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Abstract
BackgroundThe 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 interferon γ (IFNγ) and the inhibitory receptor programmed death 1 (PD1) 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.ResultsCpGs in the promoter regions of both IFNγ and PD1 were significantly (p < 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of both IFNγ and PD1 inversely correlated with the percentage of IFNγ or PD1-producing cells. Before transplantation, the methylation status of both IFNγ and PD1 was not significantly different from healthy donors. At 3 months after transplantation, irrespective of rejection and subsequent anti-rejection therapy, the IFNy methylation was significantly higher in the differentiated effector memory CD45RA+ (EMRA) CD8+ T cells (p = 0.01) whereas the PD1 methylation was significantly higher in all memory CD8+ T cell subsets (CD27+ memory; p = 0.02: CD27− memory; p = 0.02: EMRA; p = 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 PD1 methylation in the CD27− memory CD8+ T cells in rejectors (increase in rejectors 14%, increase in non-rejectors 1.9%, p = 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 IFNγ and PD1 returned to baseline levels.ConclusionsThe DNA methylation of both IFNγ and PD1 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.
Highlights
The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown
interferon γ (IFNγ) methylation is significantly decreased in CMV seropositive individuals In Peripheral blood mononuclear cells (PBMCs) of CMV seronegative healthy donors, the DNA methylation of IFNy was 51.2 ± 4.4%
The DNA methylation of programmed death 1 (PD1) in PBMCs of CMV seronegative healthy donors was comparable to the PD1 methylation in CMV seropositive healthy donors (40.5 ± 5.3 versus 38.9 ± 6.3%; Fig. 1b)
Summary
The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. We studied the methylation of two mediators of the immune response: the pro-inflammatory cytokine interferon γ (IFNγ) and the inhibitory receptor programmed death 1 (PD1) 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. The host immune response is orchestrated by a tightly regulated cascade of gene expression changes which are regulated by epigenetic mechanisms like histone modifications, DNA methylation, microRNA interactions, and chromatin remodeling complexes [5,6,7,8]. Variations in these epigenetic mechanisms might serve as an additional marker to monitor the host immune response after organ transplantation
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