Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity.

Autor:	Smirnova AO; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, Russia.; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia., Miroshnichenkova AM; Abu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab Emirates., Belyaeva LD; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia., Kelmanson IV; Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel., Lebedev YB; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.; Department of Molecular Technologies, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia., Mamedov IZ; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia., Chudakov DM; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.; Abu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab Emirates.; Department of Molecular Technologies, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia.; Central European Institute of Technology, Masaryk University, Brno, Czechia., Komkov AY; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.; Abu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab Emirates.; Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Sep 07; Vol. 14, pp. 1245175. Date of Electronic Publication: 2023 Sep 07 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1245175
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The sequences of primers specific for D-D and D-J rearrangements used in this study are intellectual property of MiLaboratories LLC., USA. (Copyright © 2023 Smirnova, Miroshnichenkova, Belyaeva, Kelmanson, Lebedev, Mamedov, Chudakov and Komkov.)
Databáze:	MEDLINE
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