Soluble IL-2Rα (sCD25) Exacerbates Autoimmunity and Enhances the Development of Th17 Responses in Mice

Russell, Shane E.; Moore, Anne; Fallon, Padraic G.; Walsh, Patrick

doi:10.1371/journal.pone.0047748

Cited by 61 publications

(55 citation statements)

References 34 publications

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“…sCD25 suppresses IL-2-induced surface CD25 expression and T cell responses in vitro [30,31,[53][54][55]. Russell et al [56] reported that sCD25 can exacerbate experimental autoimmune encephalitis by acting as a decoy receptor that sequesters IL-2, eventually altering the balance between Th1/Th17 and Tregs. A different mechanism might explain the capacity of sCD25 to subvert the immunostimulatory effects of CTLA-4 blockade.…”

Section: -Test) (F)mentioning

confidence: 99%

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Hannani¹,

Vétizou²,

Enot³

et al. 2015

Cell Res

145

111

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The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated longterm control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4 + T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 block-

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Section: -Test) (F)mentioning

confidence: 99%

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Hannani¹,

Vétizou²,

Enot³

et al. 2015

Cell Res

145

111

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“…1C) showing that the mice treated with anatabine displayed significantly milder disease symptoms than the placebo group. We euthanatized the mice at day 16 following the immunization for pathological and biochemical evaluations because it has been shown that the peak of EAE disease severity is generally reached around day 16 in similar MOG immunization models [12], [13]. We first assessed the titer of circulating antibodies reacting against murine MOG 35–55 in the serum of control non-immunized mice, EAE placebo and EAE anatabine treated mice.…”

Section: Resultsmentioning

confidence: 99%

Amelioration of Experimental Autoimmune Encephalomyelitis by Anatabine

et al. 2013

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Anatabine, a naturally occurring alkaloid, is becoming a commonly used human food supplement, taken for its claimed anti-inflammatory properties although this has not yet been reported in human clinical trials. We have previously shown that anatabine does display certain anti-inflammatory properties and readily crosses the blood-brain barrier suggesting it could represent an important compound for mitigating neuro-inflammatory conditions. The present study was designed to determine whether anatabine had beneficial effects on the development of experimental autoimmune encephalomyelitis (EAE) in mice and to precisely determine its underlying mechanism of action in this mouse model of multiple sclerosis (MS). We found that orally administered anatabine markedly suppressed neurological deficits associated with EAE. Analyses of cytokine production in the periphery of the animals revealed that anatabine significantly reduced Th1 and Th17 cytokines known to contribute to the development of EAE. Anatabine appears to significantly suppress STAT3 and p65 NFκB phosphorylation in the spleen and the brain of EAE mice. These two transcription factors regulate a large array of inflammatory genes including cytokines suggesting a mechanism by which anatabine antagonizes pro-inflammatory cytokine production. Additionally, we found that anatabine alleviated the infiltration of macrophages/microglia and astrogliosis and significantly prevented demyelination in the spinal cord of EAE mice. Altogether our data suggest that anatabine may be effective in the treatment of MS and should be piloted in clinical trials.

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“…Importantly, we observed extremely high sCD25 levels in Prf1 2/2 mice sera compared with wild-type mice on day 10 after infection (Fig 6, A). This not only recapitulates a key component of FHL, but because sCD25 might have the capacity to compete with CD25 for IL-2 binding, 24 it adds an additional mechanism by which Wild-type and Prf1 2/2 mice were infected with LCMV-Armstrong and assessed at days 0, 5, and 10 for CD8 1 T-cell activation in the lymph nodes. A, CD8 1 T-cell subpopulations were characterized as CD8 1 CD62L 1 CD44 2 naive cells, CD8 1 CD62L 1 CD44 1 central memory T cells (TCM), and CD8 1 CD62L 2 CD44 1 effector memory T cells (TEM) by means of flow cytometry.…”

Section: Lcmv Infection In Perforin-deficient Mice Disrupts Il-2 Consmentioning

confidence: 89%

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

Humblet-Baron

Franckaert

Dooley

et al. 2016

Journal of Allergy and Clinical Immunology

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Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8 1 T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and lifethreatening. Recent studies have attributed the key distal event to excessive IFN-g production; however, the proximal events driving immune dysregulation have remained undefined. Objective: We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL. Methods: Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8 1 T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and analyzed during the HLH episode. Results: We found no primary Treg cell defects in perforindeficient mice. However, Treg cell numbers collapsed after LCMV inoculation. The collapse of Treg cell numbers in LCMV-triggered perforin-deficient, but not wild-type, mice was accompanied by the combination of lower IL-2 secretion by conventional CD4 1 T cells, increased IL-2 consumption by activated CD8 1 T cells, and secretion of competitive soluble CD25. Moreover low Treg cell numbers were observed in untreated patients experiencing HLH flares. Conclusion: These results demonstrate that excessive CD8 1 T-cell activation rewires the IL-2 homeostatic network away

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Soluble IL-2Rα (sCD25) Exacerbates Autoimmunity and Enhances the Development of Th17 Responses in Mice

Cited by 61 publications

References 34 publications

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Amelioration of Experimental Autoimmune Encephalomyelitis by Anatabine

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

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