The Lack of Functional DNMT2 Gene Modulates Gvhd Process Via tRNA m⁵c Modification

Acute graft versus host disease (GVHD), one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), develops in approximately 50% of patients and even leads to death. The primary treatment is the immunosuppressive therapy, but treatment failure is common and often accompanied by infection, recurrence, and organ function damage. It is a tough clinic problem that needs to be solved urgently. RNA modifications, as emerging epigenetic regulators, play important roles in the regulation of protein translation, ribosome biosynthesis, cellular processes and the occurrence of diseases. In this study, we found that the tRNA modification signature of T-cells from liver and spleen organs (7 days post-transplantation) was altered, especially m⁶A, m³C, and m⁵C, were significantly up-regulated. Further analysis showed that levels of tRNA m³C and m⁵C in injected-derived T (45.2) cells were significantly increased compared with that in the de novo T (45.1) cells from spleen and liver. Western bolt confirmed that tRNA methyltransferase DNMT2, responsible for m⁵C modification, was highly expressed in injected-T (45.2) cells isolated from liver and spleen of GVHD model mice. Deletion of Dnmt2 led to the decrease of m⁵C in T-cell tRNA of spleen. The transplantation experiment, Dnmt2 knockout mice as donor, showed that lack of Dnmt2 in T cell could alleviate the development of GVHD, and the serum levels of IFNγ, TNFα and other pro-inflammatory cytokines were also significantly reduced. In conclusion, our data indicated that Dnmt2-mediated tRNA m⁵C modification in injected T (45.2) cells was involved in the occurrence and development of GVHD. However, the molecular mechanism under Dnmt2-mediated tRNA m⁵C regulates GVHD and its impact on immune response need to be further elucidated.

No relevant conflicts of interest to declare.