Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes

TLDR

Adoptive Treg therapy shows promise for graft‑versus‑host disease, but antigen‑specific Tregs are limited in autoimmune settings, and CAR technology offers a means to redirect T cells toward specific antigens. The authors engineered insulin‑specific CARs and transduced Foxp3 into effector T cells to convert them into insulin‑specific regulatory T cells in an off‑the‑shelf, translationally applicable approach. The resulting insulin‑specific CAR Tregs were functionally stable, suppressive, and long‑lived in vivo, demonstrating proof of concept for antigen‑specific Treg conversion.

Abstract

Adoptive immunotherapy with ex vivo expanded, polyspecific regulatory T cells (Tregs) is a promising treatment for graft-versus-host disease. Animal transplantation models used by us and others have demonstrated that the adoptive transfer of allospecific Tregs offers greater protection from graft rejection than that of polyclonal Tregs. This finding is in contrast to those of autoimmune models, where adoptive transfer of polyspecific Tregs had very limited effects, while antigen-specific Tregs were promising. However, antigen-specific Tregs in autoimmunity cannot be isolated in sufficient numbers. Chimeric antigen receptors (CARs) can modify T cells and redirect their specificity toward needed antigens and are currently clinically used in leukemia patients. A major benefit of CAR technology is its “off-the-shelf” usability in a translational setting in contrast to major histocompatibility complex (MHC)-restricted T cell receptors. We used CAR technology to redirect T cell specificity toward insulin and redirect T effector cells (Teffs) to Tregs by Foxp3 transduction. Our data demonstrate that our converted, insulin-specific CAR Tregs (cTregs) were functional stable, suppressive and long-lived in vivo. This is a proof of concept for both redirection of T cell specificity and conversion of Teffs to cTregs.