Prolonged antigen survival and cytosolic export in cross-presenting human γδ T cells

Meuter, Simone; Eberl, Matthias; Moser, Bernhard

doi:10.1073/pnas.1002769107

Cited by 65 publications

(89 citation statements)

References 39 publications

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“…However, Moser and colleagues (47,48) demonstrated that activated gd T cells can differentiate and may acquire many features of accessory cells, including increased endocytic activity, which would be required to accumulate zoledronate and to produce IPP. In addition, acquisition of accessory potential by gd T cells activated via the TCR may enable mutual costimulation (e.g., via CD70-CD27 interactions) (35,49).…”

Section: Discussionmentioning

confidence: 99%

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vγ9Vδ2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced γδ T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56brightCD11c+ NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1–mediated maturation and release of IL-18, which, in turn, induced γδ T cell CCL2. Likewise, zoledronate caused a substantial delay in γδ T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Rα (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified γδ T cells, even when starting cell numbers were as low as 104 γδ T cells. Our study reveals essential components of γδ T cell activation and indicates that exogenous IL-18, which can directly costimulate γδ T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust γδ T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes.

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Section: Discussionmentioning

confidence: 99%

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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“…Expression of HLA-DR is a well known attribute of activated T cells, and such activated T cells may be able to present antigens in appropriate contexts [117]. However, only Vc9/Vd2 T cells have been shown to be able to act as truly professional APCs, as characterized by the effective uptake and processing of exogenous antigens through endocytosis [118] and even phagocytosis [119], and the priming and differentiation of naive CD4 + and CD8 + T cells [116,120] (Fig. 1).…”

Section: Priming Of Cd4 + and Cd8 + T Cells By Vc9/vd2 T Cells: A Newmentioning

confidence: 99%

“…Activated Vc9/ Vd2 T cells turned out to be well equipped cross-presenting APCs capable of processing not only defined proteins but also complex material such as cell debris and whole bacteria, and shuttle endocytosed antigens into the cytosol for degradation by the proteasome [118][119][120]. As Vc9/Vd2 T cells retain their cytolytic potential when they acquire APC functions [127], this unique combination of direct target cytotoxicity and APC machinery allows for scenarios in which Vc9/Vd2 T cells would lyse transformed, stressed or infected cells, and take up and process released proteins for presentation to both CD4 + and CD8 + T cells, with enormous implications for novel immunotherapies and vaccines [128][129][130][131][132].…”

Section: Priming Of Cd4 + and Cd8 + T Cells By Vc9/vd2 T Cells: A Newmentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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“…28 In addition, another group has shown that cd-T cells can initiate efficient adaptive immunity through processing and presenting influenza virus-derived peptides to CD4 1 and CD8 1 T cells. 29 Moreover, cd-T cells have been found to promote the establishment of protective adaptive immunity against West Nile virus by inducing the maturation of dendritic cells (DCs). 30 However, the protective functions of cd-T cells can be impaired by some viruses.…”

Section: Involvement Of Cd-t Cells In Infectious Diseasesmentioning

confidence: 99%

“…In addition to their direct anti-infection activities, human cd-T cells act as professional APCs and take up, process and present pathogen-related antigens from both free viral particles 29 and infected cells 57,105 to other effector immune cells. 106,107 These cd-T APCs express approximately similar levels of HLA-DR and CD80/ CD86 compared to traditional APCs 29 and induce NK cell activation, 108,109 antigen-specific ab-T-cell responses 29,107 and even antibody production. 67 Although the physiological roles of cd-T APCs still need to be illuminated by more in vivo studies, recent investigations of murine cd-T cells have confirmed the general existence of cd-T APCs.…”

Section: Direct Anti-infection Activity Mediated By Cd-t Cells Directmentioning

confidence: 99%

γδ-T cells: an unpolished sword in human anti-infection immunity

et al. 2012

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cd-T cells represent a small population of immune cells, but play an indispensable role in host defenses against exogenous pathogens, immune surveillance of endogenous pathogenesis and even homeostasis of the immune system. Activation and expansion of cd-T cells are generally observed in diverse human infectious diseases and correlate with their progression and prognosis. cd-T cells have both 'innate' and 'adaptive' characteristics in the immune response, and their anti-infection activities are mediated by multiple pathways that are under elaborate regulation by other immune components. In this review, we summarize the current state of the literature and the recent advancements in cd-T cell-mediated immune responses against common human infectious pathogens. Although further investigation is needed to improve our understanding of the characteristics of different cd-T cell subpopulations under specific conditions, cd-T cell-based therapy has great potential for the treatment of infectious diseases.

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Prolonged antigen survival and cytosolic export in cross-presenting human γδ T cells

Cited by 65 publications

References 39 publications

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

γδ-T cells: an unpolished sword in human anti-infection immunity

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