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

Type 1 diabetes (T1D) is a disease of both autoimmunity and beta-cells. The beta-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 beta-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 beta-cell/immune crosstalk in an islet microenvironment; the features that make beta-cells more sensitive to autoimmunity; therapeutic agents that may modulate beta-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.Peer reviewe

The type 1 diabetes gene TYK2 regulates beta-cell development and its responses to interferon-alpha

The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates beta-cell development, but at the same time TYK2 inhibition in the islets prevents IFN alpha responses and enhances their survival against CD8(+) T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression. Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic beta-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Iota interferon (IFN-Iota) mediated intracellular signalling. To study the role of TYK2 in beta-cell development and response to IFN alpha, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromises the emergence of endocrine precursors by regulating KRAS expression, while mature stem cell-islets (SC-islets) function is not affected. In the SC-islets, the loss or inhibition of TYK2 prevents IFN alpha-induced antigen processing and presentation, including MHC Class Iota and Class Iota Iota expression, enhancing their survival against CD8(+) T-cell cytotoxicity. These results identify an unsuspected role for TYK2 in beta-cell development and support TYK2 inhibition in adult beta-cells as a potent therapeutic target to halt T1D progression.Peer reviewe