Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease

Murine intraepithelial γδ T cells include unique, tissue-protective cells selected by epithelial Butyrophilin-like (BTNL) heteromers. Interrogating whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset co-expressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease (IBD), whereas on-treatment CD103(+)γδ T cell restoration was associated with sustained IBD remission. Moreover, CD103(+)Vγ4(+)cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn’s disease. Thus, BTNL-dependent selection and/or maintenance of unique, tissue-intrinsic γδ T cells appears as an evolutionarily conserved axis limiting progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.