The Journal of Clinical Investigation (Jul 2022)

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

Journal volume & issue
Vol. 132, no. 13

Abstract

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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.

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