CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms

Maloy, Kevin J.; Salaün, Laurence; Cahill, Rachel; Dougan, Gordon; Saunders, N.; Powrie, Fiona

doi:10.1084/jem.20021345

Cited by 678 publications

(624 citation statements)

References 48 publications

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“…This suggestion is supported by recent observations that purified populations of CD4 ϩ CD25 ϩ regulatory T cells are able to inhibit the ability of H. hepaticus to induce colitis in Rag-deficient mice (12,13). However, little is known regarding the factors that regulate the inflammatory response to H. hepaticus infection.…”

Section: Nf-b Is Required Within the Innate Immune System To Inhibit mentioning

confidence: 82%

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Tomczak

Erdman

Poutahidis

et al. 2003

The Journal of Immunology

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We have previously presented evidence demonstrating that mice deficient in NF-κB subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter species, H. hepaticus. However, it has not been determined whether NF-κB is required within inhibitory lymphocyte populations, within cells of the innate immune system, or both, to suppress inflammation. To examine these issues, we have performed a series of adoptive transfer experiments using recombination-activating gene (Rag)-2−/− or p50−/−p65+/−Rag-2−/− mice as hosts for wild-type (WT) and p50−/−p65+/− lymphocyte populations. We have shown that although the ability of H. hepaticus to induce colitis in Rag-2−/− mice is inhibited by the presence of either WT or p50−/−p65+/− splenocytes, these splenocyte populations are unable to suppress H. hepaticus-induced colitis in p50−/−p65+/−Rag-2−/− mice. Colitis in these animals is characterized by increased expression of inflammatory cytokines including IL-12 p40, and depletion of IL-12 p40 from p50−/−p65+/− mice ameliorates H. hepaticus-induced disease. Consistent with a primary defect in the regulation of IL-12 expression, H. hepaticus induced markedly higher levels of IL-12 p40 in p50−/−p65+/− macrophages than in WT macrophages. These results suggest that inhibition of H. hepaticus-induced IL-12 p40 expression by NF-κB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.

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Section: Nf-b Is Required Within the Innate Immune System To Inhibit mentioning

confidence: 82%

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Tomczak

Erdman

Poutahidis

et al. 2003

The Journal of Immunology

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“…This suppression is noted at both the IL-2 mRNA and protein levels (7,9). These CD4 ϩ CD25 ϩ T reg appear to have significant in vivo functional relevance, as evidenced by their ability to prevent certain autoimmune syndromes and their regulatory role in normal immune responses (3,4,9,21,22). The suppressive function of T reg has also been demonstrated in vitro, where they have been found to suppress both anti-CD3 Ab-stimulated and Ag-specific responses of CD4 ϩ and CD8 ϩ T cells (8, 9).…”

Section: Discussionmentioning

confidence: 99%

Resistance to CD4+CD25+ Regulatory T Cells and TGF-β in Cbl-b−/− Mice

Wohlfert

Callahan

Clark

2004

The Journal of Immunology

117

132

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Cbl-b−/− mice have signaling defects that result in CD28-independent T cell activation, increased IL-2 production, hyper-reactive T cells, and increased autoimmunity. Although the increased autoimmunity in these mice is believed to result from the hyper-reactive T cells, the mechanisms leading from T cell hyper-reactivity to autoimmunity remain unclear. Specifically, the function and interaction of CD4+CD25+ regulatory T cells (Treg) and CD4+CD25− effector T cells (Teff) in Cbl-b−/− mice have not been examined. We now report that Cbl-b−/− CD4+CD25+ Treg exhibit normal regulatory function in vitro. In contrast, the in vitro response of Cbl-b−/− CD4+CD25− Teff is abnormal, in that it is not inhibited by either Cbl-b−/− or wild-type Treg. This resistance of Cbl-b−/− Teff to in vitro regulation is seen at the levels of both DNA synthesis and cell division. In addition to this resistance to CD4+CD25+ Treg, Cbl-b−/− Teff demonstrate in vitro resistance to inhibition by TGF-β. This second form of resistance in Cbl-b−/− Teff is seen despite the expression of normal levels of type II TGF-β receptors and normal levels of phosphorylated Smad3 after TGF-β stimulation. Coupled with recent reports of resistance to Treg in Teff exposed to LPS-treated dendritic cells, our present findings suggest that resistance to regulation may be a relevant mechanism in both normal immune function and autoimmunity.

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“…5,10 In addition, Treg cells suppress not only T-cell-dependent colitis, but also intestinal inflammation triggered by bacteria. 11 Together, these data provide a reason to believe that methods used to boost and/or restore Treg-cell numbers and function may be effective in the treatment of established IBD in humans.…”

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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CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms

Cited by 678 publications

References 48 publications

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Resistance to CD4+CD25+ Regulatory T Cells and TGF-β in Cbl-b−/− Mice

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

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