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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-07-01
|
| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI158047 |
| _version_ | 1811237514425401344 |
|---|---|
| author | Yiouli P. Ktena Michael A. Koldobskiy Michael I. Barbato Han-Hsuan Fu Leo Luznik Nicolas J. Llosa Azeb Haile Orly R. Klein Chen Liu Christopher J. Gamper Kenneth R. Cooke |
| author_facet | Yiouli P. Ktena Michael A. Koldobskiy Michael I. Barbato Han-Hsuan Fu Leo Luznik Nicolas J. Llosa Azeb Haile Orly R. Klein Chen Liu Christopher J. Gamper Kenneth R. Cooke |
| author_sort | Yiouli P. Ktena |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T12:25:49Z |
| format | Article |
| id | doaj.art-c4e9109a86424b8ea4684ab6e13f66fe |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-12T12:25:49Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-c4e9109a86424b8ea4684ab6e13f66fe2022-12-22T03:33:11ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-07-0113213Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantationYiouli P. KtenaMichael A. KoldobskiyMichael I. BarbatoHan-Hsuan FuLeo LuznikNicolas J. LlosaAzeb HaileOrly R. KleinChen LiuChristopher J. GamperKenneth R. CookeDNA 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.https://doi.org/10.1172/JCI158047Transplantation |
| spellingShingle | Yiouli P. Ktena Michael A. Koldobskiy Michael I. Barbato Han-Hsuan Fu Leo Luznik Nicolas J. Llosa Azeb Haile Orly R. Klein Chen Liu Christopher J. Gamper Kenneth R. Cooke Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation The Journal of Clinical Investigation 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 | Transplantation |
| url | https://doi.org/10.1172/JCI158047 |
| work_keys_str_mv | AT yioulipktena donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT michaelakoldobskiy donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT michaelibarbato donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT hanhsuanfu donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT leoluznik donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT nicolasjllosa donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT azebhaile donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT orlyrklein donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT chenliu donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT christopherjgamper donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation AT kennethrcooke donortcelldnmt3aregulatesalloreactivityinmousemodelsofhematopoieticstemcelltransplantation |