Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflammation

Chaudhry, Ashutosh; Samstein, Robert M.; Treuting, Piper M.; Liang, Yuqiong; Pils, Marina C.; Heinrich, Jan Michael; Jack, Robert Smail; Wunderlich, Frank; Brüning, Jens C.; Müller, Werner; Rudensky, Alexander Y.

doi:10.1016/j.immuni.2011.03.018

Cited by 780 publications

(642 citation statements)

References 49 publications

Supporting

Mentioning

606

Contrasting

Unclassified

Order By: Relevance

“…24 However, there are controversial results since Chaudhry and coworkers did not detect any differences in Foxp3 expression by IL-10R-deficient Foxp3 + Tregs. 25 Moreover, it is postulated that IL-10 released by Tregs acts in an autocrine manner in order to self-regulate and expand Tregs themselves. 18,23,24,26 Therefore, to exclude any influence of IL-10 deficiency with respect to Foxp3 stability, we determined the number of Foxp3 + Tregs in the inflamed kidney by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

“…11 The importance of IL-10 signaling in Tregs with respect to selective control of the Th17-mediated inflammatory process has already been investigated in the intestine. [25][26][27] Chaudhry and colleagues demonstrated that ablation of the IL-10 receptor in Treg cells resulted in dysregulation of the Th17 response, followed by the spontaneous development of severe colitis. 25 Additionally, Huber and coworkers showed that IL-17A-producing CD4 + T cells express the IL-10 receptor.…”

Section: Discussionmentioning

confidence: 99%

“…[25][26][27] Chaudhry and colleagues demonstrated that ablation of the IL-10 receptor in Treg cells resulted in dysregulation of the Th17 response, followed by the spontaneous development of severe colitis. 25 Additionally, Huber and coworkers showed that IL-17A-producing CD4 + T cells express the IL-10 receptor. Subsequently, specific blockade of the IL-10 signaling in T cells resulted in an increased frequency of IL17A + and IL-17A + IFNg + CD4 + T cells during intestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Ostmann¹,

Paust²,

Panzer³

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10-producing Foxp3 + T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3 + Tregs eliminated the ability of these cells to suppress renal and systemic production of IFNg and IL-17; these IL-10-deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Ostmann¹,

Paust²,

Panzer³

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…A Treg-specific deletion of IL-10 or the IL10R enhances inflammation and eventually leads to colitis, indicating that Tregs function both as essential source and recipient of the cytokine (19). IL-10 induces STAT3 phosphorylation in Tregs, and Tregs lacking STAT3 fail to expand in the inflamed gut even if they are still capable of suppressing CD4 T-cell proliferation in vitro (20). This suggests that IL-10-mediated homeostasis of Tregs is essential for its anti-inflammatory function.…”

Section: Il-10 Controls Tumor-promoting Inflammationmentioning

confidence: 99%

IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity

Oft

2014

Cancer Immunology Research

228

184

View full text Add to dashboard Cite

Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8 þ T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late-stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL-6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease. The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8 þ T cells and the expression of IFN-g in CD8 þ T cells. IL-10-induced tumor rejections are dependent on the expression of IFN-g and granzymes in tumor-resident CD8 þ T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL-10 increased IFN-g and granzymes in the blood of treated individuals. PEG-IL-10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation.

show abstract

“…12 IL-10 converts immature blood monocytes to tolerogenic macrophages, 13–15 has direct suppressive effects on Th17 cell activity, 16 and conversely enhances conventional regulatory T-cell (cTreg) function. 17 A series of recent studies demonstrated that IL-10 directly activates antigen-experienced CD8+ cytotoxic T-lymphocytes independent of its suppressive effects on CD4 + T-effector and/or myeloid cell subsets. 18–20 Collectively, these properties have provided the rationale for our studies evaluating the therapeutic efficacy of a novel oral formulation of IL-10 in the treatment of intestinal polyposis 21 and, more recently, of colon cancer.…”

Section: Introductionmentioning

confidence: 99%

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

Bhutiani

Anderson

et al. 2018

OncoImmunology

View full text Add to dashboard Cite

Oral IL-10 suppressed tumor growth in the APCmin/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome.

show abstract

Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflammation

Cited by 780 publications

References 49 publications

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

Contact Info

Product

Resources

About