Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells

Gober, Hans-Jürgen; Kistowska, Magdalena; Ångman, Lena; Jenö, Paul; Mori, Lucia; Libero, Gennaro De

doi:10.1084/jem.20021500

Cited by 748 publications

(808 citation statements)

References 28 publications

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“…25,26 Aminobisphosphonates, which inhibit the mevalonate pathway by reducing the activity of farnesyl pyrophosphate synthase, promote the intracellular accumulation of isopentenyl pyrophosphate, and activate cd T cells in vitro and in vivo. 5,27 As one of the new-generation aminobisphosphonates, PAM was proven to be a more potent cd T cell stimulus. 5 Compared to PAM-activated cells, cd T cells stimulated by the anti-cd TCR Ab manifested a relatively delayed activation response, followed by a mild but sustained proliferation process.…”

Section: Discussionmentioning

confidence: 99%

Anti-γδ TCR antibody-expanded γδ T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies

et al. 2011

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Cell-based immunotherapy for lymphoid malignancies has gained increasing attention as patients develop resistance to conventional treatments. cd T cells, which have major histocompatibility complex (MHC)-unrestricted lytic activity, have become a promising candidate population for adoptive cell transfer therapy. We previously established a stable condition for expanding cd T cells by using anti-cd T-cell receptor (TCR) antibody. In this study, we found that adoptive transfer of the expanded cd T cells to Daudi lymphoma-bearing nude mice significantly prolonged the survival time of the mice and improved their living status. We further investigated the characteristics of these antibody-expanded cd T cells compared to the more commonly used phosphoantigen-expanded cd T cells and evaluated the feasibility of employing them in the treatment of lymphoid malignancies. Slow but sustained proliferation of human peripheral blood cd T cells was observed upon stimulation with anti-cd TCR antibody. Compared to phosphoantigen-stimulated cd T cells, the antibody-expanded cells manifested similar functional phenotypes and cytotoxic activity towards lymphoma cell lines. It is noteworthy that the anti-cd TCR antibody could expand both the Vd1 and Vd2 subsets of cd T cells. The in vitro-expanded Vd1 T cells displayed comparable tumour cell-killing activity to Vd2 T cells. Importantly, owing to higher C-C chemokine receptor 4 (CCR4) and CCR8 expression, the Vd1 T cells were more prone to infiltrate CCL17-or CCL22-expressing lymphomas than the Vd2 T cells. Characterizing the peripheral blood cd T cells from lymphoma patients further confirmed that the anti-cd TCR antibody-expanded cd T cells could be a more efficacious choice for the treatment of lymphoid malignancies than phosphoantigen-expanded cd T cells.

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Section: Discussionmentioning

confidence: 99%

Anti-γδ TCR antibody-expanded γδ T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies

et al. 2011

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“…65,66 It was later determined that the stimulatory capacity of IPP and dimethylallyl diphosphate is actually fairly weak in comparison to some of the upstream intermediates of the alternative pathway of isoprenoid biosynthesis, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, 67 and it is usually in the context of malignancy or distress that cellular endogenous levels are able to awaken the effector functions of Vc9Vd2 T cells. 68 A class of drugs called aminobisphosphonates used for the prevention of bone fragility fractures and certain alkylamine compounds that are ubiquitously dispersed in everything from plants to amniotic fluid are also able to stimulate Vc9Vd2 T cells 69,70 by virtue of their ability to induce cellular accumulation of IPP. Both these compounds modulate IPP levels by blocking the metabolic activity of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

confidence: 99%

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

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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“…The presence of tumor-infiltrating Vd2 1 T cells in tumorbearing livers of patients may support their potential role in tumor immunosurveillance of HCC [10]. Vg9Vd2 T cells recognize small nonpeptidic phosphorylated antigens such as isopentenyl pyrophosphate produced in mammalian cells through the mevalonate pathway [11]. Aminobisphosphonate such as zoledronate may activate Vg9Vd2 T cells indirectly by blocking the mevalonate pathway and consequently promoting intracellular accumulation of isopentenyl pyrophosphate [8].…”

Section: Introductionmentioning

confidence: 98%

DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

et al. 2009

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Human Vc9Vd2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying Vc9Vd2 T-cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in cd T-cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule-1 (DNAM-1) and CD96 were expressed by Vc9Vd2 T cells. The ligands Nectin-like-5 specific of both DNAM-1 and CD96, and also Nectin-2, an additional ligand of DNAM-1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb-mediated masking experiments that cytotoxicity against HCC cells as well as IFN-c production in cd T cells were dependent on DNAM-1. Our experiments indicated that Nectin-like-5 but not Nectin-2 was involved in DNAM-1-dependent cd T-cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC.

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Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells

Cited by 748 publications

References 28 publications

Anti-γδ TCR antibody-expanded γδ T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies

Anti-γδ TCR antibody-expanded γδ T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies

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

DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

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