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β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells., (© 2021. The Author(s).)

Background: The extended and clinically silent progression of Type 1 diabetes (T1D) creates a challenge for clinical interventions and for understanding the mechanisms that underlie its pathogenesis. Over the course of the development of Type 1 diabetes, studies in animal models and of human tissues have identified adaptive changes in β cells that may affect their immunogenicity and susceptibility to killing. Loss of β cells has traditionally been identified by impairment in function but environmental factors may affect these measurements., Scope of Review: In this review we will highlight features of β cell responses to cell death, particularly in the setting of inflammation, and focus on methods of detecting β cell death in vivo., Major Conclusions: We developed an assay to measure β cell death in vivo by detecting cell free DNA with epigenetic modifications of the INS gene that are found in β cells. This assay has robust technical performance and identifies killing in individuals at very high risk for disease, but its ability to identify β cell killing in at-risk relatives is limited by the short half-life of the cell free DNA and the need for repeated sampling over an extended course. We present results from the Diabetes Prevention Trial-1 using this assay. In addition, recent studies have identified cellular adaptations in some β cells that may avoid killing but impair metabolic function. Cells with these characteristics may aggravate the autoimmune response but also may represent a potentially recoverable source of functional β cells., (Copyright © 2019. Published by Elsevier GmbH.)