In vivo expansion of T reg cells with IL-2–mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression

TLDR

Foxp3‑expressing CD4+CD25+ regulatory T cells suppress other T cells, and adoptive transfer of large numbers of these cells can dampen immune responses and promote tolerance. This study develops an in vivo strategy to expand regulatory T cells with IL‑2–IL‑2 monoclonal antibody complexes and evaluates its capacity to prevent autoimmune disease and enable transplant acceptance. Mice receive injections of IL‑2 combined with a specific IL‑2 monoclonal antibody, which rapidly expands T reg cells in multiple organs. The treatment boosts T reg cell numbers over tenfold, sustains them for 1–2 weeks with enhanced suppressive activity, protects mice from experimental autoimmune encephalomyelitis, and induces durable tolerance of fully MHC‑incompatible pancreatic islet grafts without immunosuppression.

Abstract

Via a transcription factor, Foxp3, immunoregulatory CD4+CD25+ T cells (T reg cells) play an important role in suppressing the function of other T cells. Adoptively transferring high numbers of T reg cells can reduce the intensity of the immune response, thereby providing an attractive prospect for inducing tolerance. Extending our previous findings, we describe an in vivo approach for inducing rapid expansion of T reg cells by injecting mice with interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb). Injection of these IL-2–IL-2 mAb complexes for a short period of 3 d induces a marked (>10-fold) increase in T reg cell numbers in many organs, including the liver and gut as well as the spleen and lymph nodes, and a modest increase in the thymus. The expanded T reg cells survive for 1–2 wk and are highly activated and display superior suppressive function. Pretreating with the IL-2–IL-2 mAb complexes renders the mice resistant to induction of experimental autoimmune encephalomyelitis; combined with rapamycin, the complexes can also be used to treat ongoing disease. In addition, pretreating mice with the complexes induces tolerance to fully major histocompatibility complex–incompatible pancreatic islets in the absence of immunosuppression. Tolerance is robust and the majority of grafts are accepted indefinitely. The approach described for T reg cell expansion has clinical potential for treating autoimmune disease and promoting organ transplantation.