Suppressive activity of Vδ2+ γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength

Schilbach, Karin; Krickeberg, Naomi; Kaißer, Carlotta; Mingram, Simon; Kind, Janika; Siegers, Gabrielle M.; Hashimoto, Hisayoshi

doi:10.1007/s00262-019-02469-8

Cited by 18 publications

(19 citation statements)

References 68 publications

(90 reference statements)

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“…It was observed that the suppressive activity of activated Vδ2T cells on autologous αβ T cells was dependent on the signal strength of the TCR stimulation and enforced by IL-15, but it was independent of TGF-β (in line with the independence of FOXP3). 114 The molecular mechanism of how γδ T cells suppress their neighbors is not precisely known. Conceivably, suppression might, in some instances, result from direct killing of αβ T cells by activated γδ T cells.…”

Section: γδ T Cells: Regulating and Being Regulatedmentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

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Section: γδ T Cells: Regulating and Being Regulatedmentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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“…A more recent approach for cd T cells expansion is using anti-cd TCR mAb (Fisher et al 2014;Dong et al 2018;Schilbach et al 2020). Specific subset of cd T cells can be expanded using Ab against a certain Vc or Vd chain.…”

Section: Role Of CD T Cells In Human Sars-cov-2 Infectionsmentioning

confidence: 99%

Making a case for using γδ T cells against SARS-CoV-2

Yazdanifar

Mashkour

Bertaina

2020

Critical Reviews in Microbiology

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Intensive worldwide efforts are underway to determine both the pathogenesis of SARS-CoV-2 infection and the immune responses in COVID-19 patients in order to develop effective therapeutics and vaccines. One type of cell that may contribute to these immune responses is the cd T lymphocyte, which plays a key role in immunosurveillance of the mucosal and epithelial barriers by rapidly responding to pathogens. Although found in low numbers in blood, cd T cells consist the majority of tissue-resident T cells and participate in the front line of the host immune defense. Previous studies have demonstrated the critical protective role of cd T cells in immune responses to other respiratory viruses, including SARS-CoV-1. However, no studies have profoundly investigated these cells in COVID-19 patients to date. cd T cells can be safely expanded in vivo using existing inexpensive FDA-approved drugs such as bisphosphonate, in order to test its protective immune response to SARS-CoV-2. To support this line of research, we review insights gained from previous coronavirus research, along with recent findings, discussing the potential role of cd T cells in controlling SARS-CoV-2. We conclude by proposing several strategies to enhance cd T cell's antiviral function, which may be used in developing therapies for COVID-19.

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“…It has been known for some time that the TCR is involved in the acquisition of suppressive function of γδ T cells [12][13][14] and we showed recently that suppressive activity of Vδ2 + γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength [56]. Thus TCR-independent activation of γδ T cells is highly desirable for unbiased immunotherapy in cancer to prevent unwanted effects on adaptive T cell responses.…”

Section: Discussionmentioning

confidence: 90%

In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

Schilbach

Welker

Krickeberg

et al. 2020

Cancers

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Abundant IFN-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, γδ T cells generate the pro-inflammatory cytokines TNF-α and IFN-γ, or granzymes and perforin that mediate cellular apoptosis. Despite these favorable potentials, most clinical trials testing the adoptive transfer of pharmacologically TCR-targeted and expanded γδ T cells resulted in a limited response. Recently, the TCR-independent activation of γδ T cells was identified. However, the modulation of γδ T cell’s effector functions solely by cytokines remains to be elucidated. In the present study, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of γδ T cells. Our results demonstrate that IL-12 and IL-18, when combined, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-γ production by γδ T cells in the absence of TCR signaling. Intriguingly, stimulation with IL-12 and IL-18 without TCR stimulus induces a comparable degree of anti-tumor activity in γδ T cells to TCR crosslinking by killing tumor cells and driving cancer cells into senescence. These findings approve the use of IL-12/IL-18-stimulated γδ T cells for adoptive cell therapy to boost anti-tumor activity by γδ T cells.

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Suppressive activity of Vδ2+ γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength

Cited by 18 publications

References 68 publications

Cancer immunotherapy with γδ T cells: many paths ahead of us

Cancer immunotherapy with γδ T cells: many paths ahead of us

Making a case for using γδ T cells against SARS-CoV-2

In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

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