Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs.

Autor:	Dahal-Koirala S; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway.; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway., Risnes LF; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway.; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway., Neumann RS; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway., Christophersen A; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway.; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway., Lundin KEA; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway.; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.; Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway., Sandve GK; Biomedical Informatics, Department of Informatics, University of Oslo, Oslo, Norway., Qiao SW; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway.; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway., Sollid LM; K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Oslo, Norway.; Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Apr 13; Vol. 12, pp. 639672. Date of Electronic Publication: 2021 Apr 13 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.639672
Abstrakt:	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. Competing Interests: SD-K, LR, RN, AC, KL, S-WQ, GS and LS are holders of a patent application entitled "Method of diagnosing celiac disease" (US20210010077A1) on the use of the gluten-specific T cell receptor sequences described in the current work for diagnosis of celiac disease. (Copyright © 2021 Dahal-Koirala, Risnes, Neumann, Christophersen, Lundin, Sandve, Qiao and Sollid.)
Databáze:	MEDLINE
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