Lysis of a Broad Range of Epithelial Tumour Cells by Human <i>γ</i><i>δ</i> T Cells: Involvement of NKG2D ligands and T‐cell Receptor‐ versus NKG2D‐dependent Recognition

Wrobel, Philine; Shojaei, Hamed; Schittek, Birgit; Gieseler, Frank; Wollenberg, Barbara; Kalthoff, Holger; Kabelitz, Dieter; Wesch, Daniela

doi:10.1111/j.1365-3083.2007.01963.x

Cited by 185 publications

(176 citation statements)

References 57 publications

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“…40 In fact, there is little understanding in the literature as to how ␥␦ T cells are stimulated in response to injury. Studies have shown that ␥␦ T cells may recognize "self" ligands, such as CD1c, 50 -52 T10 and T22, 53 and MHC class I related chains A and B 54 ; as well as stress proteins, such as heat shock proteins 60 55,56 and 70. 57 In humans, ␥␦ T cells have also been stimulated by various phosphoantigens.…”

Section: Discussionmentioning

confidence: 99%

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

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␥␦ T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ␥␦ T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ␦ chain of the ␥␦ T-cell receptor (␥␦ knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ␥␦ KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ␥␦ KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ␥␦ T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ␥␦ T cells produced substantial quantities of all four of these cytokines, suggesting that ␥␦ T cells are a predominant source of these proteins. To demonstrate that ␥␦ T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ␥␦ T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ␥␦ KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ␥␦ KO mice. Finally, adoptive transfer of ␥␦ T cells from CXCL10 ؊/؊ mice failed to reverse the severe fibrosis in ␥␦ KO mice. These results indicate that ␥␦ T cells promote the resolution of fibrosis through the production of

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Section: Discussionmentioning

confidence: 99%

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

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“…Natural killer (NK) cells share some characteristics with cd T cells as both are usually considered constituents of innate immunity, recognize transformed cells, play a prominent role in antiviral protection and are cytolytic lymphocytes. [8][9][10] Like NK cells, human cd T cells express activating receptors, such as NKG2D that recognizes stress-inducible MHC class I-related MICA/MICB molecules and the UL16-binding proteins that are upregulated on malignant or stressed cells and induce cytolysis, 11,12 and they are inhibited by the expression of killer Ig-like receptors, which bind certain MHC class I alleles expressed by nonmalignant cells and trophoblasts. [13][14][15] However, the versatility of cd T cells is further extended by their demonstrated ability to assume the role and appearance of professional antigen presenting cells.…”

Section: Prologuementioning

confidence: 99%

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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“…Human γδ T cells also possess IFN-γ-secreting potential, which is displayed immediately at birth (8) and display cytotoxicity against tumor lines of diverse origin, including epithelial (9,10) and hematological (11,12) tumors. This has prompted the development of cancer clinical trials targeting γδ T cells, which have produced encouraging, albeit highly variable, degrees of therapeutic responses (13)(14)(15).…”

Section: Gamma-delta T Cells | Tumor Immunologymentioning

confidence: 99%

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Rei

Gonçalves-Sousa

Lança

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

173

186

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Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumor cell growth in situ. These subsets include γδ T cells, which can infiltrate tumors and typically provide large amounts of antitumor cytokines, such as IFN-γ. By contrast, we report here that in a well-established transplantable (ID8 cell line) model of peritoneal/ovarian cancer, γδ T cells promote tumor cell growth. γδ T cells accumulated in the peritoneal cavity in response to tumor challenge and could be visualized within solid tumor foci. Functional characterization of tumor-associated γδ T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-γ. Consistent with this finding, both T cell receptor (TCR)δ-deficient and IL-17-deficient mice displayed reduced ID8 tumor growth compared with wild-type animals. IL-17 production by γδ T cells in the tumor environment was essentially restricted to a highly proliferative CD27 (−) subset that expressed Vγ6 instead of the more common Vγ1 and Vγ4 TCR chains. The preferential expansion of IL-17-secreting CD27 (−) Vγ6 (+) γδ T cells associated with the selective mobilization of unconventional small peritoneal macrophages (SPMs) that, in comparison with large peritoneal macrophages, were enriched for IL-17 receptor A, and for protumor and proangiogenic molecular mediators, which were upregulated by IL-17. Importantly, SPMs were uniquely and directly capable of promoting ovarian cancer cell proliferation. Collectively, this work identifies an IL-17-dependent lymphoid/myeloid crosstalk involving γδ T cells and SPMs that promotes tumor cell growth and thus counteracts cancer immunosurveillance. gamma-delta T cells | tumor immunologyD eveloping tumors are infiltrated by a variety of leukocyte subsets that can either promote or inhibit inflammation, and thus impact on cancer progression (1). Among such populations are γδ T cells, which are major players in lymphoid stress surveillance likely due to their recognition of stress-inducible molecules independently of MHC-mediated antigen presentation (2). Moreover, abundant IFN-γ secretion and cytotoxic effector functions endow γδ T cells with potent antitumor activity. This has been clearly documented in murine models of spontaneous (3), chemically induced (4), transgenic (5), and transplantable (6, 7) tumors. For example, in the widely used B16 melanoma model, γδ T cells were shown to infiltrate tumors very early and provided a critical source of IFN-γ that significantly delayed tumor growth (6, 7).Human γδ T cells also possess IFN-γ-secreting potential, which is displayed immediately at birth (8) and display cytotoxicity against tumor lines of diverse origin, including epithelial (9, 10) and hematological (11,12) tumors. This has prompted the development of cancer clinical trials targeting γδ T cells, which have produced encouraging, albeit highly variable, degrees of therapeutic responses (13-15). There is therefore great interest in maximizing the antitumor functions of γδ T cells for cancer ...

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Lysis of a Broad Range of Epithelial Tumour Cells by Human γδ T Cells: Involvement of NKG2D ligands and T‐cell Receptor‐ versus NKG2D‐dependent Recognition

Cited by 185 publications

References 57 publications

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

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Lysis of a Broad Range of Epithelial Tumour Cells by Human γδ T Cells: Involvement of NKG2D ligands and T‐cell Receptor‐ versus NKG2D‐dependent Recognition

Cited by 185 publications

References 57 publications

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

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Product

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Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages