Human γδ <scp>T</scp>‐cell responses in infection and immunotherapy: Common mechanisms, common mediators?

Riganti, Chiara; Massaia, Massimo; Davey, Martin S.; Eberl, Matthias

doi:10.1002/eji.201242492

Cited by 55 publications

(48 citation statements)

References 59 publications

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“…In these organisms, HMB-PP is converted into isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), two further 'phosphoantigens' with a bioactivity approx. 10,000-fold lower than that of HMB-PP [11,16]. In all other bacteria as well as in higher eukaryotes including humans, IPP and DMAPP are generated via the mevalonate pathway that is closely regulated by the action of 3-hydroxy-3-methyl-glutaryl-CoA reductase and downstream enzymes such as farnesyl pyrophosphate synthase.…”

Section: Innate-like Pattern Recognition By Human Vc9/vd2 T Cellsmentioning

confidence: 99%

“…In all other bacteria as well as in higher eukaryotes including humans, IPP and DMAPP are generated via the mevalonate pathway that is closely regulated by the action of 3-hydroxy-3-methyl-glutaryl-CoA reductase and downstream enzymes such as farnesyl pyrophosphate synthase. Overproduction of the low bioactivity compounds IPP and DMAPP as a result of a dysregulation of the mevalonate pathway in human cells, be it in metabolically active tissues including tumor cells or through inhibition of farnesyl pyrophosphate synthase by aminobisphophonates such as zoledronate, is thought to render such cells targets of Vc9/Vd2 T cells, despite the absence of the high bioactivity metabolite HMB-PP in this context [11,[16][17][18]. Zoledronate and related drugs are therefore receiving substantial attention as Vc9/Vd2 T cellstimulating agents in vivo especially with respect to immunotherapies against advanced solid and hematological tumors [19][20][21].…”

Section: Like Other 'Unconventional' T Cells Carrying An Ab Tcr Such mentioning

confidence: 99%

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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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Section: Innate-like Pattern Recognition By Human Vc9/vd2 T Cellsmentioning

confidence: 99%

Section: Like Other 'Unconventional' T Cells Carrying An Ab Tcr Such mentioning

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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“…These cells proliferate vigorously in vitro in response to stimulation of microbial or synthetic phosphoantigens [6]. They play a critical role in anti-infection immunity and anti-tumor surveillance [18, 19]. Activated Vγ9Vδ2 T cells express granulysin, perforin, Fas/Fas ligand (FasL), granzyme-A and B,to kill the asexual stages of P.falciparum and inhibit the growth of intraerythrocytic stages of P.falciparum in the blood [20].…”

Section: Classification Of γδ T Cellsmentioning

confidence: 99%

γδ T cells in cancer immunotherapy

et al. 2016

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γδ T cells are one of the three immune cell types that express antigen receptors. They contribute to lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. γδ T cells have the capacity of secreting abundant cytokines and exerting potent cytotoxicity against a wide range of cancer cells. γδ T cells exhibit important roles in immune-surveillance and immune defense against tumors and have become attractive effector cells for cancer immunotherapy. γδ T cells mediate anti-tumor therapy mainly by secreting pro-apoptotic molecules and inflammatory cytokines, or through a TCR-dependent pathway. Recently, γδ T cells are making their way into clinical trials. Some clinical trials demonstrated that γδ T cell-based immunotherapy is well tolerated and efficient. Despite the advantages that could be exploited, there are obstacles have to be addressed for the development of γδ T cell immunotherapies. Future direction for immunotherapy using γδ T cells should focus on overcoming the side effects of γδ T cells and exploring better antigens that help stimulating γδ T cell expansion in vitro.

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“…This is due to their exquisite responsiveness to the microbial isoprenoid precursor ( E )-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) that is produced by the majority of Gram-negative pathogens and a large proportion of Gram-positive species such as Clostridium difficile, Listeria monocytogenes , and Mycobacterium tuberculosis , while it is not found in other bacteria including staphylococci and streptococci as well as fungi (42–44). The rapid and sensitive response of Vγ9/Vδ2 T-cells to a broad range of pathogens evokes Janeway’s criteria for a “pathogen-associated molecular pattern” in that HMB-PP is an invariant metabolite in many different species that is essential in the microbial physiology but absent from the human host (43, 45). Bacterial extracts prepared from HMB-PP producing species typically activate Vγ9/Vδ2 T-cells much stronger than extracts prepared from HMB-PP deficient micro-organisms (42, 44, 46), and peripheral and/or local Vγ9/Vδ2 T-cell levels are often elevated in patients infected with defined HMB-PP producing pathogens (43, 47).…”

Section: Quantum Of Solace: Exploitation Of Pathogen-specific Host Rementioning

confidence: 99%