Detailed project information

Understanding the molecular mechanisms that shape an effective immune response is a fundamental question in biology. Antigen-presenting dendritic cells (DCs) are key regulators of the immune system: in peripheral tissues, they recognize foreign antigens, subsequently migrate towards the lymph nodes to activate naïve T cells and initiate an immune response.

Lipid mediators, such as prostaglandins, have been shown to be involved in several DC functions. For DCs, Prostaglandin E2 (PGE2) is a key modulator of cell migration and cytokine production. It exerts its action through the co-expressed non-redundant G-protein coupled receptor (GPCR) subtypes EP2 and EP4, both localized at the plasma membrane. These receptors couple to the stimulating G-protein Gs and activate adenylyl cyclase resulting in the production of cyclic AMP. In addition, EP4 seems to couple to the inhibitory Gi thereby activating PI3-kinase. The coupling of EP4 to Gs or Gi suggests that cross-talk between EP2 and EP4 might occur. However, how this cross-talk is regulated at the molecular level is unknown.

Recent work from myself and others has demonstrated that the function of membrane receptors can be regulated by changes of their nanoscale spatio-temporal segregation. Moreover, receptor nanoscale distribution can promote interactions with other membrane compartments, such as lipid rafts or tetraspanins, that further modulate receptor activities.

In this proposal, I will address the underlying hypothesis that the plasma membrane nanoenvironment in which EP2/EP4 engages a set of effector proteins orchestrates the ultimate signal output. The overall aim is to set up a novel research line integrating molecular, immunological and biophysical disciplines to unravel the nanoscale membrane organization, dynamics and cross-talk of the PGE2 receptors on DCs. I expect that this project will provide an important conceptual advance in our understanding of PGE2 signaling and possibly in the GPCR field.