Db130204 188..202

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 b-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of b-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 b-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-1a, and RANTES) that together enhanced b-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance b-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.