Human γδ TCR Repertoires in Health and Disease

Fichtner, Alina Suzann; Ravens, Sarina; Prinz, Immo

doi:10.3390/cells9040800

Cited by 72 publications

(60 citation statements)

References 110 publications

(217 reference statements)

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“… 59 The γδ TCR repertoire has been extensively studied during normal development and in infectious diseases. 88 Some studies have also noted different γδ TCR repertoires in the blood of cancer patients than in healthy controls. 89 However, to better understand the significance of clonal γδ T cell recruitment to the tumor site, more equivalent studies in various tumors and lymphomas are needed.…”

Section: Tumor-infiltrating γδ T Cells: Friends or Foes?mentioning

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: Tumor-infiltrating γδ T Cells: Friends or Foes?mentioning

confidence: 99%

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

et al. 2020

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“…Human γδ T cells are typically classified according to their expressed Vδ-chain 3 . To link the single-cell transcriptome profiles described above to individual γδTCR clones, we next PCRamplified and sequenced full-length V(D)J segments in a two-step enrichment process using gene-specific primers for the TRDC and TRGC genes as described in the methods section.…”

Section: Expression Of Trd Clones Clusters Immature Vδ1 + and Vδ2mentioning

confidence: 99%

“…In contrast, canonic Vγ9Vδ2 + T cells rather grouped with each other but separated into three effector types with strong parallels to lineage-specific differentiation of other PLZF + innate lymphocytes such as NKT-1, NKT-2, and NKT-17 cells 44 . As an important disclaimer, certainly not all Vδ2-chains must pair with Vγ9-chains and vice versa 3,9,20,29 . However, besides the expression of PLZF, an abundance of public TCR clones, polyclonal expansion after phosphoantigen stimulation, and the lack of an exhausted phenotype suggest an innate rather than adaptive phenotype of Vγ9Vδ2 + cells 16 .…”

Section: Delineating Vδ1 + and Vδ2 + Effector Subsets Via Flow Cytometrymentioning

confidence: 99%

“…Furthermore, Vγ9Vδ2 + T cells share common features with other human innate-like T cells like invariant natural killer T (NKT) and mucosa-associated invariant T (MAIT) cells, including expression of PLZF 8 . The remaining non-Vγ9Vδ2 + human γδ T cell subsets express diverse TRG rearrangements, preferentially paired with Vδ1 3 . Information about specific ligands binding to Vδ1 + TCRs is still fragmentary, however, recent findings showed expansion of individual Vδ1 + clones in response to environmental, e.g.…”

Section: Introductionmentioning

confidence: 99%

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A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

Tan

Fichtner

Bubke

et al. 2020

Preprint

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Accumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector γδ T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing γδ T (γδT17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired γδ TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector γδ T cell clusters. While immature γδ T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to γδTCR usage. In adult samples, mature Vδ1+ T cells segregated into exhausted PD-1hi and active PD-1low clusters. Among Vγ9Vδ2+ T cell subsets, we identified distinct PLZF-positive effector γδ T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector γδ T cells including CCR6+ γδT17 cells develop in the early fetal thymus and persist into adulthood.

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“…(I) γδ T cell subsets classified according to the usage of TCRγ-chain or δ-chain. Generally, human γδ T cells can be divided into four major groups, Vδ1, Vδ2, Vδ3 and Vδ5 γδ T cells, based on the differences of TCR δ-chain [15][16][17] (Table 1). They have different distribution and different function.…”

Section: Diversity Of Human γδ T Cell Subsetsmentioning

confidence: 99%

The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy

Liu

Zhang

2020

Cells

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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.

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Human γδ TCR Repertoires in Health and Disease

Cited by 72 publications

References 110 publications

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

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

A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy

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