Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation.

BACKGROUND

The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the pro-inflammatory cytokine () and the inhibitory receptor () in naïve and memory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both recipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection (non-rejectors) were included.

RESULTS

CpGs in the promoter regions of both and were significantly ( < 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of both and inversely correlated with the percentage of IFNγ or PD1-producing cells. Before transplantation, the methylation status of both and was not significantly different from healthy donors. At 3 months after transplantation, irrespective of rejection and subsequent anti-rejection therapy, the methylation was significantly higher in the differentiated effector memory CD45RA+ (EMRA) CD8+ T cells ( = 0.01) whereas the PD1 methylation was significantly higher in all memory CD8+ T cell subsets (CD27+ memory;  = 0.02: CD27- memory;  = 0.02: EMRA;  = 0.002). Comparing the increase in methylation in the first 3 months after transplantation between rejectors and non-rejectors demonstrated a significantly more prominent increase in the methylation in the CD27- memory CD8+ T cells in rejectors (increase in rejectors 14%, increase in non-rejectors 1.9%,  = 0.04). The increase in DNA methylation in the other memory CD8+ T cells was not significantly different between rejectors and non-rejectors. At 12 months after transplantation, the methylation of both and returned to baseline levels.

CONCLUSIONS

The DNA methylation of both and increases the first 3 months after transplantation in memory CD8+ T cells in kidney transplant recipients. This increase was irrespective of a rejection episode indicating that general factors of the kidney transplantation procedure, including the use of immunosuppressive medication, contribute to these variations in DNA methylation.