DRhigh+CD45RA−-Tregs Potentially Affect the Suppressive Activity of the Total Treg Pool in Renal Transplant Patients

Abstract

Recent studies show that regulatory T cells (Tregs) play an essential role in tolerance induction after organ transplantation. In order to examine whether there are differences in the composition of the total CD4+CD127low+/−FoxP3+- Treg cell pool between stable transplant patients and patients with biopsy proven rejection (BPR), we compared the percentages and the functional activity of the different Treg cell subsets (DRhigh+CD45RA−-Tregs, DRlow+CD45RA−-Tregs, DR−CD45RA−-Tregs, DR−CD45RA+-Tregs). All parameters were determined during the three different periods of time after transplantation (0–30 days, 31–1,000 days, >1,000 days). Among 156 transplant patients, 37 patients suffered from BPR. The most prominent differences between rejecting and non-rejecting patients were observed regarding the DRhigh+CD45RA−-Treg cell subset. Our data demonstrate that the suppressive activity of the total Treg pool strongly depends on the presence of these Treg cells. Their percentage within the total Treg pool strongly decreased after transplantation and remained relatively low during the first year after transplantation in all patients. Subsequently, the proportion of this Treg subset increased again in patients who accepted the transplant and reached a value of healthy non-transplanted subjects. By contrast, in patients with acute kidney rejection, the DRhigh+CD45RA−-Treg subset disappeared excessively, causing a reduction in the suppressive activity of the total Treg pool. Therefore, both the monitoring of its percentage within the total Treg pool and the monitoring of the HLA-DR MFI of the DR+CD45RA−-Treg subset may be useful tools for the prediction of graft rejection.

Human CD45RA− FoxP3hi Memory-Type Regulatory T Cells Show Distinct TCR Repertoires With Conventional T Cells and Play an Important Role in Controlling Early Immune Activation

“…Consistent with our data, recent reports also show stronger suppression capacity of activated memory type Treg in murine study (37)(38)(39) (42)(43)(44). It is, therefore, difficult to correlate loss of Helios expression with the stability of tTreg.…”

Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

“…6,7,35 In accordance with these findings, lower frequencies of Tregs have been correlated with poor graft outcomes. 4,11,34,36 Despite accumulating data from various experimental models, the present clinical results are insufficient to prove that Tregs play a role in the maintenance of tolerance in operationally tolerant recipients. In this article, we report on increased Foxp3 demethylation and a higher frequency of circulating mTregs in the blood of tolerant recipients compared with nontolerant equivalents and healthy controls.…”

“…31,32 Although the phenomenon of operational tolerance offers a unique model for the regulation of the immune response in humans, the mechanisms responsible for the maintenance of tolerance in these patients remain unclear. We and others previously demonstrated the possible involvement of regulatory cells, including regulatory B cells (Bregs) 33 and Tregs, 4,8,9,34 in this process. We initially reported a greater number of circulating CD4 + CD25 hi Foxp3 + cells in blood from patients with operational tolerance, 9 and previous transcriptomic studies highlighted higher mRNA levels of Foxp3 in the blood, grafts, and urine of tolerant patients compared with other transplant recipients and with HVs.…”

The role of regulatory T cell (Treg) subsets in gestational diabetes mellitus

“…Especially for Treg cells, it was shown that the highly activated DR low+ and DR high+ memory Tregs have the highest suppressive activity within the total T reg pool in normal healthy control subjects [23]. In particular, the DR high+ memory Tregs were found to be of potential importance for the suppressive activity of the total Treg pool, as these cells were shown to be reduced significantly in kidney transplant patients with acute rejection, compared to non-rejecting patients [23,24].…”