Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to shape mucosal lymphoid organ development

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Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to shape mucosal lymphoid organ development Summary During pregnancy, the fetal immune system develops in the uterine environment and relies on developmental programs to initiate the organogenesis of secondary lymphoid organs, including spleen and lymph node. This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. Lymphoid tissue inducer (LTi) cells are fetal innate lymphocytes that develop during intrauterine life and are deputed to coordinate the development of secondary lymphoid organs. People with mutations in genes controlling LTi have impaired lymph node formation and are predisposed towards mucocutaneus and systemic infection. While it is established that LTi function is critical to prepare the neonate with a functional scaffold to mount immune response, the mechanisms controlling anatomically distinct intestinal secondary organs organogenesis are unclear. We discovered that LTi that form intestinal the Peyer’s patches, gut-specific secondary lymphoid organs, require the coordinated action of two migratory G protein coupled receptor (GPCR) GPR183 (EBI2) and the chemokine receptor CCR6. However, the nature of the intestinal anatomical location attracting Peyer’s patches LTi and its effect on LTi differentiation is unknown. In this project we will test the hypothesis that intestinal LTi cells position themself in proximity of a differentiating “metabolic niche”: maternal diet provides the maturation cues, which is a cholesterol byproduct generated in the neonatal gut by resident stromal cells. This is a high risk and high reward project, designed to establish the critical importance of cholesterol metabolite production and sensing for fetal innate lymphocytes differentiation in the gut. The conceptual basis is unique as there are no precedents for the integration of GPCR- dependent maturation and metabolic switch in tissue resident innate lymphocytes during development. Moreover, no metabolic regulation intimately linked to maternal diet and mediated by fetal stromal cells that exploit same cues that will be generated during tissual adult function have been reported. This lack of precedent makes the project risky, but if proven to be accurate will fundamentally alter our understanding of mucosal innate lymphocytes sensing of environmental alterations and expand the functional domains of cholesterol and its byproducts in building and maintaining a healthy immune system, especially in newborns.