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Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation
Yiouli P. Ktena, … , Christopher J. Gamper, Kenneth R. Cooke
Yiouli P. Ktena, … , Christopher J. Gamper, Kenneth R. Cooke
Published May 24, 2022
Citation Information: J Clin Invest. 2022;132(13):e158047. https://doi.org/10.1172/JCI158047.
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Research Article Article has an altmetric score of 2

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

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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.

Authors

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

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Figure 1

DNMT3a-deficient T cells result in accelerated experimental aGVHD.

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DNMT3a-deficient T cells result in accelerated experimental aGVHD.
Letha...
Lethally irradiated recipients received BMT from syngeneic (Syn), allogeneic WT (Allo-WT), or Dnmt3a-KO donors (Allo-KO). Haploidentical B6→F1 model: (A) overall survival, (B) clinical GVHD score, (C) survival in the absence of T cells and with T cell–depleted BM only. Data from 3 experiments; Syn n = 15, Allo n = 28 each. (D) Histopathological organ-specific GVHD scores on day +7; n = 4–5 per group. (E) Serum cytokine levels by multiplex bead assay on day +7. Data from 3 experiments; Syn n = 8, Allo n = 17 each. (F) BM cellularity, T cell chimerism, and peripheral blood counts on day +14; n = 4–5 per group. (G) Fully mismatched B6→BALB/cJ model. Left to right: Survival, clinical GVHD score, weight loss. Data from 2 experiments; Syn n = 10, Allo n = 20 each. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, Mann-Whitney U test, Mantel-Cox log-rank test for survival data. ALC, absolute lymphocyte count; ANC, absolute neutrophil count; Hb, hemoglobin; Plt, platelets.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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