High circulating CD4+CD25hiFOXP3+ T-cell sub-population early after lung transplantation is associated with development of bronchiolitis obliterans syndrome

Abstract

Background: Chronic bronchiolitis obliterans syndrome (BOS) remains a major limitation for long-term survival after lung transplantation. The immune mechanisms involved and predictive biomarkers have yet to be identified. The purpose of this study was to determine whether peripheral blood T-lymphocyte profile could predict BOS in lung transplant recipients.

Methods: An in-depth profiling of CD4⁺ and CD8⁺ T cells was prospectively performed on blood cells from stable (STA) and BOS patients with a longitudinal follow-up. Samples were analyzed at 1 and 6 months after transplantation, at the time of BOS diagnosis, and at an intermediate time-point at 6 to 12 months before BOS diagnosis.

Results: Although no significant difference was found for T-cell compartments at BOS diagnosis or several months beforehand, we identified an increase in the CD4⁺CD25^hiFoxP3⁺ T-cell sub-population in BOS patients at 1 and 6 months after transplantation (3.39 ± 0.40% vs 1.67 ± 0.22% in STA, p < 0.001). A CD4⁺CD25^hiFoxP3⁺ T-cell threshold of 2.4% discriminated BOS and stable patients at 1 month post-transplantation. This was validated on a second set of patients at 6 months post-transplantation. Patients with a proportion of CD4⁺CD25^hiFoxP3⁺ T cells up to 2.4% in the 6 months after transplantation had a 2-fold higher risk of developing BOS.

Conclusions: This study is the first to report an increased proportion of circulating CD4⁺CD25^hiFoxP3⁺ T cells early post-transplantation in lung recipients who proceed to develop BOS within 3 years, which supports its use as a BOS predictive biomarker.

Trial registration: ClinicalTrials.gov NCT00980967.

Keywords: T lymphocyte; biomarker; bronchiolitis obliterans syndrome; chronic lung allograft dysfunction; regulatory T lymphocyte.