Intragraft Regulatory T Cells in Protocol Biopsies Retain Foxp3 Demethylation and Are Protective Biomarkers for Kidney Graft Outcome

Presence of subclinical rejection (SCR) with IF/TA in protocol biopsies of renal allografts has been shown to be an independent predictor factor of graft loss. Also, intragraft Foxp3+ Tregcells in patients with SCR has been suggested to differentiate harmful from potentially protective infiltrates. Nonetheless, whether presence of Foxp3 Tregcells in patients with SCR and IF/TA may potentially protect from a deleterious graft outcome has not yet been evaluated. This is a case‐control study in which 37 patients with the diagnosis of SCR and 68 control patients with no cellular infiltrates at 6‐month protocol biopsies matched for age and time of transplantation were evaluated. We first confirmed that numbers of intragraft Foxp3‐expressing T cells in patients with SCR positively correlates with Foxp3 demethylation at the Treg‐specific demethylation region. Patients with SCR without Foxp3+ Tregcells within graft infiltrates showed significantly worse 5‐year graft function evolution than patients with SCR and Foxp3+ Tregcells and those without SCR. When presence of SCR and IF/TA were assessed together, presence of Foxp3+ Tregcould discriminate a subgroup of patients showing the same graft outcome as patients with a normal biopsy. Thus, presence of Foxp3+ Tregcells in patients with SCR even with IF/TA is associated with a favorable long‐term allograft outcome.