Increasing Frequency of CD127^low Regulatory Cells Early after Lung Transplantation is Associated with Improved Freedom from Chronic Lung Allograft Rejection and Survival

Objectives: Regulatory T cells (Tregs) may counteract chronic lung allograft dysfunction (CLAD). In the present study, we analyzed Treg in peripheral blood at 3 weeks after lung transplantation and correlated the percentages of two Treg subpopulations with the later incidence of CLAD and survival, and with the presence of early anti-HLA donor specific antibodies (eDSA) developing during the first weeks after lung transplantation.

Methods: Among lung-transplanted patients between January 2009 and December 2016, only patients with sufficient Treg measurements at 3 weeks after transplantation were included into the study. Tregs were detected in peripheral blood and defined as CD4⁺CD25^high T cells and further analyzed for CD127 and FoxP3 using FACS analysis. Associations of Tregs with CLAD and graft survival, defined as patient survival and freedom from re-transplantation, were evaluated using Cox regression analysis, and association with presence of eDSA using the Student`s T-Test. Model accuracy was evaluated through the receiver operating characteristic (ROC) curves.

Results: During the study period, among the 975 lung-transplanted patients at our institution, 589 (60%) patients had Treg measurements performed at 3 weeks after transplantation. Frequencies of CD127^low cells within the CD4⁺CD25^high gate and of FoxP3⁺ cells within the CD4⁺CD25^high gate at 3 weeks amounted to 61 ± 27% and 77 ± 14%, respectively. A hundred and twenty-four (21%) patients developed early DSA. Frequency (%) of Treg subpopulations did not differ among patients with or without eDSA (67 ± 23 vs. 62 ± 58, p = 0.31 for CD127^low; and 76 ± 15 vs.77 ± 15, p = 0.65, for FoxP3⁺, respectively).

Follow-up was 37 ± 26 months. Freedom (%) from CLAD was 64 ± 3 at 5 years. Increasing frequencies of CD127^low (p < 0.01) but not of FoxP3⁺ Tregs (p = 0.20) were protective against CLAD. The area under the curve (AUC) was 0.64 (p < 0.01) for CD127^low Tregs. Graft survival (%) amounted to 67 ± 3 at 5 years. Increasing frequencies of CD127^low (p = 0.001) but not of FoxP3⁺ Tregs (p = 0.08) were associated with better graft survival. The AUC was 0.64 (p < 0.01) for CD127^low Tregs.

Conclusion: A higher frequency of CD127^low Treg in peripheral blood early after lung transplantation is protective against CLAD and associated with better survival and freedom from re-transplantation. This finding supports future cell therapies with autologous Treg in lung transplantation.

No conflict of interest has been declared by the author(s).