CXCR6 is a G protein-coupled chemokine receptor that binds CXCL16 and functions as a critical mediator of tissue-resident immune cell accumulation and intercellular communication. Primary Function: CXCR6 serves as a homing receptor enabling CD8+ T cells, CD4+ T cells, ILC3s, and NKT cells to migrate to and establish residency in various tissues including brain, kidney, and liver 1234. Mechanism: CXCL16-CXCR6 interactions orchestrate chemotaxis and tissue retention of adaptive immune populations, with CXCR6 expression required for proper tissue-resident programming and clonal expansion 1. CXCR6+ cells display enhanced effector functions and cytotoxic capacity 5. Disease Relevance: CXCR6-mediated immune responses are protective in Alzheimer's disease, limiting β-amyloid deposition and cognitive decline through CD8+ T cell accumulation near plaque-associated microglia 1. Conversely, CXCR6+ ILC3 migration to kidneys promotes renal fibrosis via PD-1-dependent IL-17A production 2. In cancer, CXCR6+ CD8+ effector T cells are reduced in malignant prostate cancer 5, while sepsis-trained macrophages enhance antitumoral tissue-resident T cells through CXCR6 stimulation 6. Clinical Significance: CXCR6 represents a therapeutic target for modulating tissue-resident immunity in neuroinflammation, fibrotic diseases, and cancer immunotherapy.