T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease

Jan Petersen, Veronica Montserrat, Jorge R Mujico, Khai Lee Loh, Dennis Beringer, Mennno van Lummel, Allan Thompson, M Luisa Mearin, Joachim Schweizer, Yvonne Kooy-Winkelaar, Jeroen van Bergen, Jan W Drijfhout, Wan-Ting Kan, Nicole L La Gruta, Robert P Anderson, Hugh Harrington Reid, Frits Koning, Jamie Rossjohn

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Abstract

Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95 of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-alpha2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
Original languageEnglish
Pages (from-to)480 - 490
Number of pages11
JournalNature Structural and Molecular Biology
Volume21
Issue number5
DOIs
Publication statusPublished - 2014

Cite this

Petersen, Jan ; Montserrat, Veronica ; Mujico, Jorge R ; Loh, Khai Lee ; Beringer, Dennis ; van Lummel, Mennno ; Thompson, Allan ; Mearin, M Luisa ; Schweizer, Joachim ; Kooy-Winkelaar, Yvonne ; van Bergen, Jeroen ; Drijfhout, Jan W ; Kan, Wan-Ting ; La Gruta, Nicole L ; Anderson, Robert P ; Reid, Hugh Harrington ; Koning, Frits ; Rossjohn, Jamie. / T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. In: Nature Structural and Molecular Biology. 2014 ; Vol. 21, No. 5. pp. 480 - 490.
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title = "T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease",
abstract = "Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95 of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-alpha2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.",
author = "Jan Petersen and Veronica Montserrat and Mujico, {Jorge R} and Loh, {Khai Lee} and Dennis Beringer and {van Lummel}, Mennno and Allan Thompson and Mearin, {M Luisa} and Joachim Schweizer and Yvonne Kooy-Winkelaar and {van Bergen}, Jeroen and Drijfhout, {Jan W} and Wan-Ting Kan and {La Gruta}, {Nicole L} and Anderson, {Robert P} and Reid, {Hugh Harrington} and Frits Koning and Jamie Rossjohn",
year = "2014",
doi = "10.1038/nsmb.2817",
language = "English",
volume = "21",
pages = "480 -- 490",
journal = "Nature Structural Biology",
issn = "1545-9993",
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Petersen, J, Montserrat, V, Mujico, JR, Loh, KL, Beringer, D, van Lummel, M, Thompson, A, Mearin, ML, Schweizer, J, Kooy-Winkelaar, Y, van Bergen, J, Drijfhout, JW, Kan, W-T, La Gruta, NL, Anderson, RP, Reid, HH, Koning, F & Rossjohn, J 2014, 'T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease', Nature Structural and Molecular Biology, vol. 21, no. 5, pp. 480 - 490. https://doi.org/10.1038/nsmb.2817

T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. / Petersen, Jan; Montserrat, Veronica; Mujico, Jorge R; Loh, Khai Lee; Beringer, Dennis; van Lummel, Mennno; Thompson, Allan; Mearin, M Luisa; Schweizer, Joachim; Kooy-Winkelaar, Yvonne; van Bergen, Jeroen; Drijfhout, Jan W; Kan, Wan-Ting; La Gruta, Nicole L; Anderson, Robert P; Reid, Hugh Harrington; Koning, Frits; Rossjohn, Jamie.

In: Nature Structural and Molecular Biology, Vol. 21, No. 5, 2014, p. 480 - 490.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease

AU - Petersen, Jan

AU - Montserrat, Veronica

AU - Mujico, Jorge R

AU - Loh, Khai Lee

AU - Beringer, Dennis

AU - van Lummel, Mennno

AU - Thompson, Allan

AU - Mearin, M Luisa

AU - Schweizer, Joachim

AU - Kooy-Winkelaar, Yvonne

AU - van Bergen, Jeroen

AU - Drijfhout, Jan W

AU - Kan, Wan-Ting

AU - La Gruta, Nicole L

AU - Anderson, Robert P

AU - Reid, Hugh Harrington

AU - Koning, Frits

AU - Rossjohn, Jamie

PY - 2014

Y1 - 2014

N2 - Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95 of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-alpha2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.

AB - Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95 of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-alpha2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.

UR - http://www.nature.com/nsmb/journal/v21/n5/pdf/nsmb.2817.pdf

U2 - 10.1038/nsmb.2817

DO - 10.1038/nsmb.2817

M3 - Article

VL - 21

SP - 480

EP - 490

JO - Nature Structural Biology

JF - Nature Structural Biology

SN - 1545-9993

IS - 5

ER -