Key result
Natural CD4+ Tregs with demethylated FOXP3 gene were significantly more abundant in endomyocardial biopsies of heart transplant patients with rejection compared to those with no rejection.
Observational
In heart transplant recipients, natural regulatory T cells are more abundant in allografts prior to acute rejection, suggesting they do not prevent rejection, whereas induced regulatory T cells may help control alloreactivity.
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Challenges assumption that natural Tregs prevent cardiac rejection; leaves open whether induced Tregs modulate alloreactivity.
In Brief Background FOXP3+ regulatory T cells (Treg) either originate in the thymus (natural [n]Treg) or are induced in the periphery by antigen exposure and cytokines (induced [i]Treg). It is currently not elucidated which and to what extent these Treg subsets regulate intracardiac allogeneic responses in transplant patients. Methods By using demethylation of the Treg-specific demethylated region in the FOXP3 gene as a marker for nTreg and FOXP3 messenger RNA expression as a marker for the total Treg population, we examined Treg in endomyocardial biopsies (EMBs) of both patients who developed an acute rejection necessitating therapy (rejectors; International Society for Heart and Lung Transplantation rejection grade ≥ 2R) and patients who remained free from rejection (nonrejectors). Results In the presence of comparable messenger RNA levels of CD3, IL-10, TGFβ, IL2, IFNγ, and IL17A, the percentage of nTreg was significantly higher in EMB with histological signs of mild rejection (rejection grade 1R) collected before rejection than in 1R EMB of nonrejectors. The total Treg population was comparable in 1R EMB of nonrejectors and 1R EMB collected before rejection, which suggests the presence of iTreg in the EMB of nonrejectors. The relative high percentage of nTreg after rejection was not related to the number of rejections, whereas the total Treg population was inversely related to the number of rejections the first year after transplantation. Conclusions Our data indicate that intragraft nTreg are unable to restrain alloreactivity leading to rejection. Moreover, the indirect evidence of the presence of intragraft iTreg suggests a possible role of iTreg in the regulation of alloreactivity. Analysis of endomyocardial biopsies from heart transplanted patients show that natural CD4+ Tregs with demethylated FOXP3 gene were more abundant in patients with rejection vs those with no rejection. In contrast, induced CD4+ Tregs with methylated FOXP3 gene were present in similar proportion in both groups. Induced CD4+FOXP3+ Tregs in non-rejectors, may play a role in controlling rejection.
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Boer et al. (2015) conducted an observational in Cardiac allograft rejection. Acute rejection necessitating therapy vs. No rejection was evaluated on Percentage of natural regulatory T cells (nTreg) in endomyocardial biopsies. Natural CD4+ Tregs with demethylated FOXP3 gene were significantly more abundant in endomyocardial biopsies of heart transplant patients with rejection compared to those with no rejection.
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