Ectopically Expressed Human Tumor Biomarker MutS Homologue 2 Is a Novel Endogenous Ligand That Is Recognized by Human γδ T Cells to Induce Innate Anti-tumor/Virus Immunity

Dai, Yumei; Chen, Hui; Chen, Mo; Cui, Lianxian; Wang, He

doi:10.1074/jbc.m111.327650

Cited by 52 publications

(53 citation statements)

References 40 publications

(47 reference statements)

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“…Furthermore, all tumor cells expressed MICA, MICB, ULBP1, ULBP2, ULBP3 and ULBP4 (data not shown), all of which can be recognized by NKG2D. 11,[42][43][44] IL-4 inhibited the expression of NKG2D on Vd1 T cells NKG2D receptor plays an important role in protecting the host from infection and cancer. NKG2D provides a powerful costimulus for the activation of cd T cells.…”

Section: Il-4-induced Vd1 T-cell Bias Weakened the Overall Immune Resmentioning

confidence: 95%

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A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

et al. 2015

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Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (cd) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of cd T cells and the balance between variable delta 1 (Vd1) and Vd2 T cells in humans. The results show that IL-4 inhibits the activation of cd T cells in the presence of cd T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated cd T cells and increased the levels of Vd1 T cells, which in turn inhibited Vd2 T-cell growth via significant IL-10 secretion. Vd1 T cells secreted significantly less interferon gamma (IFNc) and more IL-10 relative to Vd2. Furthermore, Vd1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vd1 T cells weaken the cd T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in cd T cell-mediated anti-tumor immunity. Cellular & Molecular Immunology

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Section: Il-4-induced Vd1 T-cell Bias Weakened the Overall Immune Resmentioning

confidence: 95%

“…NKG2D provides a powerful costimulus for the activation of cd T cells. 42,43,[45][46][47][48] Here, NKG2D expression on cd T cells was detected by flow cytometry. The results show that nearly all activated Vd2 T cells expressed the NKG2D receptor.…”

Section: Il-4-induced Vd1 T-cell Bias Weakened the Overall Immune Resmentioning

confidence: 99%

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

et al. 2015

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“…77 MSH2 is normally located in the nucleus where it functions as a DNA mismatch repair gene, but it is often mutated in a number of different types of epithelial cancers and can be ectopically expressed. 78 Transformation of normal human B cells by Epstein-Barr virus or subjecting renal carcinoma cell lines to oxidative stress also led to an increased surface expression of MSH2 and rendered them susceptible to Vc9Vd2 T cell-mediated cell lysis that could be blocked by the use of anti-MSH2 antibodies or downregulation of its gene expression. 78,79 These observations were collectively taken to suggest that MSH2 may be yet another damage-associated molecular pattern recognized by Vc9Vd2 T cells.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

confidence: 99%

“…78 Transformation of normal human B cells by Epstein-Barr virus or subjecting renal carcinoma cell lines to oxidative stress also led to an increased surface expression of MSH2 and rendered them susceptible to Vc9Vd2 T cell-mediated cell lysis that could be blocked by the use of anti-MSH2 antibodies or downregulation of its gene expression. 78,79 These observations were collectively taken to suggest that MSH2 may be yet another damage-associated molecular pattern recognized by Vc9Vd2 T cells. An overlooked point worth considering is the fact that MSH2 also has an intrinsic ability to bind and hydrolyze ATP, 80 which may be the property providing the common mechanism leading to the mobilization of human peripheral blood cd T cells.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

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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“…Although there are limited numbers of V␥ and V␦ genes available and preferential usage of a few V segments in V␥/V␦ combinations, extensive junctional diversity in particular in CDR3␦ makes TCR␥␦ chains substantially diverse in theory. However, only a few TCR␥␦ ligands have been identified so far, and most of them are endogenous antigens/ligands, such as MHC class I-related chains A and B (MICA/B) (4), UL16-binding proteins (ULBPs) (5, 6), F1-ATPase-apolipoprotein A-I complex (7), human MutS homologue 2 (hMSH2) (8), and phosphoantigens (9).…”

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confidence: 99%

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity

Yin

Zhang

Mao

et al. 2013

Journal of Biological Chemistry

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Background: TCR␥␦ and NKG2D are two important receptors for ␥␦T cell cytotoxicity. Results: ␥␦T cell cytotoxicity is TCR␥␦-dependent and requires the activation of Vav1-PLC-␥1 pathway. Conclusion: ␥␦T cell cytotoxicity requires a strong signal to overcome the inhibitory threshold set by Cbl-b. Significance: Our finding provides new insights into the molecular mechanisms underlying the activation of ␥␦T cell cytotoxicity.

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Ectopically Expressed Human Tumor Biomarker MutS Homologue 2 Is a Novel Endogenous Ligand That Is Recognized by Human γδ T Cells to Induce Innate Anti-tumor/Virus Immunity

Cited by 52 publications

References 40 publications

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

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

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity

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