Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells

Cell Rep. 2024 Nov 26;43(11):114994. doi: 10.1016/j.celrep.2024.114994. Epub 2024 Nov 18.

Abstract

Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation.

Keywords: CAR-Treg; CP: Stem cell research; autoimmunity; cell replacement therapy; chimeric antigen receptor; immune tolerance; regenerative medicine; regulatory T cell; stem cell-derived beta cell; transplantation; type 1 diabetes.

MeSH terms

  • Animals
  • ErbB Receptors / metabolism
  • Genetic Engineering* / methods
  • Humans
  • Insulin-Secreting Cells* / immunology
  • Insulin-Secreting Cells* / metabolism
  • Mice
  • Mice, Inbred NOD
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / metabolism
  • T-Lymphocytes, Regulatory* / immunology

Substances

  • Receptors, Chimeric Antigen
  • ErbB Receptors