Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial \u03b3\u03b4 T cell compartments

Anett Jandke,Philip East,Tomoya Narita,Daisy Melandri,Adrian Hayday,Regina Feederle,Pierre Vantourout,Dmitry S Ushakov,Hiroshi Takayanagi,Takeshi Nitta,Leticia Monin,Adam G Laing

doi:10.1038/s41467-020-17557-y

Abstract

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.

Highlights

Butyrophilin-like (Btnl) genes are emerging as major epithelial determinants of tissueassociated γδ T cell compartments
Btnl1−/− mice mostly lack intestinal Vγ7+ cells[16], while mice deficient in Skint[1] lack Vγ5Vδ1+ DETC17,18. The conservation of this biology became evident when human colonic Vγ4+ cells were shown to be regulated by BTNL316,19, while Butyrophilin 3A1 (BTN3A1) and BTN2A120 were found to be critical for signature responses of human peripheral blood Vγ9Vδ2+ cells to low molecular mass phosphoantigens such as isopentenyl pyrophosphate[21,22,23]
By showing that Vγ5Vδ1+ dendritic epidermal T cells (DETC) development depends on Skint[2] as well as on Skint[1], and that Vγ7+ intestinal intraepithelial lymphocytes (IEL) development depends on Btnl[6] as well as on Btnl[1], we provide formal genetic evidence that single Btnls are not sufficient for IEL selection

Summary

Introduction

Butyrophilin-like (Btnl) genes are emerging as major epithelial determinants of tissueassociated γδ T cell compartments. In seeking mechanisms underlying these profound effects, we show that normal gut and skin γδ IEL development requires Btnl[6] and Skint[2], respectively, and that different Btnl heteromers can seemingly shape different intestinal γδ+ IEL repertoires This formal genetic evidence for the importance of Btnl heteromers 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. Murine γδ T cells, which were revealed some 30 years ago to be prototypic tissue-associated T cells, display tissue-restricted T-cell receptor (TCR) repertoires, including Vγ5Vδ1 in the epidermis, Vγ6Vδ1 in the uterus, dermis and lung, and Vγ7+ cells expressing a variety of Vδ chains in the small intestine[13] How such TCRs contributed to tissue protection remained enigmatic, given that Vγ5Vδ1+ dendritic epidermal T cells (DETC) were shown to use innate receptors, NKG2D, to respond rapidly to epithelial cell dysregulation[14,15]. The functional significance of heteromers has not been universally accepted[26], with one concern being that the most compelling evidence is based on cellular over-expression systems[27,28]

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Results

Conclusion