Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γδ T Cell Compartments

Many body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved. Here, Btnl1 expressed by murine enterocytes is shown to shape the local TCR-Vγ7+ γδ compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCRαβ+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal Vγ7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic Vγ4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments. [Display omitted] •Gut epithelial butyrophilin-like 1 (Btnl1) shapes the local γδ T cell compartment•Other organ-specific epithelial Btnl genes select cognate γδ cells in other sites•Btnl heteromers can specifically activate γδ T cells with cognate T cell receptors•Human BTNL genes reveal a conserved biology of epithelial T cell regulation Epithelial cells provide signals that instruct the development and function of their local γδ T cell compartments so that these immune cells can support the non-immune functions of the different barrier tissues.