Individual Vγ2-Jγ1.2+ T cells respond to both isopentenyl pyrophosphate and Daudi cell stimulation: generating tumor effectors with low molecular weight phosphoantigens

Hebbeler, Andrew M.; Cairo, Cristiana; Cummings, Jean Saville; Pauza, C. David

doi:10.1007/s00262-006-0235-6

Cited by 27 publications

(51 citation statements)

References 42 publications

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“…This idea is relevant to the improvement of mAb-based cancer immunotherapy where a combination of mAbs specific to tumor Ag(s) with CD137 cross-linking induces direct NK cell-mediated tumor lysis. Specifically, our findings suggest that combination of Ab-based cancer immunotherapies with either adoptive transfer of in vitro expanded ␥␦ T lymphocytes or systemic injection of ␥␦ T-lymphocyte stimulating agents (zoledronic acid) [8][9][10] may improve clinical outcome through the enhancement of direct and ADDC tumor killing by NK cells.…”

Section: Discussionmentioning

confidence: 89%

“…7 Approximately 70% of ␥␦ T lymphocytes express the V␥2V␦2 TCR and can be expanded and activated by phosphoantigens such as the cholesterol biosynthesis intermediate, isopentenylpyrophosphate (IPP), or synthetic bisphosphonates (eg, pamidronate disodium and zoledronic acid). [8][9][10] Upon stimulation, ␥␦ T lymphocytes acquire the capacity to destroy solid tumors of diverse origins such as squamous cell carcinoma of the head and neck (SCCHN), melanoma, colon cancer, and breast carcinoma, 4,[11][12][13] suggesting that ␥␦ T lymphocytes are important antitumor effector cells. The validity of this antitumor function is further supported by mouse models demonstrating that mice deficient in ␥␦ T cells have increased sensitivity to the development of methylcholanthrene (MCA)-induced tumors.…”

Section: Introductionmentioning

confidence: 99%

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Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagement

Maniar

Zhang

Lin

et al. 2010

Blood

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IntroductionNatural killer (NK) cells contribute to innate immune responses against virally infected and neoplastic cells. 1 NK cells usually recognize and attack tumor cells that lack major histocompatibility complex (MHC) class I. 2 Our previous studies in murine tumor models clearly demonstrated that gamma delta (␥␦) T lymphocytes play an important role in the regulation of antitumor NK-cell function. 3 Specifically, we have shown that ␥␦ T lymphocytes are required for the antitumor activity of NK cells in vivo. More recently, we have demonstrated that culturing human peripheral blood mononuclear cells (PBMCs) with agents that activate ␥␦ T lymphocytes induce NK cell-mediated cytotoxicity against tumors that normally resist NK killing. 4 These findings are concordant with other studies that show that ␥␦ T lymphocytes regulate the early phase of NK cell-mediated antibacterial responses in mice. 5 Taken in concert these data strongly suggest that ␥␦ T lymphocytes are important in the regulation of NK-cell functions.␥␦ T cells are characterized by the expression of a T-cell receptor (TCR) consisting of both gamma and delta chains, 6 and account for 1% to 10% of CD3 ϩ cells in the peripheral blood of healthy adults. 7 Approximately 70% of ␥␦ T lymphocytes express the V␥2V␦2 TCR and can be expanded and activated by phosphoantigens such as the cholesterol biosynthesis intermediate, isopentenylpyrophosphate (IPP), or synthetic bisphosphonates (eg, pamidronate disodium and zoledronic acid). [8][9][10] Upon stimulation, ␥␦ T lymphocytes acquire the capacity to destroy solid tumors of diverse origins such as squamous cell carcinoma of the head and neck (SCCHN), melanoma, colon cancer, and breast carcinoma, 4,[11][12][13] suggesting that ␥␦ T lymphocytes are important antitumor effector cells. The validity of this antitumor function is further supported by mouse models demonstrating that mice deficient in ␥␦ T cells have increased sensitivity to the development of methylcholanthrene (MCA)-induced tumors. 14 In addition, a recent pilot clinical study showed that ␥␦ T lymphocyte adoptive therapy for patients with advanced renal cell carcinoma was well tolerated and induced antitumor immune responses. 15 The antitumor effects of ␥␦ T lymphocytes are recognized to result from both direct killing of tumor targets and trans-activation of adaptive immune responses. For example, recent data demonstrate that activated ␥␦ T lymphocytes cause the maturation of dendritic cells that promote development of acquired immunity. 16 In addition, ␥␦ T cells are known to cross-present tumor antigens (Ags) to CD8 ϩ cytolytic T lymphocytes. 17,18 Despite their wellcharacterized role in mediating adaptive immune responses, the mechanisms by which ␥␦ T cells regulate cells of the innate immune system, such as NK cells, are unclear.In this report we demonstrate that ␥␦ T lymphocytes provide a costimulatory function for NK cells stimulated with suboptimal doses of immobilized human immuglobulin G1 (hIgG1). Costimulated NK cells display up-regulat...

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagement

Maniar

Zhang

Lin

et al. 2010

Blood

Self Cite

182

171

View full text Add to dashboard Cite

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“…However, we showed that the response relies primarily on public Vγ2 chain sequences that exist at high frequency within the starting repertoire of BCG-naïve macaques. These same public Vγ2 chains, positively selected during normal ontogeny, encode the response to other Vγ2Vδ2 T cell antigens including alkylphosphates or tumor cells 49 , and are not specific for mycobacteria. The response to BCG is either the result of cross-recognition, where the mycobacterium mimics an antigen encountered previously, or the Vγ2Vδ2 T cell receptor recognizing a host antigen that is modulated or modified during BCG infection.…”

Section: Discussionmentioning

confidence: 99%

Innate-like γδ T cell responses to mycobacterium Bacille Calmette-Guerin using the public Vγ2 repertoire in Macaca fascicularis

et al. 2007

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The Vγ2Vδ2 T cell subset responds to Bacille Calmette-Guerin (BCG) immunization in macaques and may be a component of protective immunity against tuberculosis. We characterized the effects of BCG on the Vγ2Vδ2 T cell receptor repertoire by comparing the starting population of Vγ2 chains in cynomolgus macaques with the repertoire found after priming or booster immunization with BCG. The starting repertoire was dominated by public Vγ2 chain sequences that were found repeatedly among unrelated animals. Primary exposure to BCG triggered expansion of cells expressing public Vγ2 chains and booster immunization was often associated with contraction of these same subsets. Thus, BCG-reactive Vγ2 chains were present at high frequency in the repertoire of mycobacterianaïve macaques and they comprised the major response to primary or booster immunization. Normal selection processes that created the naïve Vγ2 repertoire in macaques, also encoded the capacity for rapid responses to mycobacteria. The unusual composition of a normal Vγ2 repertoire helps to explain the powerful γδ T cell responses to BCG immunization.

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“…ZA has also been shown to play a role in activation of γδ T cells in an antigen-dependent manner [10]. Furthermore, treatment with ZA and interleukin-2 (IL-2) results in increased serum levels of TRAIL in patients with prostate cancer [11].…”

Section: Introductionmentioning

confidence: 99%

“…Zoledronic acid (ZA) is a bisphosphonate that is used to prevent the loss of bone mass and to lower the risk of skeletal complication in patients with bone metastasis [9]. ZA has also been shown to play a role in activation of γδ T cells in an antigen-dependent manner [10]. Furthermore, treatment with ZA and interleukin-2 (IL-2) results in increased serum levels of TRAIL in patients with prostate cancer [11].…”

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Activated monocytes augment TRAIL‐mediated cytotoxicity by human NK cells through release of IFN‐γ

et al. 2012

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250Dhifaf Sarhan et al. Eur. J. Immunol. 2013. 43: 249-257 to the TNF receptor superfamily and include Fas (CD95) and TNF-related apoptosis-inducing ligand (TRAIL) receptors. We have previously demonstrated that peripheral blood NK cells express low levels of TRAIL and are unable to kill TRAIL-sensitive tumors [8]. Zoledronic acid (ZA) is a bisphosphonate that is used to prevent the loss of bone mass and to lower the risk of skeletal complication in patients with bone metastasis [9]. ZA has also been shown to play a role in activation of γδ T cells in an antigen-dependent manner [10]. Furthermore, treatment with ZA and interleukin-2 (IL-2) results in increased serum levels of TRAIL in patients with prostate cancer [11]. In these patients, high serum levels of TRAIL correlated with improved prognosis. Although ZA has been shown to upregulate NKG2D expression on NK cells in vitro [12], it has not been studied whether ZA treatment can augment the expression of TRAIL on human NK cells.Here, we investigated if exposure to ZA would increase the expression of TRAIL on human NK cells and lead to increased TRAIL-mediated killing of tumor cells. When cocultured with monocytes, ZA induced an IFN-γ-dependent upregulation of TRAIL expression on NK cells. As a result, these NK cells displayed increased cytotoxic potential against TRAIL-sensitive tumors in vitro and in vivo. Our findings suggest that adoptive infusion of ZA-primed NK cells with an improved targeting of TRAIL-sensitive tumors may lead to improved outcome in patients with cancer. ResultsTreatment with ZA induces changes in phenotype of NK cells NK cells were isolated from healthy donors and cocultured with irradiated PBMCs and IL-2 with (ZA-primed) or without ZA (unprimed). Following exposure to ZA at concentrations ranging from 1 to 10 μM, surface expression of TRAIL was upregulated compared to NK cells not treated with ZA. However, no changes in surface expression of NKG2D, DNAM-1, FasL, perforin, granzymeB, NKp30, or NKp46 were observed. A minor upregulation in expression of CD69 and NKp44 was detected on NK cells following exposure to ZA (Fig. 1A). In contrast, when purified NK cells were treated with ZA in absence of feeder cells, no changes in TRAIL expression were observed (Supporting Information Fig. 1A), suggesting a requirement for PBMC feeder cells to be present during culturing to induce upregulation of TRAIL on NK cells. ZA upregulates TRAIL expression on NK cells indirectly via monocytesTo determine what cells within the PBMC population were responsible for the increased TRAIL expression on NK cells following treatment with ZA, experiments using different feeder cells were performed. In experiments where NK cells were cocultured with Fig. 1B). In contrast, no change in NKG2D expression on NK cells was observed in presence or absence of ZA upon coculture with monocytes (Supporting Information Fig. 1C). The fold change in TRAIL expression following treatment with ZA was higher when NK cells were cocultured with purified monocytes (3.5-fold, p =...

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Individual Vγ2-Jγ1.2+ T cells respond to both isopentenyl pyrophosphate and Daudi cell stimulation: generating tumor effectors with low molecular weight phosphoantigens

Cited by 27 publications

References 42 publications

Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagement

Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagement

Innate-like γδ T cell responses to mycobacterium Bacille Calmette-Guerin using the public Vγ2 repertoire in Macaca fascicularis

Activated monocytes augment TRAIL‐mediated cytotoxicity by human NK cells through release of IFN‐γ

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