Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes

Shiva Dahal-Koirala, Laura Ciacchi, Jan Petersen, Louise Fremgaard Risnes, Ralf Stefan Neumann, Asbjørn Christophersen, Knut E.A. Lundin, Hugh H. Reid, Shuo Wang Qiao, Jamie Rossjohn, Ludvig M. Sollid

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restri-cted gluten epitopes, DQ2.5-glia-1a (PFPQPELPY) and DQ2.5-glia-1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-1a and HLA-DQ2.5–DQ2.5-glia-1 tetramers and single-cell T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-1a– and DQ2.5-glia-1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-1a (2.0 Å) and DQ2.5-glia-1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting.

Original languageEnglish
Pages (from-to)941-952
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number3
DOIs
Publication statusPublished - 18 Jan 2019

Cite this

Dahal-Koirala, S., Ciacchi, L., Petersen, J., Risnes, L. F., Neumann, R. S., Christophersen, A., ... Sollid, L. M. (2019). Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes. Journal of Biological Chemistry, 294(3), 941-952. https://doi.org/10.1074/jbc.RA118.005736
Dahal-Koirala, Shiva ; Ciacchi, Laura ; Petersen, Jan ; Risnes, Louise Fremgaard ; Neumann, Ralf Stefan ; Christophersen, Asbjørn ; Lundin, Knut E.A. ; Reid, Hugh H. ; Qiao, Shuo Wang ; Rossjohn, Jamie ; Sollid, Ludvig M. / Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 3. pp. 941-952.
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title = "Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes",
abstract = "Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restri-cted gluten epitopes, DQ2.5-glia-1a (PFPQPELPY) and DQ2.5-glia-1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-1a and HLA-DQ2.5–DQ2.5-glia-1 tetramers and single-cell T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-1a– and DQ2.5-glia-1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-1a (2.0 {\AA}) and DQ2.5-glia-1 (2.6 {\AA}). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting.",
author = "Shiva Dahal-Koirala and Laura Ciacchi and Jan Petersen and Risnes, {Louise Fremgaard} and Neumann, {Ralf Stefan} and Asbj{\o}rn Christophersen and Lundin, {Knut E.A.} and Reid, {Hugh H.} and Qiao, {Shuo Wang} and Jamie Rossjohn and Sollid, {Ludvig M.}",
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Dahal-Koirala, S, Ciacchi, L, Petersen, J, Risnes, LF, Neumann, RS, Christophersen, A, Lundin, KEA, Reid, HH, Qiao, SW, Rossjohn, J & Sollid, LM 2019, 'Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes' Journal of Biological Chemistry, vol. 294, no. 3, pp. 941-952. https://doi.org/10.1074/jbc.RA118.005736

Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes. / Dahal-Koirala, Shiva; Ciacchi, Laura; Petersen, Jan; Risnes, Louise Fremgaard; Neumann, Ralf Stefan; Christophersen, Asbjørn; Lundin, Knut E.A.; Reid, Hugh H.; Qiao, Shuo Wang; Rossjohn, Jamie; Sollid, Ludvig M.

In: Journal of Biological Chemistry, Vol. 294, No. 3, 18.01.2019, p. 941-952.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discriminative T-cell receptor recognition of highly homologous HLA-DQ2– bound gluten epitopes

AU - Dahal-Koirala, Shiva

AU - Ciacchi, Laura

AU - Petersen, Jan

AU - Risnes, Louise Fremgaard

AU - Neumann, Ralf Stefan

AU - Christophersen, Asbjørn

AU - Lundin, Knut E.A.

AU - Reid, Hugh H.

AU - Qiao, Shuo Wang

AU - Rossjohn, Jamie

AU - Sollid, Ludvig M.

PY - 2019/1/18

Y1 - 2019/1/18

N2 - Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restri-cted gluten epitopes, DQ2.5-glia-1a (PFPQPELPY) and DQ2.5-glia-1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-1a and HLA-DQ2.5–DQ2.5-glia-1 tetramers and single-cell T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-1a– and DQ2.5-glia-1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-1a (2.0 Å) and DQ2.5-glia-1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting.

AB - Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restri-cted gluten epitopes, DQ2.5-glia-1a (PFPQPELPY) and DQ2.5-glia-1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-1a and HLA-DQ2.5–DQ2.5-glia-1 tetramers and single-cell T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-1a– and DQ2.5-glia-1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-1a (2.0 Å) and DQ2.5-glia-1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting.

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U2 - 10.1074/jbc.RA118.005736

DO - 10.1074/jbc.RA118.005736

M3 - Article

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JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

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