A non-invasive piTreg-related gene signature for spontaneous tolerance in renal transplantation

Abstract

BackgroundAchieving spontaneous tolerance is the optimal goal in renal transplantation (RT). However, robust biomarkers indicating spontaneous tolerance are still lacking for RT recipients in clinics. MethodsThe peripheral blood gene expression profiles of RT recipients in the state of tolerance and other conditions from four independent cohorts were collected in databases. Immune cell abundance assessment and single-cell analysis were utilized and the peripherally induced regulatory T cell (piTreg) subset was identified as the key cell subtype. Then, a piTreg-related gene set was identified by analyzing cell induction data. Subsequently, selected biomarkers were applied to the Elastic Net for signature construction. The diagnostic ability of the signature was validated in three independent cohorts (Microarray) and our clinical cohort (RT-qPCR). Additionally, time-course analyses during short-term and long-term periods after transplantation were performed to examine whether the gene signature was affected by the administration of immunosuppressive (IS) regimens. ResultsThe piTreg subset was found to possess the best discriminating ability in the peripheral blood for tolerance. After gene set identification and filtering, a two-gene piTreg-related gene signature was constructed in the training cohort (AUC = 0.830). The signature showed robust performance in three independent validation cohorts (AUC = 0.840, 0.826, and 0.859, respectively). The signature was also proved to be not affected by IS regimens in both short-term and long-term periods after RT. ConclusionsWe developed and validated a piTreg-related two-gene signature based on the peripheral blood for tolerance in RT recipients. The non-invasive signature offered a promising potential testing method for individualized immunosuppressant management and immunologic surveillance for RT recipients in clinics.