The clinical significance of CD45RA+FOXP3low naïve and CD45RA−FOXP3high effector/memory Treg subsets in the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Introduction

It has been proposed that regulatory T cells (Tregs) might be involved in the induction of transplantation tolerance after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the role of Treg subsets in allo-HSCT outcomes, including the development of acute graft-versus-host disease (aGVHD). Herein, we assessed for the first time the association between the frequency of regulatory T cell (Treg) subsets, including CD45RA⁺FOXP3^low naïve (nTregs) and CD45RA⁻FOXP3^high effector/memory Tregs (eTregs), and aGVHD occurrence during 90 days after allo-HSCT.

Methods

Twenty-four pairs of donors/recipients with hematologic malignancies who underwent HLA-matched allo-HSCT were enrolled. The frequencies of nTregs and eTregs were determined via four-color flow cytometry.

Results

Compared with non-aGVHD patients, aGVHD patients had a lower frequency of nTregs in their donors (*P = 0.016). The reconstitution rate of nTregs was significantly slower on day +60 post-allo-HSCT in aGVHD patients than in non-aGVHD patients (*P = 0.025).

Patients who received grafts with nTregs<0.19 and a median frequency of nTregs<0.13 and eTregs<0.58 on day +30 after transplantation presented a relatively high cumulative incidence of aGVHD (*P = 0.039, *P = 0.032, and *P = 0.036, respectively). Multivariate analysis revealed that a low median total number of Tregs recovered on days +30 and + 60 post-allo-HSCT was associated with an increased incidence of aGVHD [HR = 0.199, 95 % CI, 0.041–0.969; *P = 0.046 and HR = 0.092, 95 % CI, 0.011–0.765; *P = 0.026, respectively].

Conclusion

This study provides novel insights showing that high donor nTreg content and rapid recovery of nTregs and eTregs early on day 30 post-transplantation are closely linked to protection from aGVHD.