Regulatory T cell therapy is associated with distinct immune regulatory lymphocytic infiltrates in kidney transplants
BACKGROUND: Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase I clinical trial of Treg cell therapy in living donor renal transplantation, the ONE Study (NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression. METHODS: We present seven years of follow-up data on patients treated with adoptive Treg cell therapy early post-transplantation, who exhibited focal lymphocytic infiltrates on a nine-month protocol biopsy. We phenotyped their adoptively transferred and peripherally circulating Treg compartments using CITEseq and investigated the focal lymphocytic infiltrates with spatial proteomic and transcriptomic technologies. FINDINGS: Graft survival rates were not significantly different between Treg-treated patients and the control reference group. None of the Treg-treated patients experienced clinical rejection episodes or developed de novo donor-specific antibodies, and three of ten successfully reduced their immunosuppression to tacrolimus monotherapy. All Treg-treated patients who underwent a protocol biopsy nine months post-transplantation exhibited focal lymphocytic infiltrates. Spatial profiling analysis revealed a prominent CD20+ B cell signature within cell therapy-associated immune infiltrates, distinct from the pro-inflammatory myeloid signature typically associated with the rejection biopsies. A regulatory gene expression program (IKZF2, IL10, PD-L1, TIGIT) characterized the cell therapy-associated immune infiltrates at a transcriptional level. CONCLUSIONS: We demonstrate for the first time that immune cell infiltrates in transplanted kidneys can occur following adoptive Treg cell therapy in humans, potentially facilitating within-graft T:B cell interactions that promote local immune regulation. FUNDING: 7th EU Framework Programme, Grant/Award Number: 260687; National Institute for Health Research (NIHR). Overall design: Treg were FACS sorted from PBMC samples (as CD4+CD127-CD25hi) of four patients from two time points (week 24 and week 60) and combined with adoptively transferred Treg from the cell therapy product. CITEseq was performed using the BD Rhapsody platform