Soluble Factors Secreted by T Cells Promote β-Cell Proliferation
- Ercument Dirice1,
- Sevim Kahraman1,
- Wenyu Jiang2,
- Abdelfattah El Ouaamari1,
- Dario F. De Jesus1,
- Adrian K.K. Teo1,
- Jiang Hu1,
- Dan Kawamori1,
- Jason L. Gaglia3,
- Diane Mathis4 and
- Rohit N. Kulkarni1⇑
- 1Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA
- 2Department of Pathology, Brigham and Women’s Hospital, Boston, MA
- 3Section of Immunobiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA
- 4Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA
- Corresponding author: Rohit N. Kulkarni, .
S.K. and W.J. contributed equally to this study.
Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4+ and CD8+ T cells, but not B cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic CD4+ and CD8+ T cells with NOD.RAG1−/− islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0204/-/DC1.
- Received February 5, 2013.
- Accepted September 15, 2013.
- © 2014 by the American Diabetes Association.
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