Butyrophilin-like 2 regulates site-specific adaptations of intestinal γδ intraepithelial lymphocytes

Abstract Tissue-resident γδ intraepithelial lymphocytes (IELs) orchestrate innate and adaptive immune responses to maintain intestinal epithelial barrier integrity. Epithelia-specific butyrophilin-like (Btnl) molecules induce perinatal development of distinct Vγ TCR + IELs, however, the mechanisms that control IEL maintenance within discrete segments are unclear. Here, we show Btnl2 suppressed homeostatic proliferation IELs preferentially in ileum. High throughput transcriptomic characterization site-specific -KO reveals regulated antimicrobial response module ileal IELs. deficiency shapes specificities TCRγ/δ repertoire diversity During DSS-induced colitis, mice exhibit increased inflammation delayed mucosal repair colon. Collectively, these data suggest fine-tunes frequencies inflammatory cues. Hence, Btnl-mediated targeting may help dissect their immunological functions diseases with segment-specific manifestations.