Missing HLA class I expression on Daudi cells unveils cytotoxic and proliferative responses of human γδ T lymphocytes

Rothenfußer, Simon; Buchwald, Armin; Kock, Sylvia; Ferrone, Soldano; Fisch, Paul

doi:10.1016/s0008-8749(02)00001-1

Cited by 29 publications

(28 citation statements)

References 54 publications

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“…In parallel, V9V2 T cells mature from naive through central memory to Th1 effector memory and cytotoxic TEMRa cells. TEMRa cells mediate potent natural killer-like cytotoxic responses against tumor cell targets [1,2]. These features make V9V2 T lymphocytes versatile and attractive candidates for new cancer immunotherapy [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

The PPARα pathway in Vγ9Vδ2 T cell anergy

Poupot

Boissard

Bétous

et al. 2014

Cellular and Molecular Biology Letters

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Phosphoantigens (PAgs) activate V9V2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their V9V2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating V9V2 T cells from macaques injected with PAg. We showed that three PAg injections induced the activation of the PPAR pathway in V9V2 T cells. Thus, we analyzed the in vitro response of V9V2 T cells stimulated with a PPAR agonist. We demonstrated that in vitro PPAR pathway activation led to the inhibition of the BrHPP-induced activation and proliferation of human V9V2 T cells. Since the PPAR pathway is involved in the antigen-selective desensitization of human V9V2 T cells, the use of PPAR inhibitors could enhance cancer immunotherapy based on V9V2 T cells.

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Section: Introductionmentioning

confidence: 99%

The PPARα pathway in Vγ9Vδ2 T cell anergy

Poupot

Boissard

Bétous

et al. 2014

Cellular and Molecular Biology Letters

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“…20 However, the use of statins in the work of Thompson et al may complicate the analysis of their results since statins can have multiple targets in immune modulation, 21 and the effects of the lack of 2 -microglobulin in Daudi tumor cells may also be very important in tumor cell recognition. 22 Nevertheless, what is clear is that γδ T cells are in fact stimulated by bisphosphonates at low micromolar levels. Here, we report the results of our studies of the stimulation of γδ T cells by a diverse library of bisphosphonates and the use of 3D QSAR (comparative molecular similarity index analysis, CoMSIA, and Catalyst pharmacophore modeling) techniques 23,24 to analyze γδ T cell stimulation.…”

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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“…The mode of recognition of phosphoantigen by V␥9V␦2 cells remains unclear, but their presentation by as yet undefined receptors is likely. Various receptors, such as the LFA-1 integrin, CD2 (19,20), and NK receptors, both activatory, such as NKG2D, and inhibitory, were also reported to be important for tumor cell line recognition and lysis by V␥9V␦2 T lymphocytes (14,18,(21)(22)(23)(24)(25)(26).…”

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confidence: 99%

Vγ9Vδ2 T Cell Response to Colon Carcinoma Cells

Corvaisier

Moreau-Aubry

Viles

et al. 2005

The Journal of Immunology

191

152

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During analysis of CD8 T cells derived from ascites of a colon cancer patient, we isolated a Vγ9Vδ2 T cell clone showing strong reactivity against autologous tumor cell lines. This clone killed a large fraction of allogeneic colon carcinoma and melanoma cell lines, but did not affect a normal colon cell line, colon fibroblasts, or melanocytes. Tumor cell recognition was TCR and NKG2D dependent and induced TNF-α and IFN-γ secretion by the clone; accordingly, tumor targets expressed several NKG2D ligands, such as MHC class I chain-related gene A and UL16-binding protein molecules. Colon tumor recognition by Vγ9Vδ2 T cells was highly dependent on isopentenyl pyrophosphate production and ICAM-1 expression by target cells. Finally, similar reactivity patterns against colon carcinoma cell lines were observed using polyclonal Vγ9Vδ2 T cells of various origins, and Vγ9Vδ2 lymphocytes were present in the majority of colon tumor samples studied. Together, these results suggest that Vγ9Vδ2 T cells contribute to the natural immune surveillance against colon cancers. Therefore, this study provides a strong rationale for the use of Vγ9Vδ2 T cell agonists in immunotherapies targeting colon tumors.

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Missing HLA class I expression on Daudi cells unveils cytotoxic and proliferative responses of human γδ T lymphocytes

Cited by 29 publications

References 54 publications

The PPARα pathway in Vγ9Vδ2 T cell anergy

The PPARα pathway in Vγ9Vδ2 T cell anergy

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

Vγ9Vδ2 T Cell Response to Colon Carcinoma Cells

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