TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

Conroy, Helen; Marshall, Neil A.; Mills, Kingston H. G.

doi:10.1038/sj.onc.1210910

Cited by 149 publications

(111 citation statements)

References 131 publications

(141 reference statements)

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“…[30][31][32][33][34][38][39][40] Strategies aimed at depletion/functional inhibition of these cells by molecular targeting must maintain a critical balance between tumor immunity and self-tolerance. 34,[41][42][43][44] These immunomodulation pathways may therefore have potential applications in forthcoming treatments of cancer.…”

Section: Regulatory T Cells In Endometrial Cancer/chang Et Almentioning

confidence: 99%

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Chang

Huang

et al. 2010

Cancer

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BACKGROUND: A study was carried out to determine the functional attributes of CD4 þ CD25 þ regulatory T cells in cancer progression by suppressing antitumor immunity. METHODS: Triple-color flow cytometry was used to study the phenotype expression of CD4 þ CD25 þ regulatory T cells and CD8 þ T cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters. RESULTS: The prevalence of CD4 þ CD25 þ T cells was significantly higher in the TILs than PBLs. The expression of CD4 þ CD25 þ regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4 þ CD25 þ regulatory T cells was lower in PBLs than TILs. Most tumor-infiltrating CD8 þ T cells were CD28 À CD45RA À CD45RO þ CCR7 À , suggesting good terminal differentiation. Most of them had an activated role with CD69 þ CD103 þ CD152 þ . Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8 þ cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8 þ cytotoxic T cells. CONCLUSIONS: Regulatory T cells in the tumor microenvironment may abrogate CD8 þ T cell cytotoxicity in a granzyme B-and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression. Cancer 2010;116:5777-88.

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Section: Regulatory T Cells In Endometrial Cancer/chang Et Almentioning

confidence: 99%

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Chang

Huang

et al. 2010

Cancer

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“…31 More recently, however, it has been recognized that TLRs are expressed on CD4 + T cells, and that direct engagement of TLRs on T cells also affects adaptive immunity (reviewed in refs [32][33][34] ). In the context of IBD, the role of TLRs on CD4 + T cells is of particular interest because commensal bacteria in the gut represent a large source of potential TLR ligands, and loss of integrity of the gut epithelium in IBD patients 35 could result in abnormal exposure of T cells to bacteria-derived innate immune signals, and thereby promote disease.…”

Section: Toll-like Receptor Engagement Affects Cd4 + T-effector and Tmentioning

confidence: 99%

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

Himmel¹,

Hardenberg²,

Piccirillo³

et al. 2008

Immunology

132

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SummaryTwo related chronic inflammatory diseases, Crohn's disease and ulcerative colitis, are together often referred to as inflammatory bowel disease (IBD). Current treatment options are not curative, and patients face lifelong therapy and debilitation. IBD is thought to be the product of a combination of genetic and environmental factors that result in the abnormal regulation of immune responses. Experimental models have demonstrated that normal CD4 + T-regulatory (Treg) cell responses and commensal bacteria are required for the maintenance of gut immune homeostasis. Recent evidence that CD4 + T cells express Toll-like receptors (TLRs) and respond directly to TLR ligands, suggests that signals from commensal bacteria may directly affect T-cell responses in the gut. In this review, we focus on evidence that defects in Treg cells may underlie IBD in humans. In addition, we discuss evidence that direct signaling via TLRs to T cells can affect IBD and that T-cell-dependent responses to bacterial proteins, such as flagellin, are central to the aetiology of this disease.

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“…This immune evasion may occur in different ways, including the production of inhibitory cytokines and metabolites such as interleukin (IL)-10, transforming growth factor (TGF)-b, and prostaglandins by the tumor cells themselves or by macrophages infiltrating the tumor [7]. In recent years, recruitment of regulatory T cells (Tregs) within tumors has been demonstrated to be an immune evasion mechanism [8,9].…”

Section: Introductionmentioning

confidence: 99%

CD4+ regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-β

et al. 2016

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TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

Cited by 149 publications

References 131 publications

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

CD4+ regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-β

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