Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Deltalike 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and -4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult -cells display improved glucose tolerance, increased glucosestimulated insulin secretion and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that NOTCH ligands play specific roles in the adult pancreas and highlight a novel function of the Delta-Notch pathway in β-cell insulin secretion.

The immune system in sepsis is impaired as seen by reduced numbers and function of immune cells and impaired antigen‐specific antibody responses. We studied T cell function in septic mice using cecal ligation and puncture (CLP) as a clinically relevant mouse model for sepsis. The proliferative response of CD4+ and CD8+ T cells was suppressed in septic mice. Adoptive transfer experiments demonstrated that the T cells were not intrinsically altered by CLP. Instead, the septic host environment was responsible for this T cell suppression. While CLP‐induced suppression was dependent on TNF activity, neither the activation of TNF receptors type 1 nor TNF receptor type 2 alone was sufficient to generate sepsis‐induced suppression showing that the two TNF receptors can substitute each other. Specific depletion of regulatory T (Treg) cells improved the impaired T cell proliferation in septic recipients demonstrating participation of Treg in sepsis‐induced suppression. In summary, sepsis leads to TNF‐dependent suppression of T cell proliferation in vivo involving induction of Treg cells.