Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition

Front Endocrinol (Lausanne). 2021 Jul 9:12:707881. doi: 10.3389/fendo.2021.707881. eCollection 2021.

Abstract

Type 1 diabetes results from an autoimmune attack directed at pancreatic beta cells predominantly mediated by T cells. Transplantation of stem cell derived beta-like cells (sBC) have been shown to rescue diabetes in preclinical animal models. However, how sBC will respond to an inflammatory environment with diabetogenic T cells in a strict human setting has not been determined. This is due to the lack of model systems that closely recapitulates human T1D. Here, we present a reliable in vitro assay to measure autologous CD8 T cell stimulation against sBC in a human setting. Our data shows that upon pro-inflammatory cytokine exposure, sBC upregulate Human Leukocyte Antigen (HLA) class I molecules which allows for their recognition by diabetogenic CD8 T cells. To protect sBC from this immune recognition, we utilized genome engineering to delete surface expression of HLA class I molecules and to integrate an inducible overexpression system for the immune checkpoint inhibitor Programmed Death Ligand 1 (PD-L1). Genetically engineered sBC that lack HLA surface expression or overexpress PD-L1 showed reduced stimulation of diabetogenic CD8 T cells when compared to unmodified cells. Here, we present evidence that manipulation of HLA class I and PD-L1 receptors on sBC can provide protection from diabetes-specific immune recognition in a human setting.

Keywords: PD-L1 and HLA class I; autoimmune type 1 diabetes; beta cell replacement therapy; beta- immune cell interface; direct differentiation; genome engineering; human pluripotent stem cells; stem cell derived pancreatic insulin producing beta-like cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Diabetes Mellitus / immunology*
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Stem Cells / immunology*
  • Stem Cells / metabolism
  • Stem Cells / pathology

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Histocompatibility Antigens Class I