Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

Saitō, Masako; Nagasawa, Mitsuru; Takada, Hidetoshi; Hara, Toshiro; Tsuchiya, Shigeru; Agematsu, Kazunaga; Yamada, Masafumi; Kawamura, Nobuaki; Ariga, Tadashi; Tsuge, Ikuya; Nonoyama, Shigeaki; Karasuyama, Hajime; Minegishi, Yoshiyuki

doi:10.1084/jem.20100799

Cited by 104 publications

(99 citation statements)

References 73 publications

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“…This was confirmed in a patient with dominant-negative STAT3 mutation (HIES), which suggests that, in addition to the impaired ability of IL-10-unresponsive APCs to induce iTregs in HIES (43), naive STAT3-defective CD4 + T cells may respond to IL-10 poorly, leading to poor functional capacity of the induced Tregs, thereby contributing to the immune dysregulation seen in this disease. Interestingly, a previous murine study demonstrated an important role for STAT3 in iTreg differentiation (44), whereas a more recent study suggested that STAT3 signaling inhibits iTreg generation in a murine graftversus-host disease model (45).…”

Section: Foxo1 Is Critical For Itreg Induction and Mediates The Augmementioning

confidence: 84%

IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1

Hsu

Santner-Nanan

et al. 2015

The Journal of Immunology

226

175

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Foxp3+ regulatory T cells (Tregs) play essential roles in maintaining the immune balance. Although the majority of Tregs are formed in the thymus, increasing evidence suggests that induced Tregs (iTregs) may be generated in the periphery from naive cells. However, unlike in the murine system, significant controversy exists regarding the suppressive capacity of these iTregs in humans, especially those generated in vitro in the presence of TGF-β. Although it is well known that IL-10 is an important mediator of Treg suppression, the action of IL-10 on Tregs themselves is less well characterized. In this article, we show that the presence of IL-10, in addition to TGF-β, leads to increased expansion of Foxp3+ iTregs with enhanced CTLA-4 expression and suppressive capability, comparable to that of natural Tregs. This process is dependent on IL-10R–mediated STAT3 signaling, as supported by the lack of an IL-10 effect in patients with IL-10R deficiency and dominant-negative STAT3 mutation. Additionally, IL-10–induced inhibition of Akt phosphorylation and subsequent preservation of Foxo1 function are critical. These results highlight a previously unrecognized function of IL-10 in human iTreg generation, with potential therapeutic implications for the treatment of immune diseases, such as autoimmunity and allergy.

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Section: Foxo1 Is Critical For Itreg Induction and Mediates The Augmementioning

confidence: 84%

IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1

Hsu

Santner-Nanan

et al. 2015

The Journal of Immunology

226

175

View full text Add to dashboard Cite

show abstract

“…IL-10-differentiated DCs (DC-10) induce tolerance at least in part by inducing T effector cells to differentiate into CD4 + CD25 hi FOXP3 + Tregs (62). The defective generation of IL-10-induced tolerogenic DCs and iTregs may contribute to inflammatory changes in hyper-IgE syndrome (63). Exogenously administered tolerogenic DCs may change the phenotype of the kidney resident DCs and/or further promote tolerance by inducing resident DCs to become IL-10-producing tolerogenic DCs, as we observed increased IL-10 mRNA expression in DC-αGC-ATL313-treated naive WT kidneys.…”

Section: Figurementioning

confidence: 99%

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

Huang²,

Ye³

et al. 2012

J. Clin. Invest.

142

123

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“…ϩ T cells) are the key factor for peripheral tolerance; they actively inhibit inflammation and are involved in maintaining the immune balance in the normal gut by inhibiting T cell activation and proliferation against bacterial molecules (31). Since our data showed that intracolonic LPS elicited the inflammatory responses in the intestine and, furthermore, studies suggested that intestinal inflammatory diseases are directly associated with excessive T cell activation (6), we next investigated whether T cell activation would be involved in LPS-induced intestinal inflammation.…”

Section: Intracolonic Lps Treatment Reduces Treg Cell Population Trementioning

confidence: 99%

Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice

Riegler

Pothoulakis

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Frequency of gram-negative bacteria is markedly enhanced in inflamed gut, leading to augmented LPS in the intestine. Although LPS in the intestine is considered harmless and, rather, provides protective effects against epithelial injury, it has been suggested that LPS causes intestinal inflammation, such as necrotizing enterocolitis. Therefore, direct effects of LPS in the intestine remain to be studied. In this study, we examine the effect of LPS in the colon of mice instilled with LPS by rectal enema. We found that augmented LPS on the luminal side of the colon elicited inflammation in the small intestine remotely, not in the colon; this inflammation was characterized by body weight loss, increased fluid secretion, enhanced inflammatory cytokine production, and epithelial damage. In contrast to the inflamed small intestine induced by colonic LPS, the colonic epithelium did not exhibit histological tissue damage or inflammatory lesions, although intracolonic LPS treatment elicited inflammatory cytokine gene expression in the colon tissues. Moreover, we found that intracolonic LPS treatment substantially decreased the frequency of immune-suppressive regulatory T cells (CD4+/CD25+and CD4+/Foxp3+). We were intrigued to find that LPS-promoted intestinal inflammation is exacerbated in immune modulator-impaired IL-10−/−and Rag-1−/−mice. In conclusion, our results provide evidence that elevated LPS in the colon is able to cause intestinal inflammation and, therefore, suggest a physiological explanation for the importance of maintaining the balance between gram-negative and gram-positive bacteria in the intestine to maintain homeostasis in the gut.

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Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

Abstract: Dendritic cells from patients with hyper-IgE syndrome less efficiently generate induced regulatory T cells.

Cited by 104 publications

References 73 publications

IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1

IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice

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