Introduction DNA methylation plays a critical role in the function of cells, including cells of the immune system. Little is known about the methylation status of immune related genes in relation to viral infections and alloreactivity. Here we studied the methylation status of the pro-inflammatory cytokine IFNγ in relation to CMV infection and rejection in kidney transplantation patients.

Methods The DNA methylation status of two regulatory CpGs (CpG-186 and CpG-54) in the IFNγ promoter was determined by pyrosequencing in FACS sorted naïve, central memory (CM), effector memory (EM) and EMRA CD8+ T cells of CMV-seropositive and CMV-seronegative donors and before, 3 months and 12 months after transplantation in CMV-seronegative patients. Both patients who developed a biopsy proven acute rejection (rejectors) and patients who remained free from rejection (non-rejectors) were included.

Results A clear-cut difference was seen between the IFNγ methylation in naïve CD8+ T cells (CMV-seronegative donors, CpG-186 and CpG-54, median with range: 65% (53-71) and 79% (65-83)) and the memory CD8+ T cell subsets (CM: 13% (8-17) and 17% (10-21); EM: 6% (5-13) and 8% (7-20); EMRA: 2% (2-6) and 2% (2-9)). The IFNγ methylation status inversely correlated with the % of IFNγ producing cells. Before transplantation the IFNγ methylation was comparable to the methylation status in CMV-seronegative donors and did not significantly change during the first year after transplantation. Comparing rejectors and non-rejectors did not demonstrate significant differences. In contrast to alloreactivity, CMV infection significantly (p<0.05) decreased the % of methylation of both CpGs in the naïve, CM and EM CD8+ T cells.

Conclusion Chronic kidney disease, the transplantation procedure itself and subsequent alloreactivity does not modulate the methylation status of IFNγ, while CMV infection significantly decreases the methylation status of IFNγ in CD8+ T cells.

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