T cell-specific DNMT1 knockout promotes CD4+ T cell senescence via CDKN1A upregulation, leading to long-term cardiac graft survival and reduced rejection.
Does DNMT1 deletion or inhibition prevent heart transplant rejection by inducing T cell senescence?
DNMT1 ablation promotes CD4+ T cell senescence and long-term cardiac graft survival, highlighting DNMT1 as a potential therapeutic target for preventing heart transplant rejection.
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This study investigates the role of DNA methyltransferase 1 (DNMT1) in T cell senescence and heart transplant rejection using mouse models and clinical data. In the mouse heart transplantation model, DNMT1 was found to be highly expressed in graft-infiltrating T cells. Using Dnmt1flox/floxCd4cre/+ mice, researchers demonstrated that T cell-specific knockout of DNMT1 led to long-term graft survival by impairing effector differentiation and promoting senescence in CD4+ T cells, rather than CD8+ T cells. Whole-genome methylation sequencing and RNA sequencing revealed that DNMT1 knockout decreased methylation of the cyclin-dependent kinase inhibitor 1A (CDKN1A) promoter, upregulating CDKN1A expression. Depletion of CDKN1Ahigh cells reversed DNMT1 inhibitor-induced T cell senescence. Clinically, increased T cell senescence was observed in post-transplant patients and is known to increase with age. Additionally, data from the UNOS database showed lower rejection rates in older recipients (age > 65). These findings suggest that DNMT1 ablation accelerates CD4+ T cell senescence by altering CDKN1A methylation, thereby reducing T cell function and mitigating rejection. DNMT1 may thus serve as a potential therapeutic target for heart transplant rejection.
Chen et al. (Sun,) reported a other. T cell-specific DNMT1 knockout promotes CD4+ T cell senescence via CDKN1A upregulation, leading to long-term cardiac graft survival and reduced rejection.