An Inverse Correlation of Human Peripheral Blood Regulatory T Cell Frequency with the Disease Activity of Ulcerative Colitis

Takahashi, Makoto; Nakamura, Kazuhiko; Honda, Kazuo; Kitamura, Yousuke; Mizutani, Tomohiro; Araki, Yuzuru; Kabemura, Teppei; Chijiíwa, Yoshiharu; Harada, Naohiko; Nawata, Hajime

doi:10.1007/s10620-006-3191-2

Cited by 84 publications

(71 citation statements)

References 37 publications

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“…T reg cells have been found in human lamina propria tissue in both inflamed and healthy states (52). In addition, peripheral T reg cells are significantly lower in number from patients with active ulcerative colitis (UC), a form of IBD, than those from healthy patients (53). In accordance with this, T reg cells are essential for prevention and cure of experimental colitis in murine models (54).…”

Section: Discussionmentioning

confidence: 91%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

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Section: Discussionmentioning

confidence: 91%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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“…Early studies found that patients with CD or UC have decreased numbers of peripheral suppressive CD4 + CD45RO + CD25 + FOXP3 + Treg cells during active disease, suggesting that the severity of disease is inversely correlated with the frequency of peripheral Treg cells. [12][13][14][15] In contrast, several studies have found that the lamina propria, mesenteric lymph nodes and intestinal inflamed mucosa of patients with either CD or UC actually contain increased numbers of Treg cells compared with healthy controls. 5,13,15,16 These data are consistent with findings in other gut-inflammatory conditions, such as diverticulitis, pseudomembranous colitis and cytomegalovirus-induced colitis, which show a similar correlation between an increase in FOXP3 + Treg-cell numbers and disease severity.…”

Section: M M U N O L O G Y R E V I E W a R T I C L Ementioning

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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“…6,8 Also in humans, immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is an auto-immune disease developed from a deficiency of T regs. [8][9][10][11] These observations indicate that T regs play important roles in immunological homeostasis. Although the mechanisms of suppression by T regs are still unclear, it has been reported that T regs can inhibit the function of effector T cells directly by cell to cell contact or indirectly via the secretion of immune-suppressive cytokines.…”

mentioning

confidence: 93%

CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3⁺ regulatory T cells in gastric cancer

Matsuo

Kono

Kawaguchi

et al. 2008

Intl Journal of Cancer

323

228

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It has been reported that an increased population of regulatory T cells (Tregs) is one of the reasons for impaired anti-tumor immunity. Recently, Foxp3 has been reported as a reliable marker of Tregs. The authors investigated the frequency of Foxp3 1 Tregs within CD4 1 cells in TILs, regional lymph nodes and PBLs of gastric cancer patients (n 5 45). Furthermore, to elucidate the mechanisms behind Treg accumulation within tumors, they evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3 1 Tregs in gastric cancer. CD4 1 CD25 1 Foxp3 1 Tregs as a percentage of CD4 1 cells were counted by flow cytometry and evaluated by immunohistochemistry. Moreover, an in vitro migration assay using Tregs derived from gastric cancers was performed in the presence of CCL17 or CCL22. As a result, the frequency of Foxp3 1 Tregs in TILs was significantly higher than that in normal gastric mucosa (12.4% 6 7.5% vs. 4.1% 6 5.3%, p < 0.01). Importantly, the increase in Tregs in TILs occurred to the same extent in early and advanced disease. Furthermore, the frequency of CCL17 1 or CCL22 1 cells among CD14 1 cells within tumors was significantly higher than that of normal gastric mucosa, and there was a significant correlation between the frequency of CCL17 1 or CCL22 1 cells and Foxp3 1 Tregs in TILs. In addition, the in vitro migration assay indicated that Tregs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3 1 Tregs, with such an observation occurring in early gastric cancer. ' 2008 Wiley-Liss, Inc.Key words: CCL17; CCL22; Foxp3; regulatory T cells; gastric cancer It has been reported that regulatory T cells (T regs) play important roles in immunological self-tolerance, 1-4 and are functionally immune-suppressive subsets of T cells. T regs are identified as a small population of CD4 1 cells that constitutively express CD25 (IL-2 receptor a chain) on their surface, and several other markers, including CD45RO, glucocorticoid-induced tumor-necrosis factor receptor-related protein (GITR), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), are also known to be expressed on T regs. [3][4][5] Recently, it has been reported that Foxp3, forkhead/ winged helix transcription factor, is the most reliable marker of T regs 6,7 ; therefore, it is possible to define T regs more strictly as CD4 1 CD25 1 Foxp3 1 cells.In mice, it is known that auto-immune diseases such as ulcerative colitis or Crohn's disease occur due to the depletion of T regs. 6,8 Also in humans, immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is an auto-immune disease developed from a deficiency of T regs. [8][9][10][11] These observations indicate that T regs play important roles in immunological homeostasis. Although the mechanisms of suppression by T regs are still unclear, it has been reported that T regs can inhibit the function of effector T cells directly by cell to cell contact or indirectly via the se...

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An Inverse Correlation of Human Peripheral Blood Regulatory T Cell Frequency with the Disease Activity of Ulcerative Colitis

Cited by 84 publications

References 37 publications

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

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

CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3⁺ regulatory T cells in gastric cancer

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An Inverse Correlation of Human Peripheral Blood Regulatory T Cell Frequency with the Disease Activity of Ulcerative Colitis

Cited by 84 publications

References 37 publications

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

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

CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer

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CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3⁺ regulatory T cells in gastric cancer