Tumor-Infiltrating γδ T Cells Suppress T and Dendritic Cell Function via Mechanisms Controlled by a Unique Toll-like Receptor Signaling Pathway

Peng, Guangyong; Wang, Helen Yicheng; Peng, Weiyi; Kiniwa, Yukiko; Seo, Kook Heon; Wang, Rongfu

doi:10.1016/j.immuni.2007.05.020

Cited by 367 publications

(475 citation statements)

References 47 publications

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“…Therefore, these findings provide clear evidence that gd T cells would represent a dominant IL-17-producing lymphocyte subset during physiological tumor development. Consistently, previous papers demonstrated that a substantial number of gd T cells were observed in human breast, prostate, and renal cancer tissues [39]. As we confirmed that human gd T cells differentiated into IL-17-producing cells, at least in the presence of IL-6, TGF-b and IL-23 (data not shown), IL-17 might be produced by gd T cells in these types of cancer.…”

Section: Discussionsupporting

confidence: 92%

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing cd T cells for tumor development in tumor-bearing mouse model. IL-17 À/À mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), cd T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-cd T cells showed that circulating cd T cells, but not skin resident Vc5 1 cd T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-b, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing cd T cells. IL-17 production by tumor-infiltrating cd T cells was blocked by anti-cdTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in cd T-cell activation. The IL-17-producing TIL-cd T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing cd T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis. IntroductionIn order to understand how tumor cells can escape immune surveillance mechanisms and thus develop anti-tumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. The tumor microenvironment, which is mainly composed of tumor cells, stromal cells, and tumor-infiltrating immune cells, is entirely different from noncancerous tissues. This unique microenvironment potently inhibits immune responses against tumor cells via various soluble mediators and contact-dependent mechanisms [1,2]. Previously, it was suggested that T-cell Eur. J. Immunol. 2010. 40: 1927-1937 DOI 10.1002 Cellular immune response 1927 responses within the local tumor tissue are completely inhibited. However, this concept was abandoned following the discovery of the regulatory T-cell and Th17 cell subsets, which are activated rather than suppressed in the tumor microenvironment via TGF-b and/or IL-6. Thus, the tumor microenvironment is conducive to IL-17 production. In fact, it has been shown that IL-17 is produced in human and murine tumor tissues [3][4][5]. Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6]. It has been reported that tumor cells over-expressing IL-17 significantly promote new vessel growth into the tumor tissues [5]; however, physiological effects of IL-17 on tumor progression remain to be defined. Th17 differentiation from naïve CD4 1 T cells is regulated by TGF-b and IL-6. Proliferation, maintenance and full maturation of these cells are controlled by . Recently, it has been shown that IL-17 is produced by diverse T...

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Section: Discussionsupporting

confidence: 92%

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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“…In previous studies, we demonstrated the presence of antigenspecific CD4 þ Treg cells at tumor sites (Wang et al, 2004, and showed that Treg cells suppressed the proliferation of naive CD4 þ T cells and inhibited IL-2 secretion of CD4 þ effector cells upon activation by tumor-specific antigens . Finally, we recently identified CD8 þ Treg as well as gd-TCR Treg cells in prostate and breast cancer Peng et al, 2007). The former cells expressed Foxp3 molecules, while the latter did not.…”

Section: Th17 Cellsmentioning

confidence: 93%

“…Thus, the balance between murine Treg cell-suppressive function and naive/effector T-cell proliferation is controlled by TLRs through directly acting on Treg and effector T cells and indirectly acting on DCs (Figure 2). Peng et al, 2007), and showed that they also express a low level of human TLR8 molecules. One of the important questions is whether TLR8 ligands including Poly-G3 and ssRNA40 can reverse the suppressive function of CD8 þ Treg cells and gd-TCR Treg cells.…”

Section: Functional Control Of Treg Cell Function By Tlr Signalingmentioning

confidence: 99%

Toll-like receptors and immune regulation: implications for cancer therapy

2008

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“…Once activated, Vd1 + T cells can drive DC maturation [215] but also kill DCs [216]. In addition, Vd1 + T cells can display properties of regulatory T cells and suppress immune responses through contact or cytokine dependent interactions [217][218][219][220], including the suppression of DC maturation in breast cancer [221,222]. Thus, it appears that the Vd1 + , Vd2 + and Vd3 + subsets of cd T cells as well as iNKT cells all play roles in the induction, polarization and/or regulation of adaptive immune responses in humans.…”

Section: Innate Regulation Of Adaptive Immune Responses: Vd2 + Versusmentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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Tumor-Infiltrating γδ T Cells Suppress T and Dendritic Cell Function via Mechanisms Controlled by a Unique Toll-like Receptor Signaling Pathway

Cited by 367 publications

References 47 publications

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Toll-like receptors and immune regulation: implications for cancer therapy

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

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