Regulatory T Cells and Human Disease

Cools, Nathalie; Ponsaerts, Peter; Tendeloo, Viggo Van; Berneman, Zwi

doi:10.1155/2007/89195

Cited by 154 publications

(124 citation statements)

References 140 publications

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“…The major pathway of immunosuppression by Tregs may be through direct cell-to-cell suppression of effector T cells, producing soluble factors, such as immunosuppressive IL-10 and TGF-β (20). The association between pTregs and various types of cancer has been extensively investigated (14)(15)(16)21) and the majority of those studies concluded that the frequency of pTregs in patients with cancer is elevated and is correlated with a poor prognosis, which was consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer

Hasegawa

Suzuki

Yamaura

et al. 2014

Molecular and Clinical Oncology

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Abstract. Several types of immunosuppressive mechanisms in cancer patients have been reported to date. Regulatory T cells (Tregs), which express the master control transcription factor forkhead box P3 (FoxP3), are considered to play a major role in hampering antitumor immune response. However, the clinical significance of Tregs in patients with lung cancer has not been fully elucidated. The aim of this study was to investigate the clinical significance of Tregs in the peripheral blood and in resected cancer tissue specimens. We analyzed peripheral blood mononuclear cells (PBMCs) collected prior to surgery and resected specimens obtained from 67 patients with non-small-cell lung cancer (NSCLC). Peripheral Tregs (pTregs) were detected as CD4 + and FoxP3 + cells by flow cytometry. Immunohistochemical staining for CD4, CD8 and FoxP3 expression was also performed quantitatively by analyzing three randomly selected fields from central regions (cCD4, cCD8 and cFoxP3) and interstitial regions of the tumors (iCD4, iCD8 and iFoxP3). The associations between the expression frequencies in selected cells and clinicopathological parameters were statistically analyzed. The frequency of pTregs was found to be significantly higher in patients with pleural invasion (P=0.0049), vessel invasion (P=0.0009), lymphatic vessel invasion (P=0.0053) and recurrent disease (P=0.0112). Patients with T1 exhibited a significantly higher frequency of cCD4 (P=0.0199) and cCD8 (P=0.0058), although cFoxP3 expression was not significant (P= 0.0935). Patients with low levels of cFoxP3/iFoxP3 exhibited a significantly higher frequency of pTregs (P=0.0338) and patients with a high frequency of pTregs exhibited significantly poorer recurrence-free survival (P=0.0071). The multivariate analysis identified pTreg frequency as an independent prognostic factor (P=0.0458). Although the pathological analysis remains controversial, the frequency of pTregs in NSCLC patients may be a useful prognostic biomarker.

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Section: Discussionmentioning

confidence: 99%

Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer

Hasegawa

Suzuki

Yamaura

et al. 2014

Molecular and Clinical Oncology

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“…The CD4+ CD25+ population can be divided into two different levels of expression, i.e. low CD25 level (defined CD4+ CD25low) and high CD25 level (defined CD4+ CD25bright) [9][10][11][12][13] that appear to have a tail to the right of the major population containing both CD4+ CD25low and CD4+ CD25-cells. FOXP3 expression was analysed using mononuclear cells purified from peripheral blood using Lymphoprep (1.077 g mL; AxisShield, Oslo, Norway) density gradient centrifugation.…”

Section: Patientsmentioning

confidence: 99%

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

et al. 2012

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Bullous pemphigoid (BP) is the most frequent autoimmune bullous skin disease, characterised by autoantibodies against the hemidesmosome complex. Recently, regulatory T cells (Tregs) have been implicated in the development of several autoimmune diseases; few data are available in BP, failing to demonstrate a role of this subset in disease pathogenesis. The aim of this study was to investigate the expression and phenotypes of different Tregs (CD4+ CD25brightFOXP3+ and CD8+ CD28-cells) in BP to clarify whether the depletion of this subset constitutes one mechanism of tolerance loss. The CD4+ CD25bright-FOXP3 and CD8+ CD28-circulating subsets were determined by flow-cytometry in 26 untreated BP patients and compared with a group of age-and sex-matched healthy controls (HC, n = 30). Absolute and percentage values of the CD4+ CD25brightFOXP3+ cells were significantly reduced in BP compared with HC (median CD25bright-FOXP3+ expression within CD4+ cells: 1.8 vs. 3.5%, p = 0.002); conversely, BP patients were characterised by a significant expansion of the CD25brightFOXP3-''activated'' T-cell subset. CCR4 and CD62L were expressed on the majority of CD4+ CD25brightFOXP3+ cells (75.2 and 82.3%, respectively). No differences in the CD8+ CD28-subset were found between BP and HC. This is the first report showing a significant reduction of circulating CD4+ CD25brightFOXP3+ Treg frequency in BP patients.

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“…Human T-regulatory cells (Tregs), classified immunophenotypically as naturally occurring (CD4 + CD25 + Foxp3 + ) or induced (CD4 + CD25 high ), downregulate and suppress a broad array of immune responses, including the non-specific suppression of both CD4 + and CD8 + T-cells via cellcell contact and via production of immunosuppressive cytokines such as IL-10 and TGFβ. [192][193][194][195][196][197][198] Tregs express abundant TLR8 mRNA, and TLR8 agonists have been shown to reverse Treg function via a TLR8-MyD88-IRAK4 (IL-1-receptor-associated kinase 4) signaling pathway. 199 Engagement and activation of TLR8, therefore, strongly induces innate immunity and enhances adaptive immunity.…”

Section: Intracellular Tlr7 Activation: Imidazoquinoline Ligandsmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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Regulatory T Cells and Human Disease

Cited by 154 publications

References 140 publications

Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer

Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer

Circulating CD4+ CD25brightFOXP3+ regulatory T-cells are significantly reduced in bullous pemphigoid patients

Potential adjuvantic properties of innate immune stimuli

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