Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs
Gluten-specific CD4+ T cells are drivers of celiac disease (CeD). Previous studies of gluten-specific T-cell receptor (TCR) repertoires have found public TCRs shared across multiple individuals, biased usage of particular V-genes and conserved CDR3 motifs. The CDR3 motifs within the gluten-specific...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2021-04-01
|
Series: | Frontiers in Immunology |
Subjects: | |
Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.639672/full |
id |
doaj-3aaad2845ae24bac882ae9945aa0cdde |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shiva Dahal-Koirala Shiva Dahal-Koirala Louise Fremgaard Risnes Louise Fremgaard Risnes Ralf Stefan Neumann Asbjørn Christophersen Asbjørn Christophersen Knut E. A. Lundin Knut E. A. Lundin Knut E. A. Lundin Geir Kjetil Sandve Shuo-Wang Qiao Shuo-Wang Qiao Ludvig M. Sollid Ludvig M. Sollid |
spellingShingle |
Shiva Dahal-Koirala Shiva Dahal-Koirala Louise Fremgaard Risnes Louise Fremgaard Risnes Ralf Stefan Neumann Asbjørn Christophersen Asbjørn Christophersen Knut E. A. Lundin Knut E. A. Lundin Knut E. A. Lundin Geir Kjetil Sandve Shuo-Wang Qiao Shuo-Wang Qiao Ludvig M. Sollid Ludvig M. Sollid Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs Frontiers in Immunology celiac disease T-cell receptors gluten-specific T-cell receptors CDR3 motifs public T-cell receptors R-motif |
author_facet |
Shiva Dahal-Koirala Shiva Dahal-Koirala Louise Fremgaard Risnes Louise Fremgaard Risnes Ralf Stefan Neumann Asbjørn Christophersen Asbjørn Christophersen Knut E. A. Lundin Knut E. A. Lundin Knut E. A. Lundin Geir Kjetil Sandve Shuo-Wang Qiao Shuo-Wang Qiao Ludvig M. Sollid Ludvig M. Sollid |
author_sort |
Shiva Dahal-Koirala |
title |
Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs |
title_short |
Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs |
title_full |
Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs |
title_fullStr |
Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs |
title_full_unstemmed |
Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs |
title_sort |
comprehensive analysis of cdr3 sequences in gluten-specific t-cell receptors reveals a dominant r-motif and several new minor motifs |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-04-01 |
description |
Gluten-specific CD4+ T cells are drivers of celiac disease (CeD). Previous studies of gluten-specific T-cell receptor (TCR) repertoires have found public TCRs shared across multiple individuals, biased usage of particular V-genes and conserved CDR3 motifs. The CDR3 motifs within the gluten-specific TCR repertoire, however, have not been systematically investigated. In the current study, we analyzed the largest TCR database of gluten-specific CD4+ T cells studied so far consisting of TCRs of 3122 clonotypes from 63 CeD patients. We established a TCR database from CD4+ T cells isolated with a mix of HLA-DQ2.5:gluten tetramers representing four immunodominant gluten epitopes. In an unbiased fashion we searched by hierarchical clustering for common CDR3 motifs among 2764 clonotypes. We identified multiple CDR3α, CDR3β, and paired CDR3α:CDR3β motif candidates. Among these, a previously known conserved CDR3β R-motif used by TRAV26-1/TRBV7-2 TCRs specific for the DQ2.5-glia-α2 epitope was the most prominent motif. Furthermore, we identified the epitope specificity of altogether 16 new CDR3α:CDR3β motifs by comparing with TCR sequences of 231 T-cell clones with known specificity and TCR sequences of cells sorted with single HLA-DQ2.5:gluten tetramers. We identified 325 public TCRα and TCRβ sequences of which 145, 102 and 78 belonged to TCRα, TCRβ and paired TCRαβ sequences, respectively. While the number of public sequences was depended on the number of clonotypes in each patient, we found that the proportion of public clonotypes from the gluten-specific TCR repertoire of given CeD patients appeared to be stable (median 37%). Taken together, we here demonstrate that the TCR repertoire of CD4+ T cells specific to immunodominant gluten epitopes in CeD is diverse, yet there is clearly biased V-gene usage, presence of public TCRs and existence of conserved motifs of which R-motif is the most prominent. |
topic |
celiac disease T-cell receptors gluten-specific T-cell receptors CDR3 motifs public T-cell receptors R-motif |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.639672/full |
work_keys_str_mv |
AT shivadahalkoirala comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT shivadahalkoirala comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT louisefremgaardrisnes comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT louisefremgaardrisnes comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT ralfstefanneumann comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT asbjørnchristophersen comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT asbjørnchristophersen comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT knutealundin comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT knutealundin comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT knutealundin comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT geirkjetilsandve comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT shuowangqiao comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT shuowangqiao comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT ludvigmsollid comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs AT ludvigmsollid comprehensiveanalysisofcdr3sequencesinglutenspecifictcellreceptorsrevealsadominantrmotifandseveralnewminormotifs |
_version_ |
1721529243075084288 |
spelling |
doaj-3aaad2845ae24bac882ae9945aa0cdde2021-04-13T04:41:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-04-011210.3389/fimmu.2021.639672639672Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor MotifsShiva Dahal-Koirala0Shiva Dahal-Koirala1Louise Fremgaard Risnes2Louise Fremgaard Risnes3Ralf Stefan Neumann4Asbjørn Christophersen5Asbjørn Christophersen6Knut E. A. Lundin7Knut E. A. Lundin8Knut E. A. Lundin9Geir Kjetil Sandve10Shuo-Wang Qiao11Shuo-Wang Qiao12Ludvig M. Sollid13Ludvig M. Sollid14K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayDepartment of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, NorwayK.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayDepartment of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, NorwayK.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayK.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayDepartment of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, NorwayK.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayDepartment of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, NorwayDepartment of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, NorwayBiomedical Informatics, Department of Informatics, University of Oslo, Oslo, NorwayK.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayDepartment of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, NorwayK.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, NorwayDepartment of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, NorwayGluten-specific CD4+ T cells are drivers of celiac disease (CeD). Previous studies of gluten-specific T-cell receptor (TCR) repertoires have found public TCRs shared across multiple individuals, biased usage of particular V-genes and conserved CDR3 motifs. The CDR3 motifs within the gluten-specific TCR repertoire, however, have not been systematically investigated. In the current study, we analyzed the largest TCR database of gluten-specific CD4+ T cells studied so far consisting of TCRs of 3122 clonotypes from 63 CeD patients. We established a TCR database from CD4+ T cells isolated with a mix of HLA-DQ2.5:gluten tetramers representing four immunodominant gluten epitopes. In an unbiased fashion we searched by hierarchical clustering for common CDR3 motifs among 2764 clonotypes. We identified multiple CDR3α, CDR3β, and paired CDR3α:CDR3β motif candidates. Among these, a previously known conserved CDR3β R-motif used by TRAV26-1/TRBV7-2 TCRs specific for the DQ2.5-glia-α2 epitope was the most prominent motif. Furthermore, we identified the epitope specificity of altogether 16 new CDR3α:CDR3β motifs by comparing with TCR sequences of 231 T-cell clones with known specificity and TCR sequences of cells sorted with single HLA-DQ2.5:gluten tetramers. We identified 325 public TCRα and TCRβ sequences of which 145, 102 and 78 belonged to TCRα, TCRβ and paired TCRαβ sequences, respectively. While the number of public sequences was depended on the number of clonotypes in each patient, we found that the proportion of public clonotypes from the gluten-specific TCR repertoire of given CeD patients appeared to be stable (median 37%). Taken together, we here demonstrate that the TCR repertoire of CD4+ T cells specific to immunodominant gluten epitopes in CeD is diverse, yet there is clearly biased V-gene usage, presence of public TCRs and existence of conserved motifs of which R-motif is the most prominent.https://www.frontiersin.org/articles/10.3389/fimmu.2021.639672/fullceliac diseaseT-cell receptorsgluten-specific T-cell receptorsCDR3 motifspublic T-cell receptorsR-motif |