Here, Dart et al. describe a role for butyrophilin-like (BTNL) molecules in mediating the selection of tissue-protective γδ T cells in the human colon. Previously, this pathway had only been observed in mice. The authors used colonic biopsies from individuals with inflammatory bowel disease (IBD) and non-IBD controls to comprehensively characterize the colonic γδ T cell compartment. They found that human colonic γδ T cells are diverse but contain a distinct population that co-expresses a Vγ4 Vδ1 T cell receptor (TCR) and the epithelial-interacting integrin CD103. This Vγ4+CD103+ subset showed TCR engagement with BTNL3–BTNL8 heteromers (which have been shown to be expressed by colonic epithelial cells) and was significantly reduced in individuals with a germline mutation (BTNL8*3) that cause BTNL3–BTNL8 hypomorphism. Individuals with IBD showed reduced frequencies and dysregulation of Vγ4+CD103+ cells in inflamed biopsy regions, and renormalization of the Vγ4+CD103+ cell subset was associated with better remission rates after disease treatment. Notably, BTNL8*3 homozygosity was not associated with increased IBD incidence; however, individuals with Crohn’s disease who carried BTNL8*3 developed a more severe penetrative form of the disease. These findings suggest that BTNL-selected γδ T cells contribute to tissue repair in the human gut and have a disease-modifying effect in IBD.