Regulatory T cell therapy is associated with distinct immune regulatory lymphocytic infiltrates in kidney transplants

Abstract

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 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study ( ClinicalTrials.gov : 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 7 years of follow-up data on patients treated with adoptive Treg therapy early post-transplantation who exhibited focal lymphocytic infiltrates on a 9-month protocol biopsy. We phenotyped their adoptively transferred and peripherally circulating Treg compartments using CITE-seq 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 9 months post-transplantation exhibited focal lymphocytic infiltrates. Spatial profiling analysis revealed prominent CD20 + B cell and regulatory ( IKZF2 , IL10 , PD-L1 , TIGIT ) signatures within cell-therapy-associated immune infiltrates, distinct from the pro-inflammatory myeloid signature associated with rejection biopsies. Conclusions We demonstrate for the first time that immune cell infiltrates in transplanted kidneys can occur following adoptive Treg therapy in humans, potentially facilitating within-graft T:B cell interactions that promote local immune regulation. Funding This work was funded by the 7 th EU Framework Programme, grant/award no. 260687, and the National Institute for Health Research (NIHR). • Patients receiving Treg therapy have excellent long-term outcomes • Immune infiltrates within the transplant are observed after Treg therapy • Infiltrates are enriched for regulatory genes including IKZF2 , IL10 , PD-L1 , and TIGIT • B cells are prominently enriched in infiltrates from Treg-treated patients Kidney transplantation is the gold-standard treatment for end-stage renal disease, but it requires lifelong immunosuppression with substantial side effects. Treg therapy may help to reduce the reliance on conventional immunosuppression. In the current study, the authors show that renal transplant patients receiving Treg therapy had excellent long-term kidney function with no episodes of rejection over 7 years while also developing immune cell infiltrates within the graft. These infiltrates were enriched for immunoregulatory genes and B cells. These findings are significant for the interpretation of tissue responses to regulatory cell therapies and support the idea that local immunoregulation within the transplant may contribute to the effectiveness of Treg therapy. McCallion et al. report that kidney transplant recipients treated with Treg therapy exhibit prominent immune infiltrates within the transplanted organ. Infiltrates occur in patients with excellent long-term outcomes and exhibit immunoregulatory and B cell signatures, supporting the notion that local regulation is a prominent mechanism of Treg therapy.

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