Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes

beta 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 beta cells with inflammation but its expression is reduced in surviving beta cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate beta 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 beta cells show reduced expression of IFN gamma-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between beta cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in beta cells may reduce activating pathologic immune cells and killing of beta cells. There are dynamic interactions between immune cells and beta cells that lead to beta cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of beta cells in mice.

Automated summary

In Type 1 diabetes, beta cells may contribute to their own demise through the expression of Tet2, which regulates immune killing. Tet2-KO mice receiving WT bone marrow transplants develop insulitis but not diabetes, and Tet2 deletion protects beta cells by reducing expression of inflammatory genes needed to activate diabetogenic T cells. These findings suggest that Tet2 plays a crucial role in controlling damaging inflammatory pathways and interactions between beta cells and immune cells in autoimmune diabetes.