GREMLIN · The role of GPCRs and homing molecules in the control and regionalization of mucosal immunity.

Mucosal immunity is essential to preserve homeostasis and for pathogen control within the gut and the airways. The emerging dogma of immune regionalization has opened to new questions about which elements drive cell adaptation to different niches, and how this can be targeted to cure diseases. The intestine and the airways are functionally diverse along their length, and disorders can differentially impact on different mucosal tissue regions. Mucosa-associated lymphoid tissues (MALTs) are located along the intestine and the airways to drain selective tissue segments and support protective immunity. Whether MALTs located in different tissue areas show immune regionalization remains poorly understood. Also, little is known about which molecules control such immune diversity. G protein-coupled receptors (GPCRs) are surface proteins important for cell migration and compartmentalization in lymphoid tissues, but their role in immune regionalization is not clear. We propose to apply a combination of imaging, flow cytometry, spatial gene editing and sequencing techniques to study the role of GPCRs in immune regionalization of MALTs, at steady state and in disease. In the intestine, we will phenotypically and functionally profile immune cells and GPCRs expression within Peyer's patches (PPs) from different gut regions, in physiology or in the context of inflammation and obesity. Similarly, we will analyze immune regionalization of bronchus-associated lymphoid tissues and nose-associated lymphoid tissues within the airways, at steady state or upon infections. Finally, we will characterize the role of a candidate GPCR, GPR35, in the induction of intestinal and respiratory immunity. Our preliminary data show that GPR35 shapes cell recruitment to inflamed airways and influences cell positioning within PPs. By applying the above-mentioned approaches and dedicated mouse models, we will study how GPR35 regulates mucosal immunity and if it represents an attractive clinical target.