Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Abstract

Introduction␥␦ T cells are key players in the immune surveillance of cellular distress, thanks to their ability to recognize conserved determinants up-regulated after inflammation, infection, or cell transformation. 1,2 Although ␥␦ T-cell receptors (TCRs) contribute to detection of danger-associated determinants, ligands for these receptors have been identified in a few cases only. 3 Thus, the antigenic specificity of ␥␦ T cells and their fine activation modalities in response to cell stress remain largely unknown.One of the best studied ␥␦ T-cell subsets in humans expresses V␥9V␦2 TCR and predominates in blood, composing several percent of the whole peripheral lymphoid pool in most adults. V␥9V␦2 T cells are activated by nonpeptidic phosphorylated isoprenoid pathway metabolites, 4-6 hereafter referred to as phosphoagonists (PAg). Natural V␥9V␦2-stimulating PAg include isopentenyl pyrophosphate (IPP), 7 a metabolite of the mevalonate pathway found in mammalian cells and the desoxyxylulose phosphate pathway shared by many microorganisms, and hydroxy-methyl-butyl-pyrophosphate, 8 an intermediate of the latter pathway. PAg detection by ␥␦ T cells underlies their broad reactivity toward infected and transformed cells. Indeed, tumor cell recognition by V␥9V␦2 T cells is linked to enhanced production of the weak agonist IPP, resulting from increased cell metabolism and cholesterol biosynthesis. Accordingly, pharmacologic inhibitors of the mevalonate pathway that up-regulate (eg, aminobisphosphonates, NBP) or down-regulate (eg, statins) IPP production, respectively, increase or decrease antitumor V␥9V␦2 T-cell responses. 9,10 Moreover, because of the high V␥9V␦2 T cell-stimulating activity of the microbial agonist hydroxy-methyl-butyl-pyrophosphate, V␥9V␦2 T-cell responses are elicited by infected cells producing even traces of this PAg. 8 Although PAg-induced activation is restricted to V␥9V␦2 T cells and can be conferred by V␥9V␦2 TCR gene transfer, 11,12 attempts to detect cognate interactions between PAg and V␥9V␦2 TCR have failed so far. 13 So how V␥9V␦2 T cells sense PAg remains an enigma. PAg rapidly induce Ca 2ϩ signaling and activation of V␥9V␦2 T-cell clones, but this requires cell-to-cell contact, suggesting the implication of additional target cell surface receptors in this phenomenon. 11,14 PAg elicit V␥9V␦2 T-cell responses against basically all human cells, irrespective of their tissue origin, but do not induce recognition of any murine target cells. Therefore, the putative target cell receptors involved in PAg-mediated T-cell activation are expected to be broadly expressed by human, but not murine, cells.Activation of antigen-stimulated T cells is tuned by interactions involving T cell-derived CD28-related receptors and target cellderived B7-related counter-receptors, 15 which family includes members, such as Skint and butyrophilin (BTN) receptors. The mandatory role played by Skint-1 in the intrathymic positive There is an Inside Blood commentary on this article in this issue.The online version of this...

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…The recent landmark discovery of butyrophilin 3A (BTN3A/ CD277) as the long-sought unconventional 'presenting' molecule for HMB-PP and IPP provided a molecular mechanism that elegantly integrates the action of endogenous and exogenous stimuli via binding of phosphoantigens to the intracellular B30.2 (PRY-SPRY) domain of BTN3A [22][23][24][25]. This intracellular recognition of HMB-PP and IPP evokes similar cases of B30.2-mediated innate responses through proteins such as TRIM5a and TRIM21 [26,27], thereby adding BTN3A to the rapidly growing number of innate pattern recognition receptors.…”

“…Overproduction of the low bioactivity compounds IPP and DMAPP as a result of a dysregulation of the mevalonate pathway in human cells, be it in metabolically active tissues including tumor cells or through inhibition of farnesyl pyrophosphate synthase by aminobisphophonates such as zoledronate, is thought to render such cells targets of Vc9/Vd2 T cells, despite the absence of the high bioactivity metabolite HMB-PP in this context [11,[16][17][18]. Zoledronate and related drugs are therefore receiving substantial attention as Vc9/Vd2 T cellstimulating agents in vivo especially with respect to immunotherapies against advanced solid and hematological tumors [19][20][21].The recent landmark discovery of butyrophilin 3A (BTN3A/ CD277) as the long-sought unconventional 'presenting' molecule for HMB-PP and IPP provided a molecular mechanism that elegantly integrates the action of endogenous and exogenous stimuli via binding of phosphoantigens to the intracellular B30.2 (PRY-SPRY) domain of BTN3A [22][23][24][25]. This intracellular recognition of HMB-PP and IPP evokes similar cases of B30.2-mediated innate responses through proteins such as TRIM5a and TRIM21 [26,27], thereby adding BTN3A to the rapidly growing number of innate pattern recognition receptors.…”

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

“…Exogenously added pyrophosphate antigens readily stimulate Vc9Vd2 T cells in the presence of human accessory cells, yet both these molecules require some stress-induced event for their ectopic expression-which argues for there existing some other more widely expressed candidate(s) that would be more exclusive to the primate lineage. Harly and colleagues, 81 from the working groups of Scotet and Bonneville, may have uncovered at least one of the missing pieces of the story in the form of a molecule known generically as CD277-or BTN3A. This unassuming molecule is a member of the butyrophilin/B7-like group of proteins belonging to the Ig superfamily that are found clustered at the extended end of the classical MHC I genes on human chromosome 6.…”

“…82 In a series of elegant experiments involving specific activating and inhibitory antibodies to CD277 as well as domain-swapping and knockdown experiments, the Scotet-Bonneville group shows convincing evidence that this widely expressed molecule provides the necessary support that pAgs need to awaken Vc9Vd2 T cell effector functions. 81 The fact that no functional orthologue of CD277 exists in rodents adds further credence to its purported role as the long-awaited missing link-or what may very well turn out to be a series of interconnected links.…”

Les récepteurs de nectines/nectines-likeDNAM-1 et CRTAM

“…Mais, à la différence de ce voie du métabolisme des isoprénoïdes, une voie qui est surexprimée par les cellules cancéreuses et qui peut être amplifiée par un traitement par des aminobisphosphonates [17]. La présentation des PAg n'est pas restreinte par les molécules HLA de classe I [19], mais dépend de la formation d'un complexe avec des molécules de butyrophyline 3A1 [20]. Une synapse immunologique se forme grâce aux interactions qui s'éta-blissent entre le TCR et les NKR de la cellule effectrice et leurs ligands respectifs exprimés par la cellule cible (Figure 3).…”