Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

Pierre Vantourout, Adam Laing, Martin J. Woodward, Iva Zlatareva, Luis Apolonia, Andrew W. Jones, Ambrosius P. Snijders, Michael H. Malim, Adrian C. Hayday*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)
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The long-held view that gamma delta (γδ) T cells in mice and humans are fundamentally dissimilar, as are γδ cells in blood and peripheral tissues, has been challenged by emerging evidence of the cells’ regulation by butyrophilin (BTN) and butyrophilin-like (BTNL) molecules. Thus, murine Btnl1 and the related gene, Skint1, mediate T cell receptor (TCR)-dependent selection of murine intraepithelial γδ T cell repertoires in gut and skin, respectively; BTNL3 and BTNL8 are TCR-dependent regulators of human gut γδ cells; and BTN3A1 is essential for TCR-dependent activation of human peripheral blood Vγ9Vδ2+ T cells. However, some observations concerning BTN/ Btnl molecules continue to question the extent of mechanistic conservation. In particular, murine and human gut γδ cell regulation depends on pairings of Btnl1 and Btnl6 and BTNL3 and BTNL8, respectively, whereas blood γδ cells are reported to be regulated by BTN3A1 independent of other BTNs. Addressing this paradox, we show that BTN3A2 regulates the subcellular localization of BTN3A1, including functionally important associations with the endoplasmic reticulum (ER), and is specifically required for optimal BTN3A1-mediated activation of Vγ9Vδ2+ T cells. Evidence that BTNL3/BTNL8 and Btnl1/Btnl6 likewise associate with the ER reinforces the prospect of broadly conserved mechanisms underpinning the selection and activation of γδ cells in mice and humans, and in blood and extralymphoid sites.

Original languageEnglish
Pages (from-to)1039-1044
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Early online date16 Jan 2018
Publication statusPublished - 30 Jan 2018


  • Butyrophilins
  • Endoplasmic reticulum
  • Evolutionary conservation
  • Gamma delta T cells
  • Zoledronate


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