{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have established that GPR15 is a key lymphocyte-homing receptor that directs T cells—including FOXP3⁺ regulatory T cells and specialized γδ T cell subsets—from central lymphoid organs to peripheral epithelial sites such as the large intestine and skin. Its expression is regulated by immune effectors including gut microbiota and TGF‑β, thereby contributing to mucosal immune tolerance and effective immune surveillance. These findings underscore the receptor’s pivotal role in controlling the localization of immune cells in tissues prone to chronic inflammation and autoimmunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond lymphocyte trafficking, GPR15 functions as a signaling mediator in vascular and epithelial homeostasis. It serves as a receptor for ligands such as GPR15L and the thrombomodulin-derived TME5, which activate downstream cytoprotective pathways, including ERK and NO synthesis, and inhibit NF‑κB signaling to suppress pro‑inflammatory cytokine release. These mechanisms not only improve endothelial survival and angiogenesis but also offer protection in sepsis by mitigating coagulopathy and inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, genetic and epigenetic studies have linked altered GPR15 expression and function to a range of inflammatory and cardiovascular conditions. Aberrations in GPR15—whether via differential methylation, single nucleotide polymorphisms, or dysregulated ligand interactions—have been associated with enhanced risk of myocardial infarction, autoimmune arthritis, and cutaneous inflammatory disorders such as psoriasis and bullous pemphigoid-like epidermolysis bullosa acquisita. Experimental models further demonstrate that targeting GPR15 can modulate T cell responses in settings ranging from graft‑versus‑host disease to inflammatory bowel disease, suggesting that manipulation of this receptor–ligand axis may offer novel therapeutic avenues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sangwon V Kim, Wenkai V Xiang, Changsoo Kwak, et al. 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