Background: The role of DNA methylation in the regulation of the anti-donor-directed immune response after\norgan transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the\npro-inflammatory cytokine interferon Ã?³ (IFNÃ?³) and the inhibitory receptor programmed death 1 (PD1) in naÃ?¯ve and\nmemory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both\nrecipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection\n(non-rejectors) were included.\nResults: CpGs in the promoter regions of both IFNÃ?³ and PD1 were significantly (p < 0.001) higher methylated in the\nnaÃ?¯ve CD8+ T cells compared to the memory T cell subsets. The methylation status of both IFNÃ?³ and PD1 inversely\ncorrelated with the percentage of IFNÃ?³ or PD1-producing cells. Before transplantation, the methylation status of both\nIFNÃ?³ and PD1 was not significantly different from healthy donors. At 3 months after transplantation, irrespective of\nrejection and subsequent anti-rejection therapy, the IFNy methylation was significantly higher in the differentiated\neffector memory CD45RA+ (EMRA) CD8+ T cells (p = 0.01) whereas the PD1 methylation was significantly higher in all\nmemory CD8+ T cell subsets (CD27+ memory; p = 0.02: CD27âË?â?? memory; p = 0.02: EMRA; p = 0.002). Comparing the\nincrease in methylation in the first 3 months after transplantation between rejectors and non-rejectors demonstrated a\nsignificantly more prominent increase in the PD1 methylation in the CD27âË?â?? memory CD8+ T cells in rejectors (increase\nin rejectors 14%, increase in non-rejectors 1.9%, p = 0.04). The increase in DNA methylation in the other memory CD8+\nT cells was not significantly different between rejectors and non-rejectors. At 12 months after transplantation, the\nmethylation of both IFNÃ?³ and PD1 returned to baseline levels.\nConclusions: The DNA methylation of both IFNÃ?³ and PD1 increases the first 3 months after transplantation in memory\nCD8+ T cells in kidney transplant recipients. This increase was irrespective of a rejection episode indicating that general\nfactors of the kidney transplantation procedure, including the use of immunosuppressive medication, contribute to\nthese variations in DNA methylation.
Loading....