Soluble Factors Secreted by T Cells Promote β-Cell Proliferation

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.

The impact of anti-inflammatory cytokines on the pancreatic β-cell

“…Healthy human pancreatic islets were shown to express IL-10Rb at the mRNA level and further investigation by IHC revealed that this receptor subunit is present in both a-and b-cells, but absent from d-cells. 37 We have studied the expression of IL-10 receptor subunits in INS-1E cells and in isolated human islets by RT-PCR (Fig. 2) and have confirmed that IL-10Ra and -b are each expressed in human islets, although we were unable to detect IL-10Ra in INS-1E cells.…”

“…In these experiments, adoptive transfer of various T-cell populations led to an increase in b-cell proliferation through the secretion of soluble factors including IL-10. 37 Finally, anti-inflammatory molecules are reported to inhibit changes in the microvasculature associated with diabetes progression in the NOD mouse. 24 Taken together, it can be concluded from such evidence that, while pro-inflammatory factors are likely to be of primary importance in diabetes pathogenesis, any simultaneous reduction in the level of anti-inflammatory cytokines may serve to exacerbate their negative effects on islet cell viability and function.…”

T cells expressing chimeric antigen receptor promote immune tolerance

“…Multiple cellular mechanisms could account for an improvement in this signal, including the possibility raised by others that the presence of a Treg-induced cytokine environment could promote both engraftment and islet β cell proliferation (42,43). If so, this opens the exciting possibility that CAR Tregs could provide multiple signals to improve islet transplantation outcomes.…”

Role of regeneration in tissue repairing and therapies

“…In addition, inherently suitable scaffolds and matrices are to be generated for tissue engineering, stem cell propagation and differentiation. Now it become possible to use bio-engineered organs and tissues, though its replacement is very difficult to proceed and practiced for disables [180]. Contrary to this, meniscus regeneration remain unsolved and a clinical challenge despite the wide acceptance of the degenerative consequences of meniscectomy and no surgical procedure has succeeded to date in regenerating a functional and long-lasting meniscal fibrocartilage.…”