Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

Bacher, Nicole; Raker, Verena; Hofmann, Claudia; Graulich, Edith; Schwenk, Melanie; Baumgrass, Ria; Bopp, Tobias; Zechner, Ulrich; Merten, Luzie; Becker, Christian; Steinbrink, Kerstin

doi:10.1158/0008-5472.can-12-3788

Cited by 95 publications

(75 citation statements)

References 50 publications

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“…Previous studies determined that antigen-presenting cell (APC) activation by IFN-α can decrease Treg function and enhance Th cell functions (11,21). Similarly, Bacher et al demonstrated that IFN-α can deactivate the suppressive function of human Tregs by downregulating their intracellular cyclic adenosine monophosphate (cAMP) level (22). Interestingly, we showed that IL-6 highly increased in a murine model of SLE and positively correlated with Treg percentages.…”

Section: Development Of Th Cell Subset Percentages After Pristane Injsupporting

confidence: 51%

Regulatory T Cells Compensation Failure Cause the Dysregulation of Immune Response in Pristane Induced Lupus Mice Model

Kalim

Pratama

Nugraha

et al. 2018

MJMS

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Introduction: Regulatory T cells' (Tregs') role remains unclear in the pathogenesis of systemic lupus erythematosus (SLE). This study was aimed at monitoring the percentage of Tregs within 32 weeks and monitoring its relationship with the percentage of other T helper (Th) cell subsets and the levels of autoantibodies and pro-inflammatory cytokines in a murine SLE model induced by pristane.Methods: Forty-eight female BALB/c mice were divided into a healthy control (HC) and a pristine-induced (PI) group. SLE was induced by a single 0.5 cc pristane intraperitoneal injection. Six from each group were sacrificed every eight weeks until 32 weeks post-pristane injection. Treg, Th1, Th2 and Th17 percentages from the spleen were measured using flowcytometry. ANA, IL-6 and IFN-α levels were measured from serum using ELISA.Results: The Treg percentage from the PI group increased significantly at 16 weeks compared to the HC group, while Th1, Th2 and Th17 percentages decreased. Tregs in the PI group began to reduce from the 24th to 32nd weeks, followed by an elevation of the Th1, Th2 and Th17 percentages. Tregs were negatively correlated with Th1 and Th2. Tregs in the PI group had a negative correlation with ANA and IFN-α levels from serum, whereas Tregs had a positive correlation with IL-6 levels.Conclusion: The compensation of Tregs observed at 16 weeks after pristane injection failed, marked by a decreasing number of Tregs, followed by an increase of Th subsets, proinflammatory cytokines and autoantibodies. This compensatory failure of Tregs could be affected by pro-inflammatory cytokines, such as IFN-α and IL-6.

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Section: Development Of Th Cell Subset Percentages After Pristane Injsupporting

confidence: 51%

Regulatory T Cells Compensation Failure Cause the Dysregulation of Immune Response in Pristane Induced Lupus Mice Model

Kalim

Pratama

Nugraha

et al. 2018

MJMS

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“…This is in accordance with previous reports showing higher proportions of T effector cells upon treatment with CpG (28). The TLR7 agonist imiquimod increased the T effector cell to Treg ratio in human squamous cell cancer but did not alter the proportion of antigen-specific T effector and Treg cells in the lymph node in a murine antitumor vaccine model (29,30 (15,(32)(33)(34). We describe here the blockade of Treg migration as a novel mechanism of action in the process of innate immune activation by ligands for PRR.…”

Section: Discussionmentioning

confidence: 84%

Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression

et al. 2015

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The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy.

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“…To prove that IFN-α acts via cAMP-dependent mechanisms on Tregs, we performed suppressive tests with PDE-blocking inhibitors with IFN-α-and inhibitor-treated Tregs (Figure 3b). We were able to show that the effect of IFN-α on the suppressive activity of Tregs is dependent on functional PDE and mainly on PDE4, which is active in T cells [11]. This mechanism is not controlled by STAT-mediated but by MAP kinase ERK-controlled signal transduction pathways (Figure 3b).…”

Section: State Of Researchmentioning

confidence: 90%

“…Moreover, the expression of Foxp3 (which is an essential transcription factor for Tregs) or the methylation status of a certain sequence in the FOXP3 locus, which is decisive for the stability and function of the FOXP3 molecule, was not modified by IFN-α. All in all, IFN-α has no impact on the differentiation program of human Tregs [11].…”

Section: State Of Researchmentioning

confidence: 94%

“…We managed to demonstrate that under the influence of IFN-α Tregs are no longer capable of suppressing co-cultured effector T cells. At the same time they show a significantly reduced level of intracellular cAMP (Figure 2b) [11]. Thus, it is reasonable to assume that Tregs have reduced suppressive properties following IFN-α treatment, due to a dysfunction Figure 1 The role of interferon-α within the immune system: Interferon-α strengthens the immune system's properties of successful tumor defense, but at the same time increases the risk for induction of autoimmunity.…”

Section: State Of Researchmentioning

confidence: 99%

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Research in practice: The impact of interferon‐α therapy on immune tolerance

Raker¹,

Steinbrink²

2014

J Deutsche Derma Gesell

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SummaryInterferon-α (IFN-α) is the only drug approved for adjuvant therapy of malignant melanoma and is also used in the treatment of hematological and solid tumors. Along with its proven clinical efficacy, IFN-α produces several side effects, particularly with regard to autoimmune disorders. Curious about symptoms of autoimmunity during IFN-α therapy, we asked whether IFN-α directly impacts on immune tolerance. We found that IFN-α does alter the function of tolerogenic dendritic cells (DC) as well as of induced and naturally occurring T-regulatory cells (nTregs). IFN-α blocks the tolerogenic phenotype of DC by inducing maturation and thus preventing the induction of inducible Tregs by DC. It also has direct effects on nTregs. IFN-α reduces cAMP in Tregs via ERK/phosphodiesterase-mediated pathways. Since cAMP is essentially involved in suppression by nTregs, the IFN-α-dependent reduction of cAMP levels abolishes the suppressive capacity of nTregs. Therefore, Tregs are incapable of suppressing the activity of effector T cells and natural killer cells, resulting in tumor rejection. Thus, IFN-α overcomes immunological tolerance processes, leading to an improved immunostimulation and efficient tumor rejection, but also increases the risk of autoimmunity.

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Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

Abstract: IFN-a is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune-and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-a remain incompletely understood, particularly with regard to CD4

Cited by 95 publications

References 50 publications

Regulatory T Cells Compensation Failure Cause the Dysregulation of Immune Response in Pristane Induced Lupus Mice Model

Regulatory T Cells Compensation Failure Cause the Dysregulation of Immune Response in Pristane Induced Lupus Mice Model

Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression

Research in practice: The impact of interferon‐α therapy on immune tolerance

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