Targeting of tumor cells for human gammadelta T cells by nonpeptide antigens.

Human Vgamma2/Vdelta2(+) gammadelta T cells respond to low molecular-mass nonpeptide Ags in a gammadelta TCR-dependent manner. Although requirements of Ag presentation have remained controversial, we have indicated that specific responses of the primary gammadelta T cells to pamidronate were dependent on monocytic adherent cells for Ag presentation. Here, we show that human tumor cells can efficiently present aminobisphosphonate and pyrophosphomonoester compounds to gammadelta T cells, inducing specific proliferation and IFN-gamma production. gammadelta TCR dependency of the response to Ag-pulsed tumor cells was confirmed by using a Jurkat line transfected with a Vgamma2/Vdelta2 gammadelta TCR. Furthermore, gammadelta T cells exhibited markedly enhanced cytotoxicity against the Ag-pulsed tumor cells as compared with untreated tumor cells. Survey of a number of human tumor cell lines of different origins revealed that the majority of them became susceptible for gammadelta T cell-mediated cytotoxicity following the Ag pulsing except for breast cancer lines so far examined, while normal PHA blast cells remained resistant. The results not only imply a unique mode of nonpeptide Ag recognition by human gammadelta T cells but also may provide a novel strategic clue for immunotherapy of human malignancy.     

Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli.

The gcpE and lytB gene products control the terminal steps of isoprenoid biosynthesis via the 2-C-methyl-D-erythritol 4-phosphate pathway in Escherichia coli. In lytB-deficient mutants, a highly immunogenic compound accumulates significantly, compared to wild-type E. coli, but is apparently absent in gcpE-deficient mutants. Here, this compound was purified from E. coli DeltalytB mutants by preparative anion exchange chromatography, and identified by mass spectrometry, (1)H, (13)C and (31)P NMR spectroscopy, and NOESY analysis as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP). HMB-PP is 10(4) times more potent in activating human Vgamma9/Vdelta2 T cells than isopentenyl pyrophosphate.     

SCART scavenger receptors identify a novel subset of adult gammadelta T cells

Although there has been great progress in the characterization of alphabeta T cell differentiation, selection, and function, gammadelta T cells have remained poorly understood. One of the main reasons for this is the lack of gammadelta T cell-specific surface markers other than the TCR chains themselves. In this study we describe two novel surface receptors, SCART1 and SCART2. SCARTs are related to CD5, CD6, and CD163 scavenger receptors but, unlike them, are found primarily on developing and mature gammadelta T cells. Characterization of SCART2 positive immature and peripheral gammadelta T cells suggests that they undergo lineage specification in the thymus and belong to a new IL-17-producing subset with distinct homing capabilities.     

Antiviral reactivities of gammadelta T cells

The complex antiviral immune mechanisms involve both adaptive and innate reactions mediated by gammadelta T lymphocytes, whose unique immunosurveillance contributions are analyzed here in different clinical and experimental settings. It is beyond any doubt that the fast, potent, cytotoxic as well as non-cytolytic antiviral activities of gammadelta T cells are critical in protecting the host against diverse viral pathogens.     

gammadelta T cells in malaria infections

The association of a pronounced gammadelta T-cell response with Plasmodium infections is intriguing. The ability of parasite material to activate gammadelta T cells in vitro, and the localization of these cells in vivo in the red pulp of the spleen, suggests that these cells could play a role in the killing of bloodstage malaria parasites. However, the magnitude, the response and the predominance of inflammatory cytokines secreted by these cells may also indicate a role in the pathology of malaria infections. In this article, Jean Langhorne reveiws the current status of gammadelta T cells in malaria in the context of what is known about the function and specificity of gammadelta T cells in general.     

Homing and memory patterns of human gammadelta T cells in physiopathological situations

Vgamma9Vdelta2 are a heterogeneous population of T cells and comprise distinct naive, memory and effector populations that can be distinguished on the basis of surface marker expression and effector functions. We review here these recently studied features of Vgamma9Vdelta2 T lymphocyte biology and the roles they play in infectious and autoimmune diseases.     

Vdelta1+ T cells are crucial for repertoire formation of gammadelta T cells in the lung

The pulmonary resident T lymphocytes (RPLs) expressing a nearly invariant T cell receptor γδ heterodimer (γδTCR) migrate from fetal thymus to the lung epithlium, followed by RPL subsets expressing diverse sets of γδTCRs after birth. However, it remains unclear whether the fetal type Vγ6/Vδ1⁺ RPLs are essential for γδ T cell repertoire formation in the lung epithelium. In this study, we found a marked decrease in the number of γδRPLs at 4 weeks of age in Vδ1^−/− mice and they predominantly expressed Vγ6 and Vδ4 genes. The skewed diversity towards the Vδ4-(Dδ1)-Dδ2-Jδ2 junctional region was observed only in γδ RPLs from 4-week-old Vδ1^−/− mice, compared with those from 8-week-old Vδ1^−/− mice and the both ages of wild-type mice. These results suggest that the invariant Vδ1⁺ T cells are crucial not only for optimal γδ T cell expansion but also for affecting the migration or microenvironment for other γδ T cells in the lung epithelium.     

Activation and control of self-reactive gammadelta T cells

Mammalian and avian CD3+ T cells can be separated into two lymphocyte subsets bearing heterodimeric T-cell receptors (TCR) composed of either alphabeta or gammadelta chains. Although it is now widely accepted that gammadelta and alphabeta T cells fulfill mandatory and nonredundant roles, the generality of this assumption and the exact functions played by gammadelta T cells remain uncertain. While an early protective role of gammadelta T cells has long been suspected, recent observations drawn in particular from transgenic models suggest their implication in the homeostatic control of immune and nonimmune processes. This hypothesis is also supported by the existence of several self-reactive gammadelta T-cell subsets in rodents and humans, whose specificity and effector properties will be detailed and discussed here. The present review will also describe several mechanisms that could allow efficient control of these self-reactive subsets while permitting expression of their regulatory and/or protective properties.     

Immunoregulation in the tissues by gammadelta T cells

For a T-cell subset to be classified as immunoregulatory, it might reasonably be predicted that in its absence, animals would experience pathological immune dysregulation. Moreover, reconstitution of the subset should restore normal immune regulation. So far, these criteria have been satisfied by only a few of the candidate regulatory T-cell subsets, but among them is the intraepithelial gammadelta T-cell receptor (TCR)+ subset of mouse skin. In this article, we look at immunoregulatory gammadelta T cells, and the growing evidence for tissue-associated immunoregulation mediated by both gammadelta T cells and alphabeta T cells.     

Replacing the pyrophosphate group of HMB-PP by a diphosphonate function abrogates Its potential to activate human gammadelta T cells but does not lead to competitive antagonism

The immunological characterization of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), and its methylenediphosphonate analogue, HMB-PCP, is described. With an EC(50) of 0.1-0.2 nM, HMB-PP is significantly more potent in stimulating human Vgamma9/Vdelta2 T cells than any other compound described so far. However, replacing the pyrophosphate by a P-CH(2)-P function abrogates the bioactivity drastically, with HMB-PCP having a EC(50) of only 5.3 microM.     

Biology of gammadelta T cells in tuberculosis and malaria

Tuberculosis and malaria remain the leading causes of mortality among human infectious diseases in the world. It is estimated that 3 to 5 million people die from tuberculosis and malaria each year. Although it is traditionally believed that CD4 and CD8 alphabeta T lymphocytes are mandatory for protective immune responses against Mycobacterium tuberculosis and Plasmodium falciparum (the ethiologic agents of tuberculosis and the most severe form of malaria, respectively), there is still incomplete understanding of the mechanisms of immune protection and of the causes of its failure in the affected patients. Several studies in humans and animal models have suggested that Vgamma9/Vdelta2 T cells may play an important role in the immune responses against Mycobacterium tuberculosis and Plasmodium falciparum. Vgamma9/Vdelta2 T cells represent about 75% of all circulating gammadelta T cells while they can be greatly expanded during the acute phase of Mycobacterium tuberculosis and Plasmodium falciparum malaria. Vgamma9/Vdelta2 T recognize a new class of antigenic molecules which are nonpeptidic in nature and contain critical phosphate moieties (phosphoantigens). Interestingly, phosphoantigens isolated from Mycobacterium tuberculosis and Plasmodium falciparum share strong structural homology and are probably identical. However, despite a large body of data reported in the literature, it is not yet clear whether Vgamma9/Vdelta2 T cells play a protective or pathogenic role in immune responses against Mycobacterium tuberculosis and Plasmodium falciparum. In this review we summarize our current knowledge of the biology of Vgamma9/Vdelta2 T cells in response to the two pathogens, Mycobacterium tuberculosis and Plasmodium falciparum, and provide evidence suggesting definition of a novel and important protective role through which Vgamma9/Vdelta2 T cells can contribute to the killing of microorganisms residing in intracellular compartments.     

Microbial isoprenoid biosynthesis and human gammadelta T cell activation

Human Vgamma9/Vdelta2 T cells play a crucial role in the immune response to microbial pathogens, yet their unconventional reactivity towards non-peptide antigens has been enigmatic until recently. The break-through in identification of the specific activator was only possible due to recent success in a seemingly remote field: the elucidation of the reaction steps of the newly discovered 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway of isoprenoid biosynthesis that is utilised by many pathogenic bacteria. Unexpectedly, the intermediate of the MEP pathway, (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate) (HMB-PP), turned out to be by far the most potent Vgamma9/Vdelta2 T cell activator known, with an EC(50) of 0.1 nM.     

Homing and function of human skin gammadelta T cells and NK cells: relevance for tumor surveillance

Normal (noninflamed) human skin contains a network of lymphocytes, but little is known about the homing and function of these cells. The majority of alphabeta T cells in normal skin express CCR8 and produce proinflammatory cytokines. In this study we examined other subsets of cutaneous lymphocytes, focusing on those with potential function in purging healthy tissue of transformed and stressed cells. Human dermal cell suspensions contained significant populations of Vdelta1(+) gammadelta T cells and CD56(+)CD16(-) NK cells, but lacked the subsets of Vdelta2(+) gammadelta T cells and CD56(+)CD16(+) NK cells, which predominate in peripheral blood. The skin-homing receptors CCR8 and CLA were expressed by a large fraction of both cell types, whereas chemokine receptors associated with lymphocyte migration to inflamed skin were absent. Neither cell type expressed CCR7, although gammadelta T cells up-regulated this lymph node-homing receptor upon TCR triggering. Stimulation of cutaneous Vdelta1(+) gammadelta T cell lines induced secretion of large amounts of TNF-alpha, IFN-gamma, and the CCR8 ligand CCL1. In contrast to cutaneous alphabeta T cells, both cell types had the capacity to produce intracellular perforin and displayed strong cytotoxic activity against melanoma cells. We therefore propose that gammadelta T cells and NK cells are regular constituents of normal human skin with potential function in the clearance of tumor and otherwise stressed tissue cells.     

In vivo gammadelta T cell priming to mycobacterial antigens by primary Mycobacterium tuberculosis infection and exposure to nonpeptidic ligands.

BACKGROUND: The recognition of phosphorylated nonpeptidic microbial metabolites by Vgamma9Vdelta2 T cells does not appear to require the presence of MHC molecules or antigen processing, permitting rapid responses against microbial pathogens. These may constitute an important area of natural anti-infectious immunity. To provide evidence of their involvement in immune reactivities against mycobacteria, we measured the responsiveness of peripheral blood Vgamma9Vdelta2 T cells in children with primary Mycobacterium tuberculosis (MTB) infections. MATERIALS AND METHODS: Peripheral blood mononuclear cells from 22 children with MTB infections and 16 positivity of tuberculin (PPD)-negative healthy children were exposed to nonpeptidic antigens in vitro and the reactivity of the Vgamma9Vdelta2 T cell subset with these antigens was determined using proliferation and cytokine assays. Also, responses of gammadelta T cells from rhesus monkeys stimulated with phosphoantigens in vivo were measured. RESULTS: The Vgamma9Vdelta2 T cell responses were highly increased in infected children in comparison with age-matched controls. This augmented Vgamma9Vdelta2 T cell reactivity subsided after successful antibiotic chemotherapy, suggesting that persistent exposure to mycobacterial antigens is required for the maintenance of gammadelta T cell activation in vivo. The in vivo reactivity of Vgamma9Vdelta2 T cells to phosphoantigens was also analyzed in a rhesus monkey model system. Intravenous injections of phosphoantigens induced an activated state of simian Vgamma9Vdelta2 T cells which decreased after 2 months, i.e., with a time course similar to that seen in MTB-infected children. CONCLUSIONS: The increased reactivity of Vgamma9Vdelta2 T cells to phosphoantigens appears to be dependent on constant antigenic exposure. Consequently, the assessment of Vgamma9Vdelta2 responses may be useful for monitoring the efficacy of antimycobacterial therapies.     

gammadelta T cells provide a breath of fresh air for asthma research.

gammadelta T cells downregulate airways responsiveness to allergen challenge, possibly by controlling the 'repair' response of the airway epithelium to alphabeta T cell-mediated damage (pages 1150-1156).     

Negative regulation of airway responsiveness that is dependent on gammadelta T cells and independent of alphabeta T cells.

The mechanisms regulating airway function are complex and still poorly understood. In diseases such as asthma, involvement of immune-dependent mechanisms has been suggested in causing changes in airway responsiveness to bronchoconstrictors. We now demonstrate that gammadelta T cells can regulate airway function in an alphabeta T cell-independent manner, identifying them as important cells in pulmonary homeostasis. This function of gammadelta T cells differs from previously described immune-dependent mechanisms and may reflect their interaction with innate systems of host defense.