Soluble Factors Secreted by T Cells Promote β-Cell Proliferation

  1. Rohit N. Kulkarni1
  1. 1Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA
  2. 2Department of Pathology, Brigham and Women’s Hospital, Boston, MA
  3. 3Section of Immunobiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA
  4. 4Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA
  1. Corresponding author: Rohit N. Kulkarni, rohit.kulkarni{at}joslin.harvard.edu.
  1. S.K. and W.J. contributed equally to this study.

Abstract

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.

Footnotes

  • Received February 5, 2013.
  • Accepted September 15, 2013.

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  1. Diabetes vol. 63 no. 1 188-202
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