Dirice, ErcumentKahraman, SevimDe Jesus, Dario F.El Ouaamari, AbdelfattahBasile, GiorgioBaker, Rocky L.Yigit, BurcuPiehowski, Paul D.Kim, Mi-JeongDwyer, Alexander J.Ng, RaymondSchuster, CorneliaVethe, HeidrunMartinov, TijanaIshikawa, YukiTeo, Adrian Kee KeongSmith, Richard D.Hu, JiangHaskins, KathrynSerwold, ThomasQian, Wei-JunFife, Brian T.Kissler, StephanKulkarni, Rohit2021-09-132019-05-06Dirice, Ercument, Sevim Kahraman, Dario F. De Jesus, Abdelfattah El Ouaamari, Giorgio Basile, Rocky L. Baker, Burcu Yigit et al. "Increased β-Cell Proliferation Before Immune Cell Invasion Prevents Progression of Type 1 Diabetes." Nature Metabolism 1, no. 5 (2019): 509-518. DOI: 10.1038/s42255-019-0061-82522-5812https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37369399Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total 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 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.en-USCell BiologyPhysiology (medical)Endocrinology, Diabetes and MetabolismInternal MedicineJournal Article2021-09-1310.1038/s42255-019-0061-8