In contrast to conventional T lymphocytes, which carry an αβ
T-cell receptor and recognize
antigens as
peptides presented by major histocompatibility complex class I or class II molecules, human γδ T cells recognize different metabolites such as non-peptidic
pyrophosphate molecules that are secreted by microbes or overproduced by
tumor cells. Hence, γδ T cells play a role in immunosurveillance of
infection and cellular transformation. Until recently, it has been unknown how the γδ
T-cell receptor senses such
pyrophosphates in the absence of known
antigen-presenting molecules. Recent studies from several groups have identified a unique role of
butyrophilin (BTN)
protein family members in this process, notably of BTN3A1. BTNs are a large family of transmembrane
proteins with diverse functions in
lipid secretion and innate and adaptive immunity. Here we discuss current models of how BTN molecules regulate γδ T-cell activation. We also address the implications of these recent findings on the design of novel immunotherapeutic strategies based on the activation of γδ T cells.