Highly sensitised individuals present a distinct Treg signature compared to unsensitised individuals on haemodialysis

Abstract

Introduction: Highly sensitised (HS) patients represent up to 30% of patients on the kidney transplant waiting list. When they are transplanted, they have a high risk of acute/chronic rejection and long-term allograft loss. Regulatory T cells (Tregs) (CD4+CD25hiCD127lo) are T cells involved in the suppression of immune alloresponses. A particular subset, called T follicular regulatory T cells (Tfr, CXCR5+Bcl-6+), is involved in regulating interactions between T effectors and B cells within the germinal centre and can be found in peripheral blood. Therefore, we wanted to identify specific subsets of Tregs in the peripheral blood of HS individuals.

Methods: We recruited prospectively healthy volunteers (HV) (n = 9), non-sensitised patients on haemodialysis (HD) (n = 9) and HS individuals, all of whom were on haemodialysis (n = 15).

Results: We compared the Treg phenotypes of HV, HD and HS. HS patients had more CD161+ Tregs (p = 0.02) and more CD45RA−CCR7− T effectors (Teffs) (p = 0.04, memory Teffs able to home to the germinal centre) compared to HVs. HS patients had more Bcl-6+ Tregs (p < 0.05), fewer Th1-like Tregs, more Th2-like Tregs (p < 0.001) and more CD161+ (p < 0.05) Tregs compared to HD patients. This population has been described to be highly suppressive. HD had a deficiency in a Th17-like CD161+ effector Treg cluster (cluster iii., CCR6+CCR4+CXCR3− CD39+CD15s+ICOS−CCR7−CD161+) (p < 0.05).

Discussion: This is the first study presenting a deep Treg phenotype in HS patients. We confirmed that HS patients had more of a Th17-like CD161+ effector Treg from population III (CD4+CD25hiCD127loCD45RA−) compared to non-sensitised patients on HD. The clinical relevance of this highly suppressive Tregs population remains to be determined in the context of transplantation.