Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-11

Laboratory of Innate Immunity and Inflammation, Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2009; 182(9):5763-9. DOI: 10.4049/jimmunol.0900124
Source: PubMed


Host immune responses are finely regulated by the opposing effects of Th17 and T regulatory (Treg) cells. Treg cells help to dampen inflammatory processes and Th17 cells facilitate various aspects of immune activation. The differentiation of Th cells depends on a unique combination of stimulants and subsequent activation of diverse transcription factors. In particular, cooperative activation of NFAT and Smad3 leads to the induction of Treg cells, and cooperation among STAT3 and Smad3 switches to the induction of Th17 cells. We have previously shown that the IL-1 receptor associated kinase 1 (IRAK-1) selectively activates STAT3 and inactivates NFAT. Physiological studies have shown that IRAK-1(-/-) mice are protected from developing various inflammatory diseases, including experimental autoimmune encephalomyelitis and atherosclerosis with unknown mechanism. In this study, we demonstrate that IRAK-1 plays a critical modulatory role in the differentiation of Th17 and Treg cells. Following stimulation with TCR agonists and TGFbeta, IRAK-1(-/-) CD4 Th cells display elevated nuclear NFATc2 levels and increased interaction of NFATc2 and Smad3, resulting in increased expression of Foxp3, a key marker for Treg cells. IRAK-1(-/-) mice have constitutively higher populations of Treg cells. In contrast, when stimulated with TCR agonists together with IL-6 and TGF-beta, IRAK-1(-/-) CD4 Th cells exhibit attenuated STAT3 Ser727 phosphorylation and reduced expression of IL-17 and RORgamma t compared with wild-type cells. Correspondingly, IRAK-1 deletion results in decreased IL-17 expression and dampened inflammatory responses in acute and chronic inflammatory mice models. Our data provides mechanistic explanation for the anti-inflammatory phenotypes of IRAK-1(-/-) mice.

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Available from: Sarah Davis, Oct 07, 2015
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    • "Interestingly, it seems that both Treg and Th17 levels are elevated in SSc. The opposing role of Th17 and Treg cells is evident not only in their immune modulatory functions, but also in their differentiation [13]. In fact, immune imbalance between Th17 and Treg cells is a well-documented characteristic of SSc [14], [15]. "
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    ABSTRACT: Immune imbalance between regulatory T (Treg) and Th17 cells is a characteristic of systemic sclerosis (SSc). The functional heterogeneity among Treg can be elucidated by separating Treg into different subsets based on the expression of FoxP3 and CD45RA. The aim of this study was to investigate the role of Treg subsets in the immune imbalance in naïve SSc. Peripheral blood mononuclear cells (PBMCs) of 31 SSc patients and 33 healthy controls were analyzed for the expression of CD4, CD25, CD45RA, CTLA-4, FoxP3, and IL-17 using flow cytometry. Treg immunesuppression capacity was measured in co-culture experiments. The expression of FoxP3, CTLA-4, IL-17A, and RORC mRNA was measured by real-time PCR. The frequency of CD4(+)CD25(+)FoxP3(+) Treg cells was significantly elevated in patients with SSc (3.62±1.14 vs 1.97±0.75, p<0.001) with diminished immunosuppression capacity. In SSc, the proportion of FoxP3(high)CD45RA(-) activated Treg cells (aTreg) was decreased, the proportion of FoxP3(low)CD45RA(-) T cells was increased, and the proportion of FoxP3(low)CD45RA(+) resting Treg cells (rTreg) was decreased. The immune suppression capacity of aTreg and rTreg was diminished, while FoxP3(low)CD45RA(-) T cells exhibited a lack of suppression capacity. The immune dysfunction of aTreg was accompanied by the abnormal expression of CTLA-4. Th17 cell numbers were elevated in SSc, FoxP3(low)CD45RA(-) T cells produced IL-17, confirming their Th17 potential, which was consistent with the elevated levels of FoxP3(+)IL-17(+) cells in SSc. A decrease in aTreg levels, along with functional deficiency, and an increase in the proportion of FoxP3(low)CD45RA(-) T cells, was the reason for the increase in dysfunctional Treg in SSc patients, potentially causing the immune imbalance between Treg and Th17 cells.
    PLoS ONE 06/2013; 8(6):e64531. DOI:10.1371/journal.pone.0064531 · 3.23 Impact Factor
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    • "For instance, TRAF6 regulates CD4 + T cell suppression by T reg cells through the PI3K (phosphatidylinositol 3-kinase)–Akt pathway (King et al., 2006), and it regulates CD8 + T cell memory development through the fatty acid metabolism pathway (Pearce et al., 2009). IRAK1 has been implicated in regulation of the differentiation of Th17 and T reg cells through modulating the relative activity of STAT3 and NFAT signaling pathways (Maitra et al., 2009). Therefore, targeting TRAF6 and IRAK1 allows miR-146a to modulate the cross talk between NF-B and multiple other signaling pathways, supporting its rheostat role as proposed by our NF-B negative feedback temporal control model. "
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    ABSTRACT: T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-κB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-κB is associated with T cell-mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-κB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-κB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-κB activity, at least partly through repressing the NF-κB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-κB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.
    Journal of Experimental Medicine 08/2012; 209(9):1655-70. DOI:10.1084/jem.20112218 · 12.52 Impact Factor
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    • "Second, primiparity, a change of partner and a short initial coitus-to-conception interval are all risk factors for preeclampsia, suggesting that the response to paternal antigens plays a role (Basso et al., 2001; Trogstad et al., 2011). This hypothesis is supported by the ability of seminal plasma to suppress the female recipient's response to paternal antigens (Maitra et al., 2009; Robertson et al., 2009). Finally, concentrations of inflammatory cytokines are significantly increased, and placental production of the anti-inflammatory cytokine IL-10 is decreased, in women with preeclampsia (Kupferminc et al., 1994; Vince et al., 1995; Makris et al., 2006). "
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    ABSTRACT: Preeclampsia is a pregnancy-specific disorder characterized by hypertension and excess protein excretion in the urine. It is an important cause of maternal and fetal morbidity and mortality worldwide. The disease is almost exclusive to humans and delivery of the pregnancy continues to be the only effective treatment. The disorder is probably multifactorial, although most cases of preeclampsia are characterized by abnormal maternal uterine vascular remodeling by fetally derived placental trophoblast cells. Numerous in vitro and animal models have been used to study aspects of preeclampsia, the most common being models of placental oxygen dysregulation, abnormal trophoblast invasion, inappropriate maternal vascular damage and anomalous maternal-fetal immune interactions. Investigations into the pathophysiology and treatment of preeclampsia continue to move the field forward, albeit at a frustratingly slow pace. There remains a pressing need for novel approaches, new disease models and innovative investigators to effectively tackle this complex and devastating disorder.
    Disease Models and Mechanisms 01/2012; 5(1):9-18. DOI:10.1242/dmm.008516 · 4.97 Impact Factor
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