For long known to regulate non-immune functions, butyrophilins (BTNs) are emerging as important modulators of immunity. The human BTN3A family – BTN3A1 in particular – is essential for the activation of unconventional Vg9Vd2 T cells by phosphoantigens. These phosphorylated metabolites can derive from a dysfunctional mevalonate pathway or microorganisms, such as Mycobacterium tuberculosis. In spite of their potential role in antimicrobial and anticancer immunity, little is known about the transcriptional regulation of these genes encoded in the extended major histocompatibility complex (MHC) locus.
In this study, a team of researchers from the Institute for Research in Biomedicine (Università della Svizzera italiana) together with a team of the University of Freiburg, Germany, and other national and international collaborators, identified an “SXY module” in the promoter of BTN3A1–3 genes. This regulatory motif is well known to recruit the NOD-like receptors (NLR) CIITA or NLRC5, which are transcriptional regulators of MHC class II or class I genes, respectively. Intriguingly, the SXY motif found in the BTN3A1-3 gene promoters is atypical in spacing and orientation as compared to the one described in MHC gene promoters. We demonstrate that NLRC5 occupies these promoters and transactivates this unconventional SXY, inducing BTN3A gene expression. Along these lines, analyses of cancer cells and of M. tuberculosis-infected patients’ blood show a robust correlation between NLRC5 and BTN3A gene transcript abundance. Finally, forcing NLRC5 expression promoted Vg9Vd2 T cell-mediated killing of cancer cells.
This work, published in the Cell press journal “iScience”, suggest therefore that NLRC5 manipulation, besides enhancing immunity by conventional cytotoxic T cells, also promotes killing by unconventional Vg9Vd2 T cells. These notions might open new opportunities to modulate Vg9Vd2 T cell-mediated antimicrobial and anticancer immunity.
Dang, A.T., Strietz, J., Zenobi, A., Khameneh, H.J., Brandl, S.M., Lozza, L., Conradt, G., Kaufmann, S.H.E., Reith, W., Kwee, I., Minguet, S., Chelbi, S.T., Guarda, G., ISCIENCE (2021), doi:https://doi.org/10.1016/j.isci.2020.101900.