IL-2 Mutein Promotes Antigen-Specific Acceptance of Transplanted Organs by Activating ST2+ Tissue-Resident Regulatory T Cells

Transplantation is the preferred treatment for most patients with end-stage organ disease, but long-term outcomes are hindered by immunosuppressive drug toxicity and immune-mediated injury. Developing therapies that promote immune tolerance while minimizing systemic immunosuppression is essential to improve graft health and survival. Regulatory T cell (Treg)-based therapies offer promise for inducing antigen-specific transplant tolerance, with recombinant IL-2 analogs emerging as potentially effective tools to selectively expand Tregs while minimizing adverse effects. mIL-2 therapy combined with co-stimulation blockade significantly prolonged allograft survival in an antigen-specific manner without adverse events. The immunomodulatory effects of mIL-2 persisted even after treatment cessation at 60 days after transplantation, with sustained graft function and preservation of histopathological integrity. Treatment with mIL-2 increased graft-infiltrating Tregs and decreased effector T cell activation. Donor-specific antibody production was reduced in mIL-2-treated recipients, which correlated with an enhanced follicular regulatory T-cell proportion. These findings were consistent across fully mismatched kidney and haplo-mismatched heart transplant models. Transcriptional profiling revealed the expansion of an ST2-positive, tissue-resident Treg population critical for long-term graft survival. Accordingly, the mIL-2-induced Treg suppression was abrogated in Treg-specific ST2 knockout graft recipients. We investigated the effects of a novel IL-2 mutein molecule (mIL-2) with enhanced receptor specificity and extended half-life in experimental models of solid organ transplantation. Following fully mismatched heart or kidney transplantation (BALB/c to C57BL/6), mIL-2 was administered biweekly with a single dose of CTLA-4 Ig co-stimulation blockade. Graft survival, immune cell phenotyping of graft-infiltrating cells and splenocytes, and donor-specific antibody production were assessed. Mechanistic insights into Treg function were obtained through functional suppression assays and RNA sequencing, while the role of ST2+ Tregs was studied using Treg-specific ST2 knockout mice.