New Insights Into the Regulation of γδ T Cells by BTN3A and Other BTN/BTNL in Tumor Immunity

Recent findings in the immunology field have pointed out the emergent role of buty-rophilins/butyrophilin-like molecules (BTN/BTNL in human, Btn/Btnl in mouse) in the modulation of gamma delta T cells. As long as the field develops exponentially, new relationships between certain gamma delta T cell subsets, on one hand, and their BTN/BTNL counterparts mainly present on epithelial and tumor cells, on the other, are described in the scientific literature. Btnl1/Btnl6 in mice and BTNL3/BTNL8 in humans regulate the homing and maturation of V gamma 7+ and V gamma 4+ T cells to the gut epithelium. Similarly, Skint-1 has shown to shape the dendritic epidermal T cells repertoire and their activation levels in mice. We and others have identified BTN3A proteins are the key mediators of phosphoantigen sensing by human V gamma 9V delta 2 T cells. Here, we first synthesize the modulation of specific gamma delta T cell subsets by related BTN/BTNL molecules, in human and mice. Then, we focus on the role of BTN3A in the activation of V gamma 9V delta 2 T cells, and we highlight the recent advances in the understanding of the expression, regulation, and function of BTN3A in tumor immunity. Hence, recent studies demonstrated that several signals induced by cancer cells or their microenvironment can regulate the expression of BTN3A. Moreover, antibodies targeting BTN3A have shown in vitro and in vivo efficacy in human tumors such as acute myeloid leukemia or pancreatic cancer. We thus finally discuss how these findings could help develop novel gamma delta T cell-based immunotherapeutical approaches.