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Critical role of butyrophilin 3A1 in presenting prenyl pyrophosphate antigens to human γδ T cells

Cellular & Molecular Immunology volume 11, pages 117–119 (2014)Cite this article

T lymphocytes recognize antigen via the heterodimeric T-cell receptor (TCR) which is closely associated with the signal-transducing CD3 complex. αβ TCR-expressing T cells recognize peptides presented by MHC class II (for CD4+ T cells) or MHC class I molecules (for CD8+ T cells). In striking contrast, the majority of human γδ T cells expressing the Vγ9Vδ2-encoded TCR recognize small non-peptidic phosphorylated ligands which have been identified as pyrophosphate intermediates of microbial and eukaryotic isoprenoid synthesis. However, it has been unknown for many years how such prenyl pyrophosphates are presented to the γδ TCR. In a recent paper published in Nature Immunology, Vavassori and co-workers have identified butyrophilin 3A1 as the elusive cell surface molecule that can directly bind pyrophosphate antigens for presentation to the γδ TCR.1

γδ T cells are a minor subset of T lymphocytes in the peripheral blood, but occur at higher frequency in mucosal tissue. Based on the expressed TCR repertoire, human γδ T cells come in two flavors, i.e., γδ T cells expressing Vδ2 (almost exclusively paired with Vγ9) and non-Vδ2 T cells (which usually express Vδ1, frequently paired with Vγchains other than Vγ9). In healthy adult individuals, the majority (anywhere between 50% and 95%) of peripheral blood γδ T cells express a Vγ9Vδ2 TCR.2 Vγ9Vδ2 T cells display potent cytotoxic activity, produce a range of cytokines and are thought to play important roles in microbial and tumor immunity.2 The ligands that are recognized by the Vγ9Vδ2 TCR have been identified as low molecular weight prenyl pyrophosphate intermediates in isoprenoid synthesis. Microbes use the 2-C-methyl-d-erythriol 4-phosphate pathway to generate (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) which selectively activates Vγ9Vδ2 T cells at pico- to nanomolar concentrations. Eukaryotic cells use the mevalonate pathway of isoprenoid synthesis, in which isopentenyl pyrophosphate (IPP) is an intermediate that also activates the very same Vγ9Vδ2 T cells, even though 3-log higher (i.e., micromolar) concentrations are required.3 Stressed and transformed cells frequently have a dysregulated mevalonate pathway and produce higher amounts of IPP which marks them for recognition (and killing) by Vγ9Vδ2 T cells.4 Interestingly, the endogenous levels of pyrophosphate production can be manipulated by clinically used drugs, notably aminobisphosphonates (n-BPs) and statins. n-BPs are used to treat osteoporosis and bone metastasis in some types of cancer. n-BPs increase the intracellular accumulation of IPP by inhibiting the IPP-processing enzymefarnesyl pyrophosphate synthase. As a consequence, the treatment of tumor cells with n-BP augments their susceptibility to γδ T cell-mediated killing.4 In contrast, statins (which are used to lower cholesterol levels and to prevent cardiovascular disease) inhibit HMG-CoA reductase upstream of IPP synthesis and therefore, reduce intracellular IPP levels leading to diminished sensing by Vγ9Vδ2 T cells.

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  1. Institute of Immunology, University of Kiel, Kiel, Germany

    Dieter Kabelitz

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Correspondence to Dieter Kabelitz.

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Kabelitz, D. Critical role of butyrophilin 3A1 in presenting prenyl pyrophosphate antigens to human γδ T cells. Cell Mol Immunol 11, 117–119 (2014). https://doi.org/10.1038/cmi.2013.50

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