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

18 Scopus citations

Abstract

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a nearly complete loss of β cells1. Restoration of insulin-producing β cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2–4. Here we report that enhancing β-cell mass early in life, in two models of female non-obese diabetic (NOD) mice, results in immunomodulation of T cells, reduced islet infiltration and lower β-cell apoptosis, which together protect them from developing T1D. The animals displayed altered β-cell antigens; islet transplantation studies showed prolonged graft survival in the NOD-liver-specific insulin receptor knockout (LIRKO) model. Adoptive transfer of splenocytes from NOD-LIRKO mice prevented development of diabetes in prediabetic NOD mice. A substantial increase in the splenic CD4+CD25+Foxp3+ regulatory T cell (Treg) population was observed to underlie the protected phenotype since Treg-cell depletion rendered NOD-LIRKO mice diabetic. An increase in Treg cells coupled with activation of transforming growth factor-β/SMAD family member 3 signalling pathway in pathogenic T cells favoured reduced ability to kill β cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, before islet infiltration by immune cells alters the identity of β cells, decreases pathological self-reactivity of effector T cells and increases Treg cells to prevent the 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.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

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