Vbeta bias. Moreover, CDR3 diversity accounts for TRBV9( *)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.

UR - http://www.sciencedirect.com/science/article/pii/S1074761312004190

U2 - 10.1016/j.immuni.2012.07.013

DO - 10.1016/j.immuni.2012.07.013

M3 - Article

VL - 37

SP - 611

EP - 621

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 4

ER -