BTNL8 (butyrophilin-like 8) is a membrane-associated protein that plays a critical role in intestinal immune homeostasis through regulation of γδ T cells. The protein functions as part of a heterodimeric complex with BTNL3, expressed on intestinal epithelial cells, that selects and maintains tissue-resident Vγ4+ γδ intraepithelial lymphocytes (IELs) 1. This BTNL8-BTNL3 heterodimer specifically engages Vγ4+ T cell receptors on γδ T cells, promoting their selection and regulatory function in gut homeostasis 2. Loss or dysfunction of BTNL8 leads to depletion of protective CD103+Vγ4+ γδ IELs, which is associated with increased susceptibility to inflammatory bowel disease and compromised intestinal barrier function 13. Rare deleterious variants in BTNL8 have been identified as genetic risk factors for penetrating Crohn's disease and multisystem inflammatory syndrome in children (MIS-C), with impaired BTNL8 function linked to altered intestinal permeability 2. The protein may also be expressed by regulatory T cells induced by certain macrophage populations, suggesting additional immunoregulatory roles beyond epithelial expression 4. BTNL8 represents an evolutionarily conserved mechanism for maintaining gut immune balance through specialized γδ T cell regulation.