Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes

Ercument Dirice, Sevim Kahraman, Dario F. De Jesus, Abdelfattah El Ouaamari, Giorgio Basile, Rocky L. Baker, Burcu Yigit, Paul D. Piehowski, Mi Jeong Kim, Alexander J. Dwyer, Raymond W.S. Ng, Cornelia Schuster, Heidrun Vethe, Tijana Martinov, Yuki Ishikawa, Adrian Kee Keong Teo, Richard D. Smith, Jiang Hu, Kathryn Haskins, Thomas SerwoldWei Jun Qian, Brian T. Fife, Stephan Kissler, Rohit N. Kulkarni

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells 1. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D 2-4. Here we report that enhancing β-cell mass early in life, in two models of female NOD mice, results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. The animals displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival in the NOD-LIRKO model. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented development of diabetes in pre-diabetic NOD mice. A significant increase in the splenic CD4 +CD25 +FoxP3 + regulatory T-cell (Treg) population was observed to underlie the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

Original languageEnglish (US)
Pages (from-to)509-518
Number of pages10
JournalNature Metabolism
Volume1
Issue number5
DOIs
StatePublished - May 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

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