Editorial: Activation, functions, and generation of immunological memory in γδ T lymphocytes: lessons from nonhuman primates

T cells constitute an unconventional lymphocyte population with distinct functions complementary to those of CD4 and CD8 T cells. As such, they have both adaptive features, such as expression of the TCR, and innate-like functions reminiscent of NK cells, with whom they share extensive repertoires of activating and inhibitory receptors [1, 2]. Although most antigens recognized by murine T cells remain obscure, advances have been made in identifying ligands for human T cells. The majority of circulating human T lymphocytes expresses a TCR formed by the preferentially-paired V 9 and V 2 chains (here and thereafter, called V 9V 2 T cells). Instead of binding peptides associated with molecules belonging to the MHC, V 9V 2 T cells recognize pyrophosphate intermediates of the microbial or eukaryotic isoprenoid synthesis pathways, called PAgs [3, 4]. Isoprenoids are produced by one of two major pathways: the classical mevalonate pathway and the alternative deoxyxylulose (nonmevalonate) pathway of isoprenoids synthesis that is used by numerous bacterial species and by some highly significant eukaryotic pathogens but not by vertebrate cells. IPP is an intermediate metabolite that is present in both pathways, whereas HMBPP is only produced in the nonmevalonate pathway by certain microbes, including Mycobacterium tuberculosis and Listeria monocytogenes. Given this cross-reactivity between human V 9V 2 T cells and microbial and self-PAgs, there is a great interest in the scientific community of elucidating how TCR signaling can be induced by such small molecules. PAgs can directly activate V 9V 2 T cells, but such activation is greatly enhanced by monocytes and/or DCs. Hence, either PAgs are presented as cargo to the reactive TCR or their cellular processing somehow sensitizes cell recognition through the engagement of V 9V 2 TCR (i.e., by stabilizing surface expression of TCR-binding molecules) [3, 4]. A candidate molecule involved in intracellular PAg processing is the F1-ATPase, which was reported to bind directly the V 9V 2 TCR and to also interact with IPP conjugated to AMP, an adenosine derivative of IPP [5]. Thus, V 9V 2 T cells may collectively monitor multiple components of pathways regulating cholesterol biosynthesis that are altered by infection or other forms of stress. In this regard, it was found recently that PAg-induced V 9V 2 T cell activation also involves the participation of BTN3A1, a widely expressed member of the Ig superfamily [6]. Therefore, production of exogenous HMBPP or up-regulation of endogenous IPP in human cells in response to infections or noninfective immune dysregulation provokes V 9V 2 T cell reactivity, albeit at substantially different sensitivity. Although IPP was isolated from Mycobacterium smegmatis as the first natural ligand for human T cells, it soon became clear that the amounts of IPP present in bacterial extracts do not reach the minimum threshold required for inducing V 9V 2 T cell activation in several experimental systems in vitro. HMBPP is more potent than IPP in the context of in vitro activation of V 9V 2 T cells, active at picoto nanomolar concentrations, whereas IPP requires 3-log higher concentrations within micromolar ranges. Such high concentrations are not produced in physiological conditions but are reached during the course of pathologic metabolisms of stressed or infected cells. V 9V 2 T cells evolved to detect stressed cells and microbial pathogens, although only if the local amounts of IPP released from damaged tissues are at least 10,000-fold higher than the HMBPP concentrations reached during bacterial infections. This explains the different bioactivities of these two compounds [7]. The finding that V 9V 2 T cells respond differentially in vitro to increasing concentrations of structurally related PAgs indicates that such ligands constitute agonists for the TCR at different strengths. Indeed, experimental approaches aiming to define the underlying molecular basis of T lymphocyte activation demonstrate that V 9V 2 TCR can discriminate between subtle differences of substrates. By analyzing early cellular events and late effector responses of V 9V 2 T cells, it has also been reported that IPP induces a timeand dose-dependent down-modulation of the reactive TCR, whereas HMBPP induces little or no TCR