Previous studies have established an essential function for

Previous studies have established an essential function for GPR183 and its ligand 7α,25-OHC in lymphoid organs and humoral immunity (Gatto et al., 2009, Gatto et al., 2013, Hannedouche et al., 2011, Li et al., 2016, Liu et al., 2011, Pereira et al., 2009, Yi and Cyster, 2013, Yi et al., 2012). We have now demonstrated a role for GPR183 and oxysterols in lymphoid tissue development in the large intestine. Thus, our study has established a broader function of the oxysterol-GPR183-ligand-receptor system by linking GPR183-mediated cell positioning to tissue reorganization during steady-state homeostasis and inflammation. Whereas the signals regulating the formation of SILTs in the small intestine are well known, those in the colon have remained poorly understood. As in the small intestine, LTi-like ILC3s and LTα1β2 are required for colonic lymphoid organogenesis. However, the microbiota and receptor activator of NF-κB ligand (RANKL)-RANK, CXCL13-CXCR5, and CCL20-CCR6 are required for ILF development only in the small intestine (Buettner and Lochner, 2016, Randall and Mebius, 2014). Accordingly, we have described a colon-specific pathway governing the postnatal development of lymphoid tissues. One question relates to our finding that oxysterol-GPR183 signaling is critical for CP and ILF formation in the colon but dispensable in the small intestine. GPR183 and its ligand were expressed in both the small and large intestines. Moreover, 7α,25-OHC was required for ILC3 migration to CPs not only in the colon but also in the small intestine. Despite this, lymphoid tissue development in the small intestine was normal in mice lacking 7α,25-OHC. Together, our observations indicate that, as a compensatory response, XCT790 receptor form lymphoid follicles when ILC3s are unable to migrate to CPs as a result of a lack of GPR183 ligand. This notion is supported by previous studies demonstrating lymphoid-tissue-inducing activity of B cells and compensatory lymphoid tissue formation when ILC3s are absent or when LTβR signaling is blocked in utero (Buettner and Lochner, 2016). This process must be driven by factors that operate specifically in the small intestine, because we observed compensatory B cell cluster formation only in the small intestine, but not in the colon. Such factors are the microbiota, CCL20, and CXCL13, which are all dispensable for ILC3 recruitment and CP formation but essential for B cell recruitment and ILF formation in the small intestine (Buettner and Lochner, 2016). In conclusion, we favor the concept that the 7α,25-OHC-GPR183 pathway is active, but not absolutely required for lymphoid tissue formation, in the small intestine because other redundant factors are sufficient in the absence of GPR183 ligand. Recent studies support the concept that dietary metabolites, such as retinoids and AHR ligands, regulate ILC3 function. These metabolites act through intracellular nuclear receptors that function as transcription factors, thereby controlling ILC activity through the stimulation of specific transcriptional programs. We have now shown that endogenous metabolites derived from cholesterol control ILC3 function by binding to a cell-surface receptor (GPR183). Previously, it was found that 7α,27-OHC and 7β,27-OHC can act as endogenous RORγt agonists and thereby regulate Th17 differentiation (Soroosh et al., 2014). More recently, it was reported that CYP51-dependent intermediates in cholesterol biosynthesis are ligands for RORγt (Santori et al., 2015). Chemically distinct cholesterol metabolites can therefore be sensed intracellularly through RORγt (modulating cell differentiation) and extracellularly through GPR183 (controlling ILC3 migration).