Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere158047
JournalJournal of Clinical Investigation
Issue number13
StatePublished - Jul 1 2022

ASJC Scopus subject areas

  • Medicine(all)


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