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

• Published in: Nature communications 2020-07, Vol.11 (1), p.3769-16, Article 3769
• Main Authors: Jandke, Anett, Melandri, Daisy, Monin, Leticia, Ushakov, Dmitry S., Laing, Adam G., Vantourout, Pierre, East, Philip, Nitta, Takeshi, Narita, Tomoya, Takayanagi, Hiroshi, Feederle, Regina, Hayday, Adrian
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/31; 14/63; 38/77; 38/88; 38/90; 631/250; 631/250/1619/554/2509; 631/250/2152/1566; 631/250/347; 64/60; 82/1; Animals; Butyrophilin; Butyrophilins - genetics; Butyrophilins - immunology; Butyrophilins - metabolism; Combinatorial analysis; Compartments; Digestive system; Gastrointestinal tract; Gene Expression Profiling; Genes; Humanities and Social Sciences; Immunity, Cellular; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Intestine; Intraepithelial Lymphocytes - immunology; Intraepithelial Lymphocytes - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; multidisciplinary; Phenotypes; Proteins; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Science; Science (multidisciplinary); Skin; T cell receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17557-y

Butyrophilin-like ( Btnl ) genes are emerging as major epithelial determinants of tissue-associated γδ T cell compartments. Thus, the development of signature, murine TCRγδ + 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 γδ IEL development additionally requires Btnl6 and Skint2 , respectively, and furthermore that different Btnl heteromers can seemingly shape different intestinal γδ + 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.Vγ7 + IEL phenotype, including specific responsiveness to Btnl proteins. In sum, Btnl proteins are required to select and to maintain the phenotypes of tissue-protective γδ IEL compartments, with combinatorially diverse heteromers having differential impacts on different IEL subsets. Butyrophilin-like genes are emerging as central to tissue associated γδ T cell compartments. Here, the authors show that the butyropilin-like gene-products exert their effects as combinatorially diverse heteromers that differentially affect the selection and maintenance of skin-resident and gut-resident intraepithelial γδ T-cell populations.