Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments

Butyrophilin-like (Btnl) genes are emerging as major epithelial determinants of tissueassociated gamma delta T cell compartments. Thus, the development of signature, murine TCR gamma delta(+) intraepithelial lymphocytes (IEL) in gut and skin depends on Btnl family members, Btnl1 and Skint1, respectively. In seeking mechanisms underlying these profound effects, we now show that normal gut and skin gamma delta IEL development additionally requires Btnl6 and Skint2, respectively, and furthermore that different Btnl heteromers can seemingly shape different intestinal gamma delta(+) IEL repertoires. This formal genetic evidence for the importance of Btnl heteromers also applied to the steady-state, since sustained Btnl expression is required to maintain the signature TCR.V gamma 7(+) IEL phenotype, including specific responsiveness to Btnl proteins. In sum, Btnl proteins are required to select and to maintain the phenotypes of tissue-protective gamma delta IEL compartments, with combinatorially diverse heteromers having differential impacts on different IEL subsets.