Abstract
SummaryGroup 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis.
Highlights
We report that ILC3s sensed oxysterols through G-protein-coupled receptor 183 (GPR183), which was highly expressed by lymphoid tissue inducer (LTi)-like ILC3s. 7a,25OHC-synthesizing enzymes were produced by fibroblastic stromal cells found in intestinal lymphoid structures, and the GPR183 ligand 7a,25-OHC acted as a chemoattractant for ILC3s
LTi-like ILC3s Highly Express GPR183 and Migrate toward 7a,25-OHC It is unknown whether Innate lymphoid cells (ILCs) express GPR183 and whether the GPR183 ligand 7a,25-OHC regulates ILC function
Splenic LTi-like ILC3s showed a typical bell-shaped chemotactic response to 7a,25-OHC (Figure 1D), demonstrating that GPR183 is functional in ILC3s
Summary
Innate lymphoid cells (ILCs) are recently described immune cells of lymphoid origin and include cytotoxic natural killer (NK) cells and interleukin-7 receptor alpha ( known as CD127)+ subsets, which, similar to T helper (Th) lymphocytes, can be distinguished on the basis of signature transcription factors and effector cytokines: (1) ILC1s require the transcription factor T-BET and produce interferon-g. (2) ILC2s express the transcription factor GATA3 and produce the type 2 cytokines interleukin 5 (IL-5) and IL-13. (3) ILC3s are dependent on the transcription factor RAR-related orphan receptor gamma t (RORgt) and have the ability to produce IL-17 and/or IL-22.ILC3s are enriched in the intestine, where they maintain healthy tissue function by orchestrating lymphoid-organ development, containment of commensal bacteria, tissue repair, host defense, and regulation of adaptive immunity (Artis and Spits, 2015; Diefenbach et al, 2014; Eberl et al, 2015; McKenzie et al, 2014; Serafini et al, 2015; Sonnenberg and Artis, 2015). ILC3s can be divided into two main populations with distinct ontogeny, transcriptional programs, and localization within the gut: (1) C-C motif chemokine receptor 6 (CCR6)À ILC3s coexpressing RORgt and T-BET are mainly found scattered throughout the lamina propria (Luci et al, 2009; Sanos et al, 2009; Satoh-Takayama et al, 2008). (2) CCR6+NKp46À fetal lymphoid tissue inducer (LTi) and adult LTi-like cells expressing c-KIT ( known as CD117) seed the gut during fetal development, develop along a pathway distinct from that of other ILCs, and promote lymphoid tissue development (Eberl and Littman, 2004; Eberl et al, 2004; Mebius et al, 1997; Sawa et al, 2010).
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