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Gamma Delta T Cells (γδ T Cells) in Health and...
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Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 104551

Special Issue Editor

Prof. Dr. Dieter Kabelitz

E-Mail Website
Guest Editor
Institute of Immunology, Christian-Albrechts University of Kiel, Kiel, Germany
Interests: human gamma/delta T cells; T-cell activation; adoptive immunotherapy; tumor immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gamma/delta T cells differ from conventional alpha/beta T cells in that they recognize their ligands in an MHC/HLA-nonrestricted manner. Moreover, the germline repertoire of the gamma/delta variable T-cell receptor gene segments is much smaller compared to that of the alpha/beta T-cell receptor gene segments. Gamma/delta T cells recognize metabolites overproduced by stressed and transformed cells, as well as surface molecules upregulated upon cellular stress. Because of their potent anti-tumor activity, gamma/delta T cells have recently attracted much attention as effector cells for cancer immunotherapy. However, gamma/delta T cells also contribute to anti-infective immunity and are involved in autoimmunity. Increasing evidence also supports an important regulatory role of gamma/delta T cells in the interplay with other immune cells including alpha/beta T cells and dendritic cells. This Special Issue of Cells aims to provide an update of our current knowledge of the role of gamma/delta T cells under normal physiologic conditions as well as in diseases, including infectious diseases, autoimmunity, and cancer.  Moreover, we welcome contributions which highlight the translational and therapeutic potential of gamma/delta T cells.

This Special Issue is dedicated to the memory of Prof. Wendy Havran, a pioneer in the field of gamma/delta T-cell research, who unexpectedly passed away on 20 January 2020. Dr. Havran made major contributions to the role of gamma/delta T-cell in local immune surveillance and epithelial immunity. She will remain with us, an outstanding member of the gamma/delta T-cell community, and a close friend to many of us.

Prof. Dr. Dieter Kabelitz
Guest Editor

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Keywords

  • gamma delta T cells
  • infectious diseases
  • tumor immunology
  • autoimmunity
  • cellular immunotherapy

Published Papers (18 papers)

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Editorial

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7 pages, 242 KiB  
Editorial
Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran
by Dieter Kabelitz
Cells 2020, 9(12), 2564; https://doi.org/10.3390/cells9122564 - 30 Nov 2020
Cited by 9 | Viewed by 2858
Abstract
Gamma delta (γδ) T cells are a small subset of CD3-positive T cells in the peripheral blood but occur at increased frequency in mucosal tissues [...] Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
2 pages, 141 KiB  
Editorial
Wendy L. Havran, PhD: 1955–2020
by Deborah A. Witherden
Cells 2020, 9(4), 1039; https://doi.org/10.3390/cells9041039 - 22 Apr 2020
Cited by 2 | Viewed by 2407
Abstract
Wendy Havran, Professor and Associate Dean of Graduate Studies at Scripps Research, passed away on January 20th, 2020 following a heart attack [...] Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)

Research

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16 pages, 2558 KiB  
Article
Comparable Vδ2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals
by Matthew L. Clohosey, Brendan T. Mann, Paul L. Ryan, Tatiyana V. Apanasovich, Sanjay B. Maggirwar, Daniel J. Pennington and Natalia Soriano-Sarabia
Cells 2020, 9(12), 2568; https://doi.org/10.3390/cells9122568 - 1 Dec 2020
Cited by 7 | Viewed by 2057
Abstract
Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like γδ T cells promote immunity by facilitating communication between the two compartments and exerting cytotoxic effector functions. Dysregulation of γδ T [...] Read more.
Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like γδ T cells promote immunity by facilitating communication between the two compartments and exerting cytotoxic effector functions. Dysregulation of γδ T cell populations is a byproduct of primary Humanimmunodeficiency virus (HIV) infection. This is most pronounced in the depletion and loss of function within cells expressing a Vγ9Vδ2 TCR (Vδ2 cells). Whether or not prolonged viral suppression mediated by antiretroviral therapy (ART) can reverse these effects has yet to be determined. In this study, we present evidence of similar Vδ2 cell functional responses within a cohort of people living with HIV (PLWH) that has been stably suppressed for >1 year and uninfected donors. Through the use of aminobisphosphonate drugs, we were able to generate a comprehensive comparison between ex vivo and expanded Vδ2 cells within each group. Both groups had largely similar compositions of memory and effector phenotypes, post-expansion TCR repertoire diversity, and cytotoxic capabilities. Our findings support the notion that ART promotes the recovery of Vδ2 polyfunctionality and provides insight for strategies aiming to reconstitute the full immune response after infection with HIV. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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14 pages, 2438 KiB  
Article
Mistletoe-Extract Drugs Stimulate Anti-Cancer Vγ9Vδ2 T Cells
by Ling Ma, Swati Phalke, Caroline Stévigny, Florence Souard and David Vermijlen
Cells 2020, 9(6), 1560; https://doi.org/10.3390/cells9061560 - 26 Jun 2020
Cited by 9 | Viewed by 3843
Abstract
Human phosphoantigen-reactive Vγ9Vδ2 T cells possess several characteristics, including MHC-independent recognition of tumor cells and potent killing potential, that make them attractive candidates for cancer immunotherapeutic approaches. Injectable preparations from the hemi-parasite plant Viscum album L. (European mistletoe) are commonly prescribed as complementary [...] Read more.
Human phosphoantigen-reactive Vγ9Vδ2 T cells possess several characteristics, including MHC-independent recognition of tumor cells and potent killing potential, that make them attractive candidates for cancer immunotherapeutic approaches. Injectable preparations from the hemi-parasite plant Viscum album L. (European mistletoe) are commonly prescribed as complementary cancer therapy in European countries such as Germany, but their mechanism of action remains poorly understood. Here, we investigated in-depth the in vitro response of human T cells towards mistletoe-extract drugs by analyzing their functional and T-cell-receptor (TCR) response using flow cytometry and high-throughput sequencing respectively. Non-fermented mistletoe-extract drugs (AbnobaViscum), but not their fermented counterparts (Iscador), induced specific expansion of Vγ9Vδ2 T cells among T cells. Furthermore, AbnobaViscum rapidly induced the release of cytotoxic granules and the production of the cytokines IFNγ and TNFα in Vγ9Vδ2 T cells. This stimulation of anti-cancer Vγ9Vδ2 T cells was mediated by the butyrophilin BTN3A, did not depend on the accumulation of endogenous phosphoantigens and involved the same Vγ9Vδ2 TCR repertoire as those of phosphoantigen-reactive Vγ9Vδ2 T cells. These insights highlight Vγ9Vδ2 T cells as a potential target for mistletoe-extract drugs and their role in cancer patients receiving these herbal drugs needs to be investigated. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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18 pages, 3668 KiB  
Article
Diversity of Tumor-Infiltrating, γδ T-Cell Abundance in Solid Cancers
by Ghita Chabab, Florence Boissière-Michot, Caroline Mollevi, Jeanne Ramos, Evelyne Lopez-Crapez, Pierre-Emmanuel Colombo, William Jacot, Nathalie Bonnefoy and Virginie Lafont
Cells 2020, 9(6), 1537; https://doi.org/10.3390/cells9061537 - 24 Jun 2020
Cited by 29 | Viewed by 3798
Abstract
γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive [...] Read more.
γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive therapeutic target for immunotherapies, but their presence and abundance in the tumor microenvironment are not routinely assessed in patients with cancer. Here, we validated an antibody for immunohistochemistry analysis that specifically detects all γδ T-cell subpopulations in healthy tissues and in the microenvironment of different cancer types. Tissue microarray analysis of breast, colon, ovarian, and pancreatic tumors showed that γδ T-cell density varies among cancer types. Moreover, the abundance of γδ tumor-infiltrating lymphocytes was variably associated with the outcome depending on the cancer type, suggesting that γδ T-cell recruitment is influenced by the context. These findings also suggest that γδ T-cell detection and analysis might represent a new and interesting diagnostic or prognostic marker. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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22 pages, 2846 KiB  
Article
Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells
by Hannah Jonescheit, Hans-Heinrich Oberg, Daniel Gonnermann, Martin Hermes, Vjola Sulaj, Christian Peters, Dieter Kabelitz and Daniela Wesch
Cells 2020, 9(5), 1140; https://doi.org/10.3390/cells9051140 - 6 May 2020
Cited by 25 | Viewed by 3560
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant gastrointestinal disease. The enzyme indoleamine-2,3-dioxgenase (IDO) is often overexpressed in PDAC and its downstream metabolite kynurenine has been reported to inhibit T cell activation and proliferation. Since γδ T cells are of high interest for [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant gastrointestinal disease. The enzyme indoleamine-2,3-dioxgenase (IDO) is often overexpressed in PDAC and its downstream metabolite kynurenine has been reported to inhibit T cell activation and proliferation. Since γδ T cells are of high interest for T cell-based immunotherapy against PDAC, we studied the impact of IDO and kynurenine on γδ T cell cytotoxicity against PDAC cells. Methods: IDO expression was determined in PDAC cells by flow cytometry and Western blot analysis. PDAC cells were cocultured with γδ T cells in medium or were stimulated with phosphorylated antigens or bispecific antibody in the presence or absence of IDO inhibitors. Additionally, γδ T cells were treated with recombinant kynurenine. Read-out assays included degranulation, cytotoxicity and cytokine measurement as well as cell cycle analysis. Results: Since IDO overexpression was variable in PDAC, IDO inhibitors improved γδ T cell cytotoxicity only against some but not all PDAC cells. γδ T cell degranulation and cytotoxicity were significantly decreased after their treatment with recombinant kynurenine. Conclusions: Bispecific antibody drastically enhanced γδ T cell cytotoxicity against all PDAC cells, which can be further enhanced by IDO inhibitors against several PDAC cells, suggesting a striking heterogeneity in PDAC escape mechanisms towards γδ T cell-mediated anti-tumor response. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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40 pages, 4407 KiB  
Article
Human Peripheral Blood Gamma Delta T Cells: Report on a Series of Healthy Caucasian Portuguese Adults and Comprehensive Review of the Literature
by Sónia Fonseca, Vanessa Pereira, Catarina Lau, Maria dos Anjos Teixeira, Marika Bini-Antunes and Margarida Lima
Cells 2020, 9(3), 729; https://doi.org/10.3390/cells9030729 - 16 Mar 2020
Cited by 31 | Viewed by 5864
Abstract
Gamma delta T cells (Tc) are divided according to the type of Vδ and Vγ chains they express, with two major γδ Tc subsets being recognized in humans: Vδ2Vγ9 and Vδ1. Despite many studies in pathological conditions, only a few have quantified the [...] Read more.
Gamma delta T cells (Tc) are divided according to the type of Vδ and Vγ chains they express, with two major γδ Tc subsets being recognized in humans: Vδ2Vγ9 and Vδ1. Despite many studies in pathological conditions, only a few have quantified the γδ Tc subsets in healthy adults, and a comprehensive review of the factors influencing its representation in the blood is missing. Here we quantified the total γδ Tc and the Vδ2/Vγ9 and Vδ1 Tc subsets in the blood from 30 healthy, Caucasian, Portuguese adults, we characterized their immunophenotype by 8-color flow cytometry, focusing in a few relevant Tc markers (CD3/TCR-γδ, CD5, CD8), and costimulatory (CD28), cytotoxic (CD16) and adhesion (CD56) molecules, and we examined the impacts of age and gender. Additionally, we reviewed the literature on the influences of race/ethnicity, age, gender, special periods of life, past infections, diet, medications and concomitant diseases on γδ Tc and their subsets. Given the multitude of factors influencing the γδ Tc repertoire and immunophenotype and the high variation observed, caution should be taken in interpreting “abnormal” γδ Tc values and repertoire deviations, and the clinical significance of small populations of “phenotypically abnormal” γδ Tc in the blood. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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15 pages, 3766 KiB  
Article
Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes
by Ruben Serrano, Daniela Wesch and Dieter Kabelitz
Cells 2020, 9(3), 713; https://doi.org/10.3390/cells9030713 - 13 Mar 2020
Cited by 20 | Viewed by 4667 | Correction
Abstract
Background: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation [...] Read more.
Background: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation in a monocyte-dependent manner. Therefore, we studied the modulation of human γδ T-cell activation by TLR7/8 ligands. Methods: Peripheral blood mononuclear cells (PBMC) or purified γδ T cells together with purified monocytes were stimulated with zoledronic acid or phosphoantigens in the absence or presence of various imidazoquinoline TLR7 or TLR8 agonists. Read-out systems included interferon-γ induction and cellular expansion of γδ T cells, as well as viability, cell surface antigen modulation, and IL-1β and TNF-α production of monocytes. Results: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-γ expression in γδ T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-γ expression in γδ T cells. On the other hand, TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1β and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. Conclusions: TLR8 ligand-activated monocytes potently co-stimulate early γδ T-cell activation but failed to provide accessory cell function for in vitro expansion of γδ T cells. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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Review

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26 pages, 3696 KiB  
Review
An Update on the Molecular Basis of Phosphoantigen Recognition by Vγ9Vδ2 T Cells
by Thomas Herrmann, Alina Suzann Fichtner and Mohindar Murugesh Karunakaran
Cells 2020, 9(6), 1433; https://doi.org/10.3390/cells9061433 - 9 Jun 2020
Cited by 43 | Viewed by 6078
Abstract
About 1–5% of human blood T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains contain a rearrangement of Vγ9 with JP (TRGV9JP or Vγ2Jγ1.2) and are paired with Vδ2 (TRDV2)-containing [...] Read more.
About 1–5% of human blood T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains contain a rearrangement of Vγ9 with JP (TRGV9JP or Vγ2Jγ1.2) and are paired with Vδ2 (TRDV2)-containing δ-chains. These TCRs respond to phosphoantigens (PAg) such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which is found in many pathogens, and isopentenyl pyrophosphate (IPP), which accumulates in certain tumors or cells treated with aminobisphosphonates such as zoledronate. Until recently, these cells were believed to be restricted to primates, while no such cells are found in rodents. The identification of three genes pivotal for PAg recognition encoding for Vγ9, Vδ2, and butyrophilin (BTN) 3 in various non-primate species identified candidate species possessing PAg-reactive Vγ9Vδ2 T cells. Here, we review the current knowledge of the molecular basis of PAg recognition. This not only includes human Vγ9Vδ2 T cells and the recent discovery of BTN2A1 as Vγ9-binding protein mandatory for the PAg response but also insights gained from the identification of functional PAg-reactive Vγ9Vδ2 T cells and BTN3 in the alpaca and phylogenetic comparisons. Finally, we discuss models of the molecular basis of PAg recognition and implications for the development of transgenic mouse models for PAg-reactive Vγ9Vδ2 T cells. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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26 pages, 1626 KiB  
Review
γδ T Cells: The Ideal Tool for Cancer Immunotherapy
by Mahboubeh Yazdanifar, Giulia Barbarito, Alice Bertaina and Irma Airoldi
Cells 2020, 9(5), 1305; https://doi.org/10.3390/cells9051305 - 24 May 2020
Cited by 87 | Viewed by 17163
Abstract
γδ T cells have recently gained considerable attention as an attractive tool for cancer adoptive immunotherapy due to their potent anti-tumor activity and unique role in immunosurveillance. The remarkable success of engineered T cells for the treatment of hematological malignancies has revolutionized the [...] Read more.
γδ T cells have recently gained considerable attention as an attractive tool for cancer adoptive immunotherapy due to their potent anti-tumor activity and unique role in immunosurveillance. The remarkable success of engineered T cells for the treatment of hematological malignancies has revolutionized the field of adoptive cell immunotherapy. Accordingly, major efforts are underway to translate this exciting technology to the treatment of solid tumors and the development of allogeneic therapies. The unique features of γδ T cells, including their major histocompatibility complex (MHC)-independent anti-cancer activity, tissue tropism, and multivalent response against a broad spectrum of the tumors, render them ideal for designing universal ‘third-party’ cell products, with the potential to overcome the challenges of allogeneic cell therapy. In this review, we describe the crucial role of γδ T cells in anti-tumor immunosurveillance and we summarize the different approaches used for the ex vivo and in vivo expansion of γδ T cells suitable for the development of novel strategies for cancer therapy. We further discuss the different transduction strategies aiming at redirecting or improving the function of γδ T cells, as well as, the considerations for the clinical applications. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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17 pages, 655 KiB  
Review
The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy
by Yuxia Liu and Cai Zhang
Cells 2020, 9(5), 1206; https://doi.org/10.3390/cells9051206 - 13 May 2020
Cited by 36 | Viewed by 7205
Abstract
γδ T cells are a distinct subset of T cells whose T cell receptors consist of γ chains and δ chains, different from conventional αβ T cells. γδ T cells are considered as a member of the innate immunity because of their non-MHC [...] Read more.
γδ T cells are a distinct subset of T cells whose T cell receptors consist of γ chains and δ chains, different from conventional αβ T cells. γδ T cells are considered as a member of the innate immunity because of their non-MHC restricted antigen recognition, rapid response to invading pathogens and sense early changes of malignant cells. Upon activation, they can further promote the activation of adaptive immune cells, such as T cells and B cells, by secreting various cytokines. Thus, γδ T cells are regarded as a bridge between innate immunity and acquired immunity. γδ T cells are involved in a variety of immune response processes, including immune defense and immune surveillance against infection and tumorigenesis. γδ T cells recognize multiple tumor-associated antigens or molecules in T cell receptors (TCRs)-dependent and natural killer cell receptors (NKRs)-dependent ways. γδ T cells not only display a direct killing capacity on a variety of tumors, but also exert anti-tumor immune responses indirectly by facilitating the function of other immune cells, such as dendritic cells (DCs), B cells and CD8+ T cells. In this review, we summarize the major subpopulations, the tumor recognition mechanisms, and the anti-tumor effects of human γδ T cells, particularly the potential of γδ T cells for cancer immunotherapy. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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18 pages, 948 KiB  
Review
The Aging of γδ T Cells
by Weili Xu, Zandrea Wan Xuan Lau, Tamas Fulop and Anis Larbi
Cells 2020, 9(5), 1181; https://doi.org/10.3390/cells9051181 - 9 May 2020
Cited by 24 | Viewed by 6769
Abstract
In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as [...] Read more.
In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently—resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the human γδ T cell family and its ligands before discussing parallels in mice. By covering the ontogeny and homeostasis of γδ T cells during their lifespan, we will better capture their evolution and responses to age-related stressors. Finally, we will identify knowledge gaps within these topics that can advance our understanding of the relationship between γδ T cells and aging, as well as age-related diseases such as cancer. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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23 pages, 1466 KiB  
Review
Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?
by Klaus-Peter Künkele, Daniela Wesch, Hans-Heinrich Oberg, Martin Aichinger, Verena Supper and Christoph Baumann
Cells 2020, 9(4), 829; https://doi.org/10.3390/cells9040829 - 30 Mar 2020
Cited by 19 | Viewed by 5546
Abstract
Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T [...] Read more.
Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of Vγ9Vδ2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for Vγ9Vδ2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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14 pages, 621 KiB  
Review
Human γδ TCR Repertoires in Health and Disease
by Alina Suzann Fichtner, Sarina Ravens and Immo Prinz
Cells 2020, 9(4), 800; https://doi.org/10.3390/cells9040800 - 26 Mar 2020
Cited by 63 | Viewed by 8369
Abstract
The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T [...] Read more.
The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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14 pages, 546 KiB  
Review
Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance
by Oliver Nussbaumer and Martin Thurnher
Cells 2020, 9(3), 772; https://doi.org/10.3390/cells9030772 - 22 Mar 2020
Cited by 12 | Viewed by 3821
Abstract
Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. [...] Read more.
Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. Vγ9Vδ2 T cells, which cannot be studied easily in vivo because they do not exist in rodents, are often referred to as innate-like T cells. The genetically recombined γδ T cell receptor (TCR) that responds to isoprenoid-derived pyrophosphates (phosphoantigens) produced by infected and malignant cells in a butyrophilin-dependent manner qualifies them as therapeutically relevant components of the adaptive immune system. On the other hand, cell-surface proteins such as the C-type lectin CD161 mark a functional phenotype of Vγ9Vδ2 T cells that mediates TCR-independent innate-like responses. Moreover, CD56 (neural cell adhesion molecule, NCAM) and the G protein-coupled receptor GPR56 define Vγ9Vδ2 T cells with increased cytolytic potential and, like CD161, may also be expressed by dendritic cells, principally facilitating the generation of an innate-like immunological synapse. In this review, we summarise current knowledge of Vγ9Vδ2 T cell functional phenotypes that are critical to lymphoid stress surveillance. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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11 pages, 699 KiB  
Review
Revisiting the Interaction of γδ T-Cells and B-Cells
by Francesca Rampoldi, Leon Ullrich and Immo Prinz
Cells 2020, 9(3), 743; https://doi.org/10.3390/cells9030743 - 18 Mar 2020
Cited by 30 | Viewed by 5486
Abstract
Right after the discovery of γδ T-cells in 1984, people started asking how γδ T-cells interact with other immune cells such as B-cells. Early reports showed that γδ T-cells are able to help B-cells to produce antibodies and to sustain the production of [...] Read more.
Right after the discovery of γδ T-cells in 1984, people started asking how γδ T-cells interact with other immune cells such as B-cells. Early reports showed that γδ T-cells are able to help B-cells to produce antibodies and to sustain the production of germinal centers. Interestingly, the presence of γδ T-cells seems to promote the generation of antibodies against “self” and less against challenging pathogens. More recently, these hypotheses were supported using γδ T-cell-deficient mouse strains, in different mouse models of systemic lupus erythematous, and after induction of epithelial cell damage. Together, these studies suggest that the link between γδ T-cells and the production of autoantibodies may be more relevant for the development of autoimmune diseases than generally acknowledged and thus targeting γδ T-cells could represent a new therapeutic strategy. In this review, we focus on what is known about the communication between γδ T-cells and B-cells, and we discuss the importance of this interaction in the context of autoimmunity. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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19 pages, 1268 KiB  
Review
The Role of Tissue-resident γδ T Cells in Stress Surveillance and Tissue Maintenance
by Margarete D. Johnson, Deborah A. Witherden and Wendy L. Havran
Cells 2020, 9(3), 686; https://doi.org/10.3390/cells9030686 - 11 Mar 2020
Cited by 25 | Viewed by 5154
Abstract
While forming a minor population in the blood and lymphoid compartments, γδ T cells are significantly enriched within barrier tissues. In addition to providing protection against infection, these tissue-resident γδ T cells play critical roles in tissue homeostasis and repair. γδ T cells [...] Read more.
While forming a minor population in the blood and lymphoid compartments, γδ T cells are significantly enriched within barrier tissues. In addition to providing protection against infection, these tissue-resident γδ T cells play critical roles in tissue homeostasis and repair. γδ T cells in the epidermis and intestinal epithelium produce growth factors and cytokines that are important for the normal turnover and maintenance of surrounding epithelial cells and are additionally required for the efficient recognition of, and response to, tissue damage. A role for tissue-resident γδ T cells is emerging outside of the traditional barrier tissues as well, with recent research indicating that adipose tissue-resident γδ T cells are required for the normal maintenance and function of the adipose tissue compartment. Here we review the functions of tissue-resident γδ T cells in the epidermis, intestinal epithelium, and adipose tissue, and compare the mechanisms of their activation between these sites. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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30 pages, 1751 KiB  
Review
The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases
by Ilan Bank
Cells 2020, 9(2), 462; https://doi.org/10.3390/cells9020462 - 18 Feb 2020
Cited by 36 | Viewed by 7319
Abstract
Autoimmune rheumatic diseases (ARDs), affecting ~1–1.5% of all humans, are associated with considerable life long morbidity and early mortality. Early studies in the 1990s showed numerical changes of the recently discovered γδ T cells in the peripheral blood and in affected tissues of [...] Read more.
Autoimmune rheumatic diseases (ARDs), affecting ~1–1.5% of all humans, are associated with considerable life long morbidity and early mortality. Early studies in the 1990s showed numerical changes of the recently discovered γδ T cells in the peripheral blood and in affected tissues of patients with a variety of ARDs, kindling interest in their role in the immuno-pathogenesis of these chronic inflammatory conditions. Indeed, later studies applied rapid developments in the understanding of γδ T cell biology, including antigens recognized by γδ T cells, their developmental programs, states of activation, and cytokine production profiles, to analyze their contribution to the pathological immune response in these disorders. Here we review the published studies addressing the role of γδ T in the major autoimmune rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus and scleroderma, and animal models thereof. Due to their unique properties spanning adaptive and innate immune functions, the ever deeper understanding of this unique T cell population is shedding new light on the pathogenesis of, while potentially enabling new therapeutic approaches to, these diseases. Full article
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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