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

The long-held view that gamma delta (gamma delta) T cells in mice and humans are fundamentally dissimilar, as are gamma delta 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 gamma delta T cell repertoires in gut and skin, respectively; BTNL3 and BTNL8 are TCR-dependent regulators of human gut gamma delta cells; and BTN3A1 is essential for TCR-dependent activation of human peripheral blood V gamma 9V delta 2(+) T cells. However, some observations concerning BTN/Btnl molecules continue to question the extent of mechanistic conservation. In particular, murine and human gut gamma delta cell regulation depends on pairings of Btnl1 and Btnl6 and BTNL3 and BTNL8, respectively, whereas blood gamma delta 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 V gamma 9V delta 2(+) 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 gamma delta cells in mice and humans, and in blood and extralymphoid sites.