BTNL3 is an immunoregulatory protein that functions as a direct ligand for γδ T cell receptors, particularly those expressing Vγ4. 1 It operates through heteromeric interactions with BTNL8 to regulate tissue-resident γδ T cell selection and maintenance in the intestinal epithelium. 2 BTNL3-BTNL8 heterodimers mediate non-clonotypic, superantigen-like TCR interactions through germline-encoded Vγ4 regions, distinct from conventional CDR3-dependent binding. 1 In disease contexts, BTNL3 dysregulation contributes to multiple pathologies. Germline BTNL3/BTNL8 hypomorphism is a risk factor for penetrating Crohn's disease, and reduced BTNL3 expression correlates with diminished protective CD103+Vγ4+ γδ T cells in inflammatory bowel disease. 3 In ulcerative colitis, decreased epithelial BTNL3 expression associates with loss of protective γδ intraepithelial lymphocytes and expansion of pathogenic subsets. 4 Chr5 inflammation in celiac disease depletes BTNL3/BTNL8-specific Vγ4+/Vδ1+ cells permanently. 5 BTNL3 frameshift mutations occur in microsatellite instability-high colorectal cancers, with expression loss in ~30% of cases, suggesting immune evasion mechanisms. 6 Additionally, BTNL3/BTNL8 variants impair γδ T cell regulation in multiple sclerosis pathogenesis. 78