Escherichia coli Produces Phosphoantigens Activating Human γδ T Cells

Feurle, Juliane; Espinosa, Éric; Eckstein, Susanne; Pont, Frédéric; Kunzmann, Volker; Fournié, Jean‐Jacques; Herderich, Markus; Wilhelm, Martin

doi:10.1074/jbc.m106443200

Cited by 53 publications

(45 citation statements)

References 39 publications

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“…They do not require Ag processing, and only recently have some of their structures been precisely identified (33,72,79). E. coli was shown to produce phosphoantigens as a result of the Rohmer metabolic pathway of isoprenoid biosynthesis (76,78), a pathway used by many pathogenic bacteria. Thus, small, nonprotein, phosphate-containing molecules produced by Leptospira could be one possible candidate for how Leptospira activate TCR␥␦ ϩ T cells.…”

Section: Figure 6 Tcr␥␦mentioning

confidence: 99%

Leptospira interrogansActivation of Human Peripheral Blood Mononuclear Cells: Preferential Expansion of TCRγδ+ T Cells vs TCRαβ+ T Cells

Klimpel

Matthias

Vinetz

2003

The Journal of Immunology

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Innate and adaptive immune responses induced by leptospirosis have not been well characterized. In this study we show that in vitro exposure of naive human PBMC to Leptospira interrogans results in cell proliferation and the production of IFN-γ, IL-12, and TNF-α. Cell proliferation was highest when using high numbers of Leptospira. Optimal cell proliferation occurred at 6–8 days, and the majority of cells contained in these cultures were γ/δ T cells. These cultures showed a 10- to 50-fold expansion of γ/δ T cells compared with the initial cellular input. Additionally, these cultures contained elevated numbers of NK cells. In contrast, exposure of PBMC to low numbers of Leptospira failed to induce γδ T cell or NK cell expansion, but induced significant αβ T cell expansion. Vγ9/Vδ2 were expressed on all γ/δ T cells expanded by exposure of PBMC to Leptospira. Leptospira stimulation of purified TCRγδ+ T cells, obtained from 8-day cultures of Leptorspira-stimulated PBMC, induced high levels of IFN-γ production, but no cell proliferation, suggesting that such stimulation of γδ T cells did not depend on specialized accessory cells or Ag processing. Finally, in patients with acute leptospirosis, there was a significant (4- to 5-fold) increase in the number of peripheral blood TCRγδ+ T cells. These results indicate that Leptospira can activate γδ T cells and αβ T cells and will guide further investigations into the roles of these T cell populations in host defense and/or the pathology of leptospirosis.

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Section: Figure 6 Tcr␥␦mentioning

confidence: 99%

Leptospira interrogansActivation of Human Peripheral Blood Mononuclear Cells: Preferential Expansion of TCRγδ+ T Cells vs TCRαβ+ T Cells

Klimpel

Matthias

Vinetz

2003

The Journal of Immunology

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“…These comprise either natural or synthetic pyrophosphoesters referred to as phosphoantigens (33,34), therapeutic aminobisphosphonates (35), and natural or synthetic alkylamines (36). Natural phosphoantigens such as 3-formyl-1-butyl pyrophosphate (3fbPP) were isolated from various bacteria including Mycobacterium tuberculosis (37) and Escherichia coli (38). Among other powerful phosphoantigens, isopentenyl pyrophosphate (IPP) is a ubiquitous metabolite (39), and the synthetic agonist bromohydrin pyrophosphate (BrHPP) was recently produced in our laboratory (40).…”

Section: U Pon Ag Recognition B and T Cells Establish With Target Cementioning

confidence: 99%

Synaptic Transfer by Human γδ T Cells Stimulated with Soluble or Cellular Antigens

Espinosa

Tabiasco

Hudrisier

et al. 2002

The Journal of Immunology

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B, αβ T, and NK lymphocytes establish immunological synapses (IS) with their targets to enable recognition. Transfer of target cell-derived Ags together with proximal molecules onto the effector cell appears also to occur through synapses. Little is known about the molecular basis of this transfer, but it is assumed to result from Ag receptor internalization. Because human γδ T cells recognize soluble nonpeptidic phosphoantigens as well as tumor cells such as Daudi, it is unknown whether they establish IS with, and extract molecules from, target cells. Using flow cytometry and confocal microscopy, we show in this work that Ag-stimulated human Vγ9/Vδ2 T cells conjugate to, and perform molecular transfer from, various tumor cell targets. The molecular transfer appears to be linked to IS establishment, evolves in a dose-dependent manner in the presence of either soluble or cellular Ag, and requires γδ TCR ligation, Src family kinase signaling, and participation of the actin cytoskeleton. Although CD45 exclusion characterized the IS performed by γδ T cells, no obvious capping of the γδ TCR was detected. The synaptic transfer mediated by γδ T cells involved target molecules unrelated to the cognate Ag and occurred independently of MHC class I expression by target cells. From these observations, we conclude thatm despite the particular features of γδ T cell activation, both synapse formation and molecular transfer of determinants belonging to target cell characterize γδ T cell recognition of Ags.

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“…[1][2][3][4] They recognize, and are activated by, several phosphorus-containing bacterial and protozoan metabolites [5][6][7][8][9][10] ("phosphoantigens"), such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP, 1), by synthetic phosphoantigens, such as the bromohydrin of isopentenyl pyrophosphate (Phosphostim, 2; refs 11 and 12), and by the bisphosphonate drugs commonly used in bone resorption therapy. 13,14 This activation by synthetic drug or drug-like molecules has led to the idea that γδ T cell activation may be used in the immunotherapy of some forms of cancer, 15,16 in the immunotherapy of infectious diseases, 13 and, potentially, in vaccine development.…”

Section: Introductionmentioning

confidence: 99%

A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

Kotsikorou

Oldfield

2003

J. Med. Chem.

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γδ T cells are the first line of defense against many infectious organisms and are also involved in tumor cell surveillance and killing. They are stimulated by a broad range of small, phosphorus-containing antigens (phosphoantigens) as well as by the bisphosphonates commonly used in bone resorption therapy, such as pamidronate and risedronate. Here, we report the activation of γδ T cells by a broad range of bisphosphonates and develop a pharmacophore model for γδ T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between γδ T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R 2 values of ∼0.8-0.9 and q 2 values of ∼0.5-0.6 for a training set of 45 compounds. Using an external test set, the activities (IC 50 values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of ∼40% hydrophobic, ∼40% electrostatic, and ∼20% steric interactions. Since bisphosphonates are known to be potent, nanomolar inhibitors of the mevalonate/isoprene pathway enzyme farnesyl pyrophosphate synthase (FPPS), we also compared the pharmacophores for γδ T cell activation with those for FPPS inhibition, using the Catalyst program. The pharmacophores for γδ T cell activation and FPPS inhibition both consisted of two negative ionizable groups, a positive charge feature and an endocyclic carbon feature, all having very similar spatial dispositions. In addition, the CoMSIA fields were quite similar to those found for FPPS inhibition by bisphosphonates. The activities of the bisphosphonates in γδ T cell activation were highly correlated with their activities in FPPS inhibition: R ) 0.88, p ) 0.002, versus a human recombinant FPPS (N ) 9 compounds); R ) 0.82, p < 0.0001, for an expressed Leishmania major FPPS (N ) 45 compounds). The bisphosphonate γδ T cell activation pharmacophore differs considerably, however, from that reported previously for γδ T cell activation by phosphoantigens (Gossman, W.; Oldfield, E. J. Med. Chem. 2002, 45, 4868-4874), suggesting different primary targets for the two classes of compounds. The ability to quite accurately predict the activity of bisphosphonates as γδ T cell activators by using 3D QSAR techniques can be expected to help facilitate the design of additional bisphosphonates for potential use in immunotherapy.

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Escherichia coli Produces Phosphoantigens Activating Human γδ T Cells

Cited by 53 publications

References 39 publications

Leptospira interrogansActivation of Human Peripheral Blood Mononuclear Cells: Preferential Expansion of TCRγδ+ T Cells vs TCRαβ+ T Cells

Leptospira interrogansActivation of Human Peripheral Blood Mononuclear Cells: Preferential Expansion of TCRγδ+ T Cells vs TCRαβ+ T Cells

Synaptic Transfer by Human γδ T Cells Stimulated with Soluble or Cellular Antigens

A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

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