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Donor-reactive memory cells represent a barrier to long-term kidney graft survival. A better understanding of regulatory mechanisms that counterbalance alloreactive memory responses may help to identify patients with operational tolerance. This prospective study investigated the equilibrium between memory T-cell subsets and regulatory T or B cells (Tregs, Bregs) in peripheral blood of kidney transplant recipients with operational tolerance (N = 8), chronic rejection (N = 8), and different immunosuppressive treatment regimens (N = 81). Patients on hemodialysis and healthy individuals served as controls (N = 50). In addition, the expression of Treg- and Breg-associated molecule genes was analyzed. Patients with chronic rejection showed a disrupted memory T-cell composition with a significantly higher frequency of circulating CD8+ terminally differentiated effector memory (TEMRA) T cells than patients with operational tolerance, patients on hemodialysis, or healthy controls (P < 0.001). Low frequency of CD8+ TEMRA and high frequency of Tregs and transitional Bregs were found in operationally tolerant patients. Consequently, operationally tolerant patients showed, as compared to all other transplant recipients with different immunosuppressive regiments, the lowest ratios between CD8+ TEMRA T cells and Tregs or Bregs (for both P < 0.001). Moreover, a specific peripheral blood transcription pattern was found in operationally tolerant patients with an increased expression of Breg- and Treg-associated genes CD22 and FoxP3 and a decreased FcγRIIA/FcγRIIB transcript ratio (for all P < 0.001). In conclusion, monitoring the balance between circulating CD8+ TEMRA T cells and regulatory cell subsets and their transcripts may help to distinguish transplant recipients with operational tolerance from recipients at risk of graft loss. We show that a balance between effector mechanisms mediated by CD8 + TEMRA T cells and regulatory cell populations such as Bregs, Tregs, or naive T cells determines long-term kidney graft survival. Monitoring the balance between circulating CD8 + TEMRA T cells and regulatory cell subsets and their transcripts may help to distinguish transplant recipients with OT from recipients at risk of graft loss. Our study provides evidence in favor of regulatory mechanisms that counterbalance alloreactive memory immune responses and may encourage further investigations whether the ratio between CD8 + TEMRA T cells and Tregs or Bregs can help to safely guide minimization of immunosuppression in selected patients. Graphical Abstract [ABSTRACT FROM AUTHOR]

The mechanisms underlying maintenance of renal allografts in humans under minimal or conventional immunosuppression are poorly understood. There is evidence that CD4+ CD25+ regulatory T cells and clonal deletion, among other mechanisms of tolerance, could play a key role in clinical allograft survival. Twenty-four TCR-Vβ families were assessed in CD4+ CD25−, CD4+ CD25low and CD4+ CD25high T cells from patients with long-term renal allograft survival (LTS), patients exhibiting chronic rejection (ChrRx), patients on dialysis (Dial) and healthy controls (HC) by flow cytometry. LTS patients presented a higher variability in their TCR-Vβ repertoire, such decreased percentage of Vβ2+, Vβ8a+ and Vβ13+ in CD4+ CD25low and high compared with CD4+ CD25− subset and increased Vβ4 and Vβ7 families in CD4+ CD25high T cells exclusively. Additionally, LTS patients, particularly those that were not receiving calcineurin inhibitors (CNI), had increased percentages of CD4+ CD25high T cells when compared with Dial ( P < 0.05) and ChrRx ( P < 0.05) patients. Our results suggest that a differential expression of particular TCR-Vβ families and high levels of circulating CD4+ CD25high T cells in long-term surviving renal transplant patients could contribute to an active and specific state of immunologic suppression. However, the increase in this T cell subset with regulatory phenotype can be affected by CNI. [ABSTRACT FROM AUTHOR]