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.

Die Autoren geben an, dass kein Interessenkonflikt besteht.