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

Jinxiu Rui, Songyan Deng, Ana Luisa Perdigoto, Gerald Ponath, Romy Kursawe, Nathan Lawlor, Tomokazu Sumida, Maya Levine-Ritterman, Michael L. Stitzel, David Pitt, Jun Lu and Kevan C. Herold ()
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Jinxiu Rui: Yale University
Songyan Deng: Yale University
Ana Luisa Perdigoto: Yale University
Gerald Ponath: Department of Neurology, Yale School of Medicine
Romy Kursawe: The Jackson Laboratory for Genomic Medicine
Nathan Lawlor: The Jackson Laboratory for Genomic Medicine
Tomokazu Sumida: Department of Neurology, Yale School of Medicine
Maya Levine-Ritterman: Department of Neurology, Yale School of Medicine
Michael L. Stitzel: The Jackson Laboratory for Genomic Medicine
David Pitt: Department of Neurology, Yale School of Medicine
Jun Lu: Yale University
Kevan C. Herold: Yale University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25367-z

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