Tet2 Controls Beta cells Responses to Inflammation in Type 1 Diabetes

Rui, J.; Deng, S.; Ponath, G.; Kursawe, R.; Lawlor, N.; Sumida, T.; Levine-Ritterman, M.; Perdigoto, A. L.; Stitzel, M. L.; Pitt, D. L.; Lu, J.; Herold, K. C.

doi:10.1101/2020.09.01.278028

bioRxiv · 10.1101/2020.09.01.278028

Tet2 Controls Beta cells Responses to Inflammation in Type 1 Diabetes

Rui, J.·Deng, S.·Ponath, G.·Kursawe, R.·Lawlor, N.·Sumida, T.·Levine-Ritterman, M.·Perdigoto, A. L.·Stitzel, M. L.·Pitt, D. L.·Lu, J.·Herold, K. C.

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Abstract

{beta} cells may participate and contribute to their own demise during Type 1 diabetes (T1D). We identified a novel role of Tet2 in regulating immune killing of {beta} cells. 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 {beta} cells show reduced expression of inflammatory genes, associated with closed transcription factor binding sites. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells. We conclude that Tet2 regulates pathologic interactions between {beta} cells and immune cells and controls intrinsic protective pathways. Modulating TET2 may enable survival of {beta} cells or their replacements in the setting of pathologic immune cells.

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Rui, J., Deng, S., Ponath, G., Kursawe, R., Lawlor, N., Sumida, T., Levine-Ritterman, M., Perdigoto, A. L., Stitzel, M. L., Pitt, D. L., Lu, J., Herold, K. C.. 2020-09-02. Tet2 Controls Beta cells Responses to Inflammation in Type 1 Diabetes. https://doi.org/10.1101/2020.09.01.278028

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