Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity
T-cell receptor (TR) diversity of the variable domains is generated by recombination of both the alpha (TRA) and beta (TRB) chains. The textbook process of TRB chain production starts with TRBD and TRBJ gene rearrangement, followed by the rearrangement of a TRBV gene to the partially rearranged D-J...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1245175/full |
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| author | Anastasia O. Smirnova Anastasia O. Smirnova Anna M. Miroshnichenkova Laima D. Belyaeva Ilya V. Kelmanson Yuri B. Lebedev Yuri B. Lebedev Ilgar Z. Mamedov Dmitriy M. Chudakov Dmitriy M. Chudakov Dmitriy M. Chudakov Dmitriy M. Chudakov Alexander Y. Komkov Alexander Y. Komkov Alexander Y. Komkov |
| author_facet | Anastasia O. Smirnova Anastasia O. Smirnova Anna M. Miroshnichenkova Laima D. Belyaeva Ilya V. Kelmanson Yuri B. Lebedev Yuri B. Lebedev Ilgar Z. Mamedov Dmitriy M. Chudakov Dmitriy M. Chudakov Dmitriy M. Chudakov Dmitriy M. Chudakov Alexander Y. Komkov Alexander Y. Komkov Alexander Y. Komkov |
| author_sort | Anastasia O. Smirnova |
| collection | DOAJ |
| description | T-cell receptor (TR) diversity of the variable domains is generated by recombination of both the alpha (TRA) and beta (TRB) chains. The textbook process of TRB chain production starts with TRBD and TRBJ gene rearrangement, followed by the rearrangement of a TRBV gene to the partially rearranged D-J gene. Unsuccessful V-D-J TRB rearrangements lead to apoptosis of the cell. Here, we performed deep sequencing of the poorly explored pool of partial TRBD1-TRBD2 rearrangements in T-cell genomic DNA. We reconstructed full repertoires of human partial TRBD1-TRBD2 rearrangements using novel sequencing and validated them by detecting V-D-J recombination-specific byproducts: excision circles containing the recombination signal (RS) joint 5’D2-RS – 3’D1-RS. Identified rearrangements were in compliance with the classical 12/23 rule, common for humans, rats, and mice and contained typical V-D-J recombination footprints. Interestingly, we detected a bimodal distribution of D-D junctions indicating two active recombination sites producing long and short D-D rearrangements. Long TRB D-D rearrangements with two D-regions are coding joints D1-D2 remaining classically on the chromosome. The short TRB D-D rearrangements with no D-region are signal joints, the coding joint D1-D2 being excised from the chromosome. They both contribute to the TRB V-(D)-J combinatorial diversity. Indeed, short D-D rearrangements may be followed by direct V-J2 recombination. Long D-D rearrangements may recombine further with J2 and V genes forming partial D1-D2-J2 and then complete V-D1-D2-J2 rearrangement. Productive TRB V-D1-D2-J2 chains are present and expressed in thousands of clones of human antigen-experienced memory T cells proving their capacity for antigen recognition and actual participation in the immune response. |
| first_indexed | 2024-03-12T01:59:22Z |
| format | Article |
| id | doaj.art-7c744d23d4c24f8fa70e56c8a7bd5e3e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T01:59:22Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7c744d23d4c24f8fa70e56c8a7bd5e3e2023-09-07T21:09:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12451751245175Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversityAnastasia O. Smirnova0Anastasia O. Smirnova1Anna M. Miroshnichenkova2Laima D. Belyaeva3Ilya V. Kelmanson4Yuri B. Lebedev5Yuri B. Lebedev6Ilgar Z. Mamedov7Dmitriy M. Chudakov8Dmitriy M. Chudakov9Dmitriy M. Chudakov10Dmitriy M. Chudakov11Alexander Y. Komkov12Alexander Y. Komkov13Alexander Y. Komkov14Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, RussiaGenomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, RussiaAbu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab EmiratesGenomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, RussiaDepartment of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, IsraelGenomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, RussiaDepartment of Molecular Technologies, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, RussiaGenomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, RussiaGenomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, RussiaAbu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab EmiratesDepartment of Molecular Technologies, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, RussiaCentral European Institute of Technology, Masaryk University, Brno, CzechiaGenomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, RussiaAbu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab EmiratesDmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, RussiaT-cell receptor (TR) diversity of the variable domains is generated by recombination of both the alpha (TRA) and beta (TRB) chains. The textbook process of TRB chain production starts with TRBD and TRBJ gene rearrangement, followed by the rearrangement of a TRBV gene to the partially rearranged D-J gene. Unsuccessful V-D-J TRB rearrangements lead to apoptosis of the cell. Here, we performed deep sequencing of the poorly explored pool of partial TRBD1-TRBD2 rearrangements in T-cell genomic DNA. We reconstructed full repertoires of human partial TRBD1-TRBD2 rearrangements using novel sequencing and validated them by detecting V-D-J recombination-specific byproducts: excision circles containing the recombination signal (RS) joint 5’D2-RS – 3’D1-RS. Identified rearrangements were in compliance with the classical 12/23 rule, common for humans, rats, and mice and contained typical V-D-J recombination footprints. Interestingly, we detected a bimodal distribution of D-D junctions indicating two active recombination sites producing long and short D-D rearrangements. Long TRB D-D rearrangements with two D-regions are coding joints D1-D2 remaining classically on the chromosome. The short TRB D-D rearrangements with no D-region are signal joints, the coding joint D1-D2 being excised from the chromosome. They both contribute to the TRB V-(D)-J combinatorial diversity. Indeed, short D-D rearrangements may be followed by direct V-J2 recombination. Long D-D rearrangements may recombine further with J2 and V genes forming partial D1-D2-J2 and then complete V-D1-D2-J2 rearrangement. Productive TRB V-D1-D2-J2 chains are present and expressed in thousands of clones of human antigen-experienced memory T cells proving their capacity for antigen recognition and actual participation in the immune response.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1245175/fullTRB repertoireVDJ recombinationNGS - next generation sequencingT cellThymus |
| spellingShingle | Anastasia O. Smirnova Anastasia O. Smirnova Anna M. Miroshnichenkova Laima D. Belyaeva Ilya V. Kelmanson Yuri B. Lebedev Yuri B. Lebedev Ilgar Z. Mamedov Dmitriy M. Chudakov Dmitriy M. Chudakov Dmitriy M. Chudakov Dmitriy M. Chudakov Alexander Y. Komkov Alexander Y. Komkov Alexander Y. Komkov Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity Frontiers in Immunology TRB repertoire VDJ recombination NGS - next generation sequencing T cell Thymus |
| title | Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity |
| title_full | Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity |
| title_fullStr | Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity |
| title_full_unstemmed | Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity |
| title_short | Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity |
| title_sort | novel bimodal trbd1 trbd2 rearrangements with dual or absent d region contribute to trb v d j combinatorial diversity |
| topic | TRB repertoire VDJ recombination NGS - next generation sequencing T cell Thymus |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1245175/full |
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