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Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation
- Source :
- The Journal of Clinical Investigation, Vol 132, Iss 13 (2022)
- Publication Year :
- 2022
- Publisher :
- American Society for Clinical Investigation, 2022.
-
Abstract
- 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.
- Subjects :
- Transplantation
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 15588238
- Volume :
- 132
- Issue :
- 13
- Database :
- Directory of Open Access Journals
- Journal :
- The Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.4e9109a86424b8ea4684ab6e13f66fe
- Document Type :
- article
- Full Text :
- https://doi.org/10.1172/JCI158047