Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. Vγ9Vδ2 T cells, which cannot be studied easily in vivo because they do not exist in rodents, are often referred to as innate-like T cells. The genetically recombined γδ T cell receptor (TCR) that responds to isoprenoid-derived pyrophosphates (phosphoantigens) produced by infected and malignant cells in a butyrophilin-dependent manner qualifies them as therapeutically relevant components of the adaptive immune system. On the other hand, cell-surface proteins such as the C-type lectin CD161 mark a functional phenotype of Vγ9Vδ2 T cells that mediates TCR-independent innate-like responses. Moreover, CD56 (neural cell adhesion molecule, NCAM) and the G protein-coupled receptor GPR56 define Vγ9Vδ2 T cells with increased cytolytic potential and, like CD161, may also be expressed by dendritic cells, principally facilitating the generation of an innate-like immunological synapse. In this review, we summarise current knowledge of Vγ9Vδ2 T cell functional phenotypes that are critical to lymphoid stress surveillance.
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