Butyrophilin (BTN) molecules control γδ T cells in tissue epithelia

Abstract

Abstract Gammadelta (γδ) T cells are a lineage of innate-like T lymphocytes with potent cytotoxic, pro-inflammatory and regulatory properties. They express, as a defining feature, a T cell receptor (TCR) composed of a γ and δ chain heterodimer, both products of V(D)J recombination, which distinguishes them from conventional αβ T cells. Although restricted to anatomical locations including skin and intestinal epithelium, major sites of interaction with the microbiota and of autoimmune pathology, the role of γδ T cells in immune surveillance is poorly understood. It is now clear that butyrophilins (BTNs) are pivotal in the maintenance of immune homeostasis in tissue epithelium, by controlling activation of γδ T cells. Despite homology to B7 costimulatory receptors like CD80/86 and PD-L1, ligands for BTN molecules have remained elusive. Some data show a direct interaction of BTNs with the γδ TCR, although this remains to be confirmed. We aim to understand the function of BTNs in the regulation of γδ T cells and how their dysregulation contributes to disease. The model system we study is the human BTN3A proteins and their role in the activation of Vγ9/Vδ2 T cells, a prominent γδ T cell lineage in human blood and tissues. Since it is clear that specific BTN molecules control defined γδ T cell subsets, this work is relevant to other systems of γδ T cell activation. I will highlight how these new data on the molecular control of a major T cell compartment is relevant to human autoimmunity and cancer.