Variation in numbers of CD4⁺CD25^highFOXP3⁺T cells with normal immuno-regulatory properties in long-term graft outcome

Abstract

Summary Chronic rejection (CR) is a major cause of long‐term graft loss that would be avoided by the induction of tolerance. We previously showed that renal transplant patients with CR have lower numbers of peripheral CD4+CD25high T cells than operationally tolerant patients, patients with stable graft function and healthy volunteers (HV). We explored here the profile of CD4+CD25high blood T cells in these patients focusing on their expression of the regulatory T cells (Treg) gene Forkhead Box P3 (FOXP3) and their suppressive function. We show that CR is associated with a decreased number of CD4+CD25highFOXP3+T cells with normal regulatory profile, whereas graft acceptance is associated with CD4+CD25highFOXP3+T cell numbers similar to HVs. These data suggest that Treg numbers, rather than their intrinsic suppressive capacity, may contribute to determining the long‐term fate of renal transplants.

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

“…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.…”

“…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. 6,7,35 In accordance with these findings, lower frequencies of Tregs have been correlated with poor graft outcomes.…”

“…[5][6][7][8] In parallel, some studies, including ours, also suggest a potential role for regulatory T cells (Tregs) in these patients, with overexpression of several genes associated with regulatory functions. 6,[8][9][10] In particular, stable patients and recipients with ongoing chronic rejection display lower levels and proportions of CD4 + CD25 + Foxp3 + T cells compared with operationally tolerant patients and healthy volunteers. 9,11 However, when polyclonally stimulated, Tregs from tolerant patients failed to exhibit an increase in suppressive properties compared with Tregs from other patients.…”

“…6,[8][9][10] In particular, stable patients and recipients with ongoing chronic rejection display lower levels and proportions of CD4 + CD25 + Foxp3 + T cells compared with operationally tolerant patients and healthy volunteers. 9,11 However, when polyclonally stimulated, Tregs from tolerant patients failed to exhibit an increase in suppressive properties compared with Tregs from other patients. 9 Thus, although the potency of Tregs for the prevention of graft rejection and the induction of transplant tolerance has been clearly demonstrated in experimental models, [12][13][14] the role of these cells in the clinical setting is yet to be precisely defined.…”

“…9,11 However, when polyclonally stimulated, Tregs from tolerant patients failed to exhibit an increase in suppressive properties compared with Tregs from other patients. 9 Thus, although the potency of Tregs for the prevention of graft rejection and the induction of transplant tolerance has been clearly demonstrated in experimental models, [12][13][14] the role of these cells in the clinical setting is yet to be precisely defined.…”