Increased Frequency of Regulatory CD127^low T Cells Early after Lung Transplant Is Associated with Improved Graft 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 four Treg subpopulations with the later incidence of CLAD and survival.

Methods: Among lung-transplanted patients between January 2009 and April 2018, only adult 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^highT cells and further analyzed for CD127^low, FoxP3⁺, IL2⁺, and CD152⁺ 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. Model accuracy was evaluated through the receiver operating characteristic (ROC) curves.

Results: During the study period, among the 1,044 lung-transplanted adult patients at our institution, 724 (69%) patients had Treg measurements performed at 3 weeks after transplantation. Frequencies (%) of CD127^low and IL2⁺ cells within the CD4⁺CD25^high gate at 3 weeks were higher in patients without CLAD than in patients with CLAD (74.2 ± 19.3 vs. 65.8 ± 20.4, p < 0.001; 28.4 ± 22.2 vs. 19.5 ± 17.9, p < 0.001, respectively) and in patients with better graft survival (74.2 ± 18.4 vs. 66.9 ± 22.5, p = 0.001; 27.7 ± 21.0 vs. 22.8 ± 23.0, p = 0.002, respectively). Frequencies (%) of FoxP3⁺and IL152⁺cells within the CD4⁺CD25^highgate at 3 weeks did not differ between patients with and without CLAD (p = 0.49 and p = 0.29, respectively) and between patients with better and worse graft survival (p = 0.63 and p = 0.42, respectively).

Follow-up was 41 ± 28 months. Freedom (%) from CLAD was 66 ± 2 at 5 years. At the Cox analysis, increasing frequencies of CD127^low (HR = 0.99, p = 0.018) and of FoxP3⁺ Tregs (HR = 0.98, p = 0.022) were protective against CLAD. The area under the curve (AUC) was 0.62 (p < 0.01) for CD127^low Tregs, but only 0.48 (p = 0.57) for FoxP3+ Tregs. Graft survival (%) amounted to 68 ± 2 at 5 years. Only increasing frequencies of CD127^lowTregs (HR = 0.99, p = 0.006) were associated with better graft survival. The AUC was 0.59 (p < 0.01) for CD127^lowTregs.

Conclusion: A higher frequency of CD127^lowTregs in peripheral blood early after lung transplantation is protective against CLAD and associated with better survival. This finding may support future cell therapies with autologous Treg in lung transplantation.