In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities

Front Endocrinol (Lausanne). 2023 Jan 16:13:1076683. doi: 10.3389/fendo.2022.1076683. eCollection 2022.

Abstract

Type 1 diabetes (T1D) is a disease of both autoimmunity and β-cells. The β-cells play an active role in their own demise by mounting defense mechanisms that are insufficient at best, and that can become even deleterious in the long term. This complex crosstalk is important to understanding the physiological defense mechanisms at play in healthy conditions, their alterations in the T1D setting, and therapeutic agents that may boost such mechanisms. Robust protocols to develop stem-cell-derived islets (SC-islets) from human pluripotent stem cells (hPSCs), and islet-reactive cytotoxic CD8+ T-cells from peripheral blood mononuclear cells offer unprecedented opportunities to study this crosstalk. Challenges to develop in vitro β-cell killing models include the cluster morphology of SC-islets, the relatively weak cytotoxicity of most autoimmune T-cells and the variable behavior of in vitro expanded CD8+ T-cells. These challenges may however be highly rewarding in light of the opportunities offered by such models. Herein, we discuss these opportunities including: the β-cell/immune crosstalk in an islet microenvironment; the features that make β-cells more sensitive to autoimmunity; therapeutic agents that may modulate β-cell vulnerability; and the possibility to perform analyses in an autologous setting, i.e., by generating T-cell effectors and SC-islets from the same donor.

Keywords: T-cells; beta-cells; cytotoxicity; human leukocyte antigen (HLA); iPSCs; stem-cell-derived islets; type 1 diabetes.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes
  • Cell Death
  • Diabetes Mellitus, Type 1* / therapy
  • Humans
  • Leukocytes, Mononuclear
  • Pluripotent Stem Cells*

Grants and funding

The Laboratory of T.O. acknowledges the support from the Academy of Finland (MetaStem Center of Excellence grant 312437), the Novo Nordisk Foundation and the Sigrid Jusélius Foundation. The Laboratory of R.M. acknowledges the support of grants from The Leona M. and Harry B. Helmsley Charitable Trust (1901-03689), Agence Nationale de la Recherche (ANR-19-CE15-0014-01) and Fondation pour la Recherche Medicale (EQU20193007831). Both Laboratories acknowledge the support of the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 (INNODIA) and 945268 (INNODIA HARVEST), supported by the European Union’s Horizon 2020 research and innovation programme. These joint undertakings receive support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA), JDRF, and the Leona M. and Harry B. Helmsley Charitable Trust.