Project

Understanding the role of Notch in Dendritic Cell biology

Duration
01 November 2021 → Ongoing
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Animal cell and molecular biology
    • Animal immunology
    • Single-cell data analysis
  • Medical and health sciences
    • Adaptive immunology
    • Innate immunity
Keywords
Dendritic Cell Maturation Notch Signaling Single Cell Sequencing
 
Project description

Notch signalling is known to control many developmental decision steps, also in immune cells. In dendritic cells (DCs), Notch signaling is typically associated with cDC2 biology. Genetic deficiency of Notch leads to elimination of ESAM+ cDC2s, a major subset of conventional DCs (cDCs) known to be important for efficient CD4 T cell priming in the spleen and orchestration of intestinal immunity to bacterial pathogens. We found that also cDC1s appear to be Notch-dependent, but in contrast to cDC2, this does not rely on canonical RBPJk-dependent signaling. On the contrary, Notch signaling in cDC1s appears required for full-blown activation of IRE1, an endoplasmic reticulum-based sensor of the unfolded protein response. Our lab previously found that IRE1 is highly active in cDC1s, and coordinates apoptotic cell engulfment and homeostatic maturation of cDC1s. Unexpectedly, activation of IRE1 partly depends on Notch signaling and loss of Notch in cDC1s phenocopies the loss of IRE1 in cDC1s with strong decrease of the late immature and mature cDC1 subsets. The aim of the current proposal is to investigate in fine detail the role of Notch in cDC1 biology and to assess the interplay between IRE1 and Notch signaling. This will help us to understand better what determines homeostatic DC maturation, a process essential for generating tolerance.