Antigen recognition by human γδ T cells: pattern recognition by the adaptive immune system

Morita, Craig T.; Mariuzza, Roy A.; Brenner, Michael B.

doi:10.1007/s002810000042

Cited by 158 publications

(162 citation statements)

References 168 publications

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“…[1][2][3][4] They recognize, and are activated by, several phosphorus-containing bacterial and protozoan metabolites [5][6][7][8][9][10] ("phosphoantigens"), such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP, 1), by synthetic phosphoantigens, such as the bromohydrin of isopentenyl pyrophosphate (Phosphostim, 2; refs 11 and 12), and by the bisphosphonate drugs commonly used in bone resorption therapy. 13,14 This activation by synthetic drug or drug-like molecules has led to the idea that γδ T cell activation may be used in the immunotherapy of some forms of cancer, 15,16 in the immunotherapy of infectious diseases, 13 and, potentially, in vaccine development.…”

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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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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“…[5][6][7] T cells expressing the Vg9Vd2 T cell receptor (TCR) play an important role in immune system surveillance and defense. [8][9][10][11] Most current immunotherapeutic approaches aim at inducing antitumor response via stimulation of the adaptive immune system, which is dependent on major histocompatibility complex (MHC)-restricted ab T cells. However, loss of MHC molecules is often observed in cancer cells, rendering tumor cells resistant to ab T cell-mediated cytotoxicity.…”

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confidence: 99%

Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy

Satô

Kimura

Segawa

et al. 2005

Intl Journal of Cancer

133

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Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gdT cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gd T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 mM ZOL plus IL-2 increased the absolute number of gdT cells 298-768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 mM ZOL showed a marked increase in sensitivity to lysis by gdT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gdT cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 mg/kg ZOL also significantly enhanced the antitumor activity of gdT cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gdT cells and that gdT cells required pre-treatment with ZOL for cytotoxic activity against target cells. ' 2005 Wiley-Liss, Inc.

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“…CDR3 length distribution in cdTCRs is more similar to antibodies than to abTCRs, as the CDR3d loops are long and variable, while the CDR3c loops are short and constrained (47). However, cd T cell reactivity seems to correlate with V gene usage, suggesting that CDR3 diversity has little role on the recognition of specific ligands (48).…”

Section: Interaction Of CD T Cell Receptors With Their Ligandsmentioning

confidence: 98%

Structural immunology and crystallography help immunologists see the immune system in action: How T and NK cells touch their ligands

et al. 2009

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SummaryHost immune system is an important and sophisticated system, maintaining the balance of host response to ''foreign'' antigens and ignorance to the normal-self. To fulfill this achievement the system manipulates a cell-cell interaction through appropriate interactions between cell-surface receptors and cellsurface ligands, or cell-secreted soluble effector molecules to their ligands/receptors/counter-receptors on the cell surface, triggering further downstream signaling for response effects. T cells and NK cells are important components of the immune system for defending the infections and malignancies and maintaining the proper response against over-reaction to the host. Receptors on the surface of T cells and NK cells include a number of important protein molecules, for example, T cell receptor (TCR), co-receptor CD8 or CD4, co-stimulator CD28, CTLA4, KIR, CD94/NKG2, LILR (ILT/LIR/CD85), Ly49, and so forth. These receptor molecules interact with their ligands on the target cells, including major histocompatibility complex (MHC) (or human leukocyte antigen, HLA), CD80, CD86, and so forth. Detailed understanding of these receptor-ligand pair interactions is crucial for our full knowledge of the immune system, ultimately for us to manipulate the T cell and NK cell functions. Accumulations of the receptor-ligand complex crystal structures in the recent years have provided us a unique angel to see how the immune cells interacting with their partner cells. In this review, we discussed binding specificity, plasticity, and flexibility of the T cell and NK cell receptor/ligand interaction, fitting the structural data with their functions. Structural immunology indeed helps us see how T and NK cells ''touch'' their target cells in our immune system.

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Antigen recognition by human γδ T cells: pattern recognition by the adaptive immune system

Cited by 158 publications

References 168 publications

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

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

Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy

Structural immunology and crystallography help immunologists see the immune system in action: How T and NK cells touch their ligands

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