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Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation
DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246380/ https://www.ncbi.nlm.nih.gov/pubmed/35608905 http://dx.doi.org/10.1172/JCI158047 |
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author | Ktena, Yiouli P. Koldobskiy, Michael A. Barbato, Michael I. Fu, Han-Hsuan Luznik, Leo Llosa, Nicolas J. Haile, Azeb Klein, Orly R. Liu, Chen Gamper, Christopher J. Cooke, Kenneth R. |
author_facet | Ktena, Yiouli P. Koldobskiy, Michael A. Barbato, Michael I. Fu, Han-Hsuan Luznik, Leo Llosa, Nicolas J. Haile, Azeb Klein, Orly R. Liu, Chen Gamper, Christopher J. Cooke, Kenneth R. |
author_sort | Ktena, Yiouli P. |
collection | PubMed |
description | DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice were used as donors in allo-BMT models. Mice receiving allo-BMT from KO donors developed severe acute graft-versus-host disease (aGVHD), with increases in inflammatory cytokine levels and organ histopathology scores. KO T cells migrated and proliferated in secondary lymphoid organs earlier and demonstrated an advantage in trafficking to the small intestine. Donor T cell subsets were purified after BMT for whole-genome bisulfite sequencing (WGBS) and RNA-Seq. KO T cells had global methylation similar to that of WT cells, with distinct, localized areas of hypomethylation. Using a highly sensitive computational method, we produced a comprehensive profile of the altered epigenome landscape. Hypomethylation corresponded with changes in gene expression in several pathways of T cell signaling and differentiation. Additionally, Dnmt3a-KO T cells resulted in superior graft-versus-tumor activity. Our findings demonstrate a critical role for DNMT3a in regulating T cell alloreactivity and reveal pathways that control T cell tolerance. These results also provide a platform for deciphering clinical data that associate donor DNMT3a mutations with increased GVHD, decreased relapse, and improved survival. |
format | Online Article Text |
id | pubmed-9246380 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-92463802022-07-02 Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation Ktena, Yiouli P. Koldobskiy, Michael A. Barbato, Michael I. Fu, Han-Hsuan Luznik, Leo Llosa, Nicolas J. Haile, Azeb Klein, Orly R. Liu, Chen Gamper, Christopher J. Cooke, Kenneth R. J Clin Invest Research Article DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice were used as donors in allo-BMT models. Mice receiving allo-BMT from KO donors developed severe acute graft-versus-host disease (aGVHD), with increases in inflammatory cytokine levels and organ histopathology scores. KO T cells migrated and proliferated in secondary lymphoid organs earlier and demonstrated an advantage in trafficking to the small intestine. Donor T cell subsets were purified after BMT for whole-genome bisulfite sequencing (WGBS) and RNA-Seq. KO T cells had global methylation similar to that of WT cells, with distinct, localized areas of hypomethylation. Using a highly sensitive computational method, we produced a comprehensive profile of the altered epigenome landscape. Hypomethylation corresponded with changes in gene expression in several pathways of T cell signaling and differentiation. Additionally, Dnmt3a-KO T cells resulted in superior graft-versus-tumor activity. Our findings demonstrate a critical role for DNMT3a in regulating T cell alloreactivity and reveal pathways that control T cell tolerance. These results also provide a platform for deciphering clinical data that associate donor DNMT3a mutations with increased GVHD, decreased relapse, and improved survival. American Society for Clinical Investigation 2022-07-01 2022-07-01 /pmc/articles/PMC9246380/ /pubmed/35608905 http://dx.doi.org/10.1172/JCI158047 Text en © 2022 Ktena et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Ktena, Yiouli P. Koldobskiy, Michael A. Barbato, Michael I. Fu, Han-Hsuan Luznik, Leo Llosa, Nicolas J. Haile, Azeb Klein, Orly R. Liu, Chen Gamper, Christopher J. Cooke, Kenneth R. Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
title | Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
title_full | Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
title_fullStr | Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
title_full_unstemmed | Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
title_short | Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
title_sort | donor t cell dnmt3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246380/ https://www.ncbi.nlm.nih.gov/pubmed/35608905 http://dx.doi.org/10.1172/JCI158047 |
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