Notch ligands jagged-1 and delta-like 4 differentially regulate effector and memory CD4+ T cell expansion during Th2 inflammation (90.21)

Abstract

Abstract Notch ligand jagged-1 is constitutively expressed on dendritic cells, whereas Notch ligand delta-4 is induced by TLRs. It has been hypothesized that jagged-1 is important for directing Th2 responses, while delta-4 plays a role in suppressing Th2 cytokines. To determine the role of jagged-1 in Th2 responses, we administered anti jagged-1 antibody to mice during the formation of S. Mansoni induced lung granulomas in sensitized mice. Our results showed a higher amount of IL-4 in lymph nodes and an increase in the CD4 effector cell population (CD44hi CD62lo). To determine if this increase in effector cells arose from an increase in effector or memory cell proliferation, we transferred either memory (CD44hiCD62L+CCR7+) or effector cells into congenic S. Mansoni sensitized mice, induced granuloma formation, and administered anti jagged-1 antibody. Our results indicate that effector cell expansion is significantly reduced in the absence of jagged-1, and central memory cell expansion is increased under the same conditions. This occurred in an antigen specific manner and was true regardless of if the inflammation was Th1 or Th2 in nature. Additional experiments revealed that delta-4 had the opposite effect as jagged-1. A blockade of delta-4 during Th2 inflammation caused an increase in effector cell proliferation, thus defining opposing roles for these two molecules in directing memory and effector cell expansion. Funding provided by NIH: N0105330-397736