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 T1D2,3,4. 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.
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Transcriptomics data have been deposited with the National Center for Biotechnology Information Gene Expression Omnibus under accession code GSE128315 for the murine microarray analysis. The mass spectrometry proteomics data reported in this paper have been deposited with ProteomeXchange (accession code: PXD013100) and MassIVE (accession code: MSV000083576). Further information on statistical parameters, software and study design can be found in the Nature Research Reporting Summary. The data that support the plots within this article and other findings of this study are available from the corresponding author upon reasonable request.
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We thank the late A. Rossini for discussions during the early stages of this project. We thank C. R. Kahn for discussions and sharing the LIRKO model. We thank D. Mathis, J. Gaglia, C. Mathews, G. C. Weir and F. Bosch for discussions regarding various aspects of the studies and the NOD-RAG1−/− mice. We thank H. Davidson for kindly providing the anti-ZnT8 (C-term) and anti-Phogrin (C-term) sera and F. M. Jarvis for assistance with the E2 assays. We thank C. Cahill for assistance with confocal microscopy, L. Kannan, Z. Fu and G. Sankaranarayanan for the ELISAs, J. Hollister-Lock for assistance with the mouse islet isolations and J. Dreyfuss and H. Pan for assistance in the data analyses. The proteomics experiments were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the United States Department of Energy (DOE) and located at the Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under contract no. DE-AC05-76RL0 1830. E.D. was supported by a Senior Juvenile Diabetes Research Foundation Fellowship (no. JDRF-3-APF-2014-220-A-N). This project was funded by JDRF grant no. 1-SRA-355-Q-R (to R.N.K.) and in part from National Institutes of Health (NIH) grant no. RO1 067536 (to R.N.K.), NIH grant no. RO1 103215 (to R.N.K.) and grant no. UC4 DK104167 (to W.J.Q. and R.N.K.). R.N.K. acknowledges support from the Margaret A. Congleton Chair, Joslin Diabetes and Endocrinology Research Center (grant no. P30 386836). R.D.S. was supported by grant no. P41 GM103493. B.T.F. was supported by grant no. R01 AI106791. R.L.B. was supported by grant no. R21 AI133059 and an ADA Junior Faculty Award no. 1-15-JF-04. K.H. was supported by grant no. R01 DK081166.
Supplementary Figs. 1–12
Selected pathways upregulated in 8 week CD8+ T cells.
Selected pathways upregulated in 12 week CD8+ T cells.
Selected pathways downregulated in 12 week CD8+ T cells.
Selected pathways upregulated in 8 week Treg cells.
Selected pathways downregulated in 12 week Treg cells.
Selected pathways upregulated in 12 week Treg cells.
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Nature Metabolism (2019)