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. 2023 Oct 30:2:1165320.
doi: 10.3389/frtra.2023.1165320. eCollection 2023.

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

C Dudreuilh  1   2 , S Basu  1   2 , O Shaw  3 , H Burton  1   2 , N Mamode  1   2 , F Harris  4 , T Tree  4 , P Nedyalko  5 , M Terranova-Barberio  5 , G Lombardi  4 , C Scottà  4 , A Dorling  1   2
Affiliations

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

C Dudreuilh et al. Front Transplant. .

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.

Keywords: T follicular regulatory cells; haemodialysis; highly sensitised; regulatory T cells; sensitisation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors CD and GL declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 5
Figure 5
CITRUS analysis of Tregs from extracellular panel comparing HV, unsensitised HD and AIT patients.
Figure 7
Figure 7
CITRUS analysis of intracellular panel.
Figure 1
Figure 1
Gating strategy to identify Th-like subpopulations of Tregs.
Figure 2
Figure 2
Tfr and bTfr extracellular phenotyping. Description of expression of different markers in the Tfr population (CXCR5+ Tregs) (left panel, A) and on the PD-1neg and ICOSneg (bTfr) subpopulation (right panel, B). The bTf is obtained by selecting PD-1 negative and ICOS negative cells out of the Tfr population.
Figure 3
Figure 3
Phenotyping analysis of Tregs in HV, non-sensitised HD, and HS patients. In (A) some common Tregs markers, and the population I, II and III are presented. bTfr were defined as CXCR5+PD-1−ICOS-Tregs. In (B) the markers associated with the Th-like populations are presented. There was no difference in the CD45RA/CCR7 groups (C), but HS patients had a trend towards increase in the CD45RA+CCR7− naïve Tregs population (p = 0.0817).
Figure 4
Figure 4
Phenotyping analysis of Teffs in HV, non-sensitised HD, and HS patients. In (A) some common Teffs markers are presented. In (B) the markers associated with the Th-like populations and subpopulations based on the expression of CD45RA and CCR7 are presented. There was no difference in the CD45RA/CCR7 groups (C), but HS patients had a trend towards increase in the CD45RA+CCR7− naïve Tregs population (p = 0.0817).
Figure 6
Figure 6
Biased analysis of cluster iii.
See this image and copyright information in PMC

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