The Influence of Excessive IL-6 Production In Vivo on the Development and Function of Foxp3+ Regulatory T Cells

Fujimoto, Minoru; Nakano, Mayumi; Terabe, Fumitaka; Kawahata, Hirohisa; Ohkawara, Tomoharu; Han, Yongmei; Ripley, Barry; Serada, Satoshi; Nishikawa, Teppei; Kimura, Akihiro; Nomura, Shosaku; Kishimoto, Tadamitsu; Naka, Tetsuji

doi:10.4049/jimmunol.0903314

Cited by 140 publications

(121 citation statements)

References 24 publications

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“…C26-inoculated mice. However, C26 cells are known to produce IL-6 in addition to TGF-β (24), and IL-6 inhibits the induction of Tregs from naïve CD4 + T cells (25). Therefore, there is a possibility that, although the levels of both TGF-β and IL-6 increased in the i.c.…”

Section: Discussionmentioning

confidence: 90%

Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum

Tanaka

Matsui

Ishikawa³

et al. 2011

Oncol Rep

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Abstract. We previously reported that oral ingestion of Lentinula edodes mycelia (L.E.M.) extract can inhibit the growth of a subcutaneously established melanoma in a T cell-dependent manner via mitigation of regulatory T cell (Treg)-mediated immunosuppression. In this study, we tested the antitumor effect and mechanism of oral ingestion of L.E.M. extract following inoculation of murine colon carcinoma colon-26 (C26) cells into the subserosal space of the cecum (i.c.) of syngeneic mice. In this model, the primary site of the immune response was gut-associated lymphoid tissue (GALT), which is known to be an immunological toleranceinducing site for numerous dietary antigens. Oral ingestion of the L.E.M. extract suppressed the growth of i.c.-inoculated C26 cells in a T cell-dependent manner and restored the T cell response of the mesenteric lymph nodes and the spleen, not only to a tumor antigen-derived peptide, presented on H-2L d molecules, but also to C26 cells. I.c. inoculation of C26 cells increased the potential of CD4 + T cells of the mesenteric lymph nodes to produce transforming growth factor (TGF)-β, but ingestion of the L.E.M. extract decreased the ability of both CD4 + and CD8 + T cells in the mesenteric lymph nodes to produce this immunosuppressive cytokine. Although ingestion of L.E.M. showed only a marginal effect on Tregs in this model, this treatment significantly reduced the plasma levels of TGF-β and IL-6, both of which were increased in the i.c. C26-inoculated mice. In summary, our results indicate that oral ingestion of L.E.M. extract can restore antitumor T cell responses of mice even when the primary antitumor immune response is elicited in GALT, and provide important implications for anticancer immunotherapy of human colon cancer. IntroductionStudies on tumor-reactive cytotoxic T lymphocytes (CTLs) and tumor-related antigens have enabled the design of specific anticancer immunotherapies (1,2). Anticancer vaccines and adoptive immunotherapy have been applied clinically, although their efficacy has been unsatisfactory (3). Although several explanations of their unsatisfactory performance could be proposed, the major reason that these therapies fail is believed to be due to the emergence of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) (4,5). In addition, the tumor-bearing state is accompanied by chronic inflammation, and it is thought that the inflammatory state of cancer patients inhibits the efficacy of anticancer immunotherapy (6,7).Lentinula edodes mycelia extract (L.E.M.) is a dried powder of a hot water extract of the mycelia of L. edodes before germination, which were cultured in a medium composed of bagasse and rice bran (8). This L.E.M. extract has been reported to exhibit antitumor activity and immunomodulatory effects both in vitro and in vivo (9,10). L.E.M. can mitigate inflammation in the liver of mice (11), suggesting that it also has an anti-inflammatory effect. In addition, we recently reported that oral ingestion of ...

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Section: Discussionmentioning

confidence: 90%

Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum

Tanaka

Matsui

Ishikawa³

et al. 2011

Oncol Rep

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“…In fact, the role played by IL-6 in the inhibition of Tregs has been debated and it has been suggested that this cytokine preferentially drives the differentiation of Th-0 cells toward Th-17 cells through the blockade of the pathway to Tregs, but does not directly inhibit the proliferation of already differentiated Tregs. 35,36 We were able to retrieve the biopsy taken at the moment of diagnosis of leprosy in five T1R and eight T2R patients, before they developed the reaction episodes. We then compared these biopsies with those taken during the reactions.…”

Section: Resultsmentioning

confidence: 99%

Development of Type 2, But Not Type 1, Leprosy Reactions is Associated with a Severe Reduction of Circulating and In situ Regulatory T-Cells

Vieira¹,

Trindade²,

Pagliari³

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Abstract. Leprosy is frequently complicated by the appearance of reactions that are difficult to treat and are the main cause of sequelae. We speculated that disturbances in regulatory T-cells (Tregs) could play a role in leprosy reactions. We determined the frequency of circulating Tregs in patients with type 1 reaction (T1R) and type 2 reaction (T2R). The in situ frequency of Tregs and interleukin (IL)-17, IL-6, and transforming growth factor beta (TGF)-β-expressing cells was also determined. T2R patients showed markedly lower number of circulating and in situ Tregs than T1R patients and controls. This decrease was paralleled by increased in situ IL-17 expression but decreased TGF-β expression. Biopsies from T1R and T2R patients before the reaction episodes showed similar number of forkhead box protein P3 + (FoxP3+) and IL-17+ cells. However, in biopsies taken during the reaction, T2R patients showed a decrease in Tregs and increase in IL-17+ cells, whereas T1R patients showed the opposite: Tregs increased but IL-17+ cells decreased. We also found decreased expansion of Tregs upon in vitro stimulation with Mycobacterium leprae and a trend for lower expression of FoxP3 and the immunosuppressive molecule cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in T2R Tregs. Our results provide some evidence to the hypothesis that, in T2R, downmodulation of Tregs may favor the development of T-helper-17 responses that characterize this reaction.

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“…Interestingly, although both IL-10 and IL-6 signal through phosphorylation of STAT3, they have distinct anti-and proinflammatory functions, with IL-6 being critical for Th17 cell induction (8) and unfavorable for iTreg induction (9,10). In this context, the role of IL-10 in iTreg induction remains unanswered.…”

Section: Foxp3mentioning

confidence: 99%

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

Hsu

Santner-Nanan

et al. 2015

The Journal of Immunology

225

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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The Influence of Excessive IL-6 Production In Vivo on the Development and Function of Foxp3+ Regulatory T Cells

Cited by 140 publications

References 24 publications

Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum

Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum

Development of Type 2, But Not Type 1, Leprosy Reactions is Associated with a Severe Reduction of Circulating and In situ Regulatory T-Cells

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

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