Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

Smeltz, Ronald B.; Chen, June; Hu‐Li, Jane; Shevach, Ethan M.

doi:10.1084/jem.194.2.143

Cited by 92 publications

(72 citation statements)

References 36 publications

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“…It had been reported that IL-18R␣ is upregulated in established Th1 cells by TCR stimulation and IL-12, a STAT4 activator (19), which might question a role for T-bet in regulation of IL-18R␣ expression. However, TCR/IL-12-dependent upregulation of IL-18R␣ does not occur in Th1 cells prepared from IFN␥-deficient CD4 T cells and is restored by addition of exogenous IFN␥ (20). Because IFN␥ activates T-bet, these reports are consistent with a role for T-bet in Th1-cell IL-18R␣ induction.…”

Section: Upregulation Of Receptors For Il-1 Family Members and Mastersupporting

confidence: 78%

IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells

Guo

Wei

Zhu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

373

355

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an IL-1 family member and a specific STAT activator, implying an innate mechanism through which memory CD4 T cells are recruited by an induced cytokine environment. IL-33 ͉ TSLP ͉ IL-18 ͉ STAT5 ͉ T1ST2I L-33, a member of the IL-1 family, is synthesized as a 31-kDa precursor and cleaved in vitro by caspase-1 to a mature 18-kDa form (1). T1ST2, originally identified as an orphan receptor expressed primarily on Th2 and mast cells (2-4), has now been shown to bind to IL-33 and to form a complex with IL-1RAcP (5, 6) that mediates IL-33 signaling (1). IL-33 transduces its effects through the classical IL-1 signaling machinery, including activation of NF-B and MAPKs (1).Administration of IL-33 to mice causes profound alterations in mucosal tissues, including lung, esophageal, and intestinal eosinophilia, and splenomegaly, and enhanced serum IgA and IgE (1). Inhibition of IL-33, either by anti-T1ST2 antibody or T1ST2 immunoglobin, blocks secretion of IL-4, IL-5, and IL-13 and markedly suppresses eosinophilic inflammation in recipients of ovalbumin-specific Th2 cells challenged with ovalbumin (2, 7). T1ST2-deficient mice show a defect in primary response to schistosoma egg antigens (8) and IL-33 treatment at the time of Trichuris muris infection allows susceptible mice to expel the parasite (9).These results indicate an important role for IL-33 and T1ST2 in allergic/parasite-induced inflammatory responses. However, the molecular regulation of T1ST2 expression and how IL-33 mediates its function remain unclear. Here we show that T1ST2 expression by Th2 cells is regulated by GATA3 and STAT5. Further, IL-33 and STAT5 activators such as IL-2, IL-7, and TSLP act synergistically to induce and maintain GATA3 expression. IL-33 then acts on T1ST2-expressing Th2 cells to induce production of IL-13, but not IL-4, in a TCR-independent, NF-B-, and p38-dependent manner. Such TCR-independent IL-13 production by Th2 cells is similar to the previous demonstration by others that treatment of Th1 cells with IL-18 and IL-12 induces IFN␥ production (10). Consistent with these findings, we also show that Th17 cells (11-13) treated with IL-1␤ and a STAT3 activator (IL-6, IL-21, or IL-23) produce IL-17A in a TCR-independent manner. Thus, all 3 effector Th populations respond to an IL-1 family member and a STAT activator with the production of a key effector cytokine, providing a mechanism for innate activation of memory or effector CD4 T cells. Results T1ST2 Expression on Th2Cells. T1ST2 is under tight regulation while IL-1RAcP is broadly expressed. Naïve CD4 T cells do not express detectable T1ST2 (Fig. 1A). Culture under Th2 conditions for 4 days (1xTh2) results in a small fraction of the cells expressing high levels of T1ST2. More Th2 cells express T1ST2 after a second round of priming (2xTh2) and essentially all 3-round primed Th2 cells (3xTh2) express T1ST2 (Fig. 1 A). T1ST2 expression falls strikingly when 3xTh2 cells are ''rested'' in IL-2- (Fig. 1 A and B), IL-7-, or TSLP-containing medium (Fig. 1B). Rested Th2 cells expressing low leve...

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Section: Upregulation Of Receptors For Il-1 Family Members and Mastersupporting

confidence: 78%

IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells

Guo

Wei

Zhu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

373

355

View full text Add to dashboard Cite

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“…1B). Although both Th1 and Th2 cells predominantly express the p38␣ isoform (our unpublished data), it is not surprising that there is no effect on Th2 cells since IL-4 negatively modulates the receptors for both IL-12 and IL-18 (10,11).…”

Section: Resultsmentioning

confidence: 99%

Regulation and Phenotype of an Innate Th1 Cell: Role of Cytokines and the p38 Kinase Pathway

Tripp²,

Russell

2003

The Journal of Immunology

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We have explored the phenotype and regulation of Th1 cell activation by the cytokines IL-12 and IL-18. We demonstrate that these two cytokines selectively induce IFN-γ in a differentiated Th1 cell population through the previously described p38 mitogen-activated protein (MAP) kinase pathway. Using a highly selective p38 MAP kinase inhibitor, we demonstrate that it is possible to block IFN-γ induction from activated, differentiated Th1 cells via p38 MAP kinase without disrupting the activation and differentiation of naive T cells or the proliferation of naive or differentiated T cells. In addition, IL-12 and IL-18 provide an Ag and IL-2-independent survival signal to this uniquely differentiated Th1 cell population. We hypothesize that this Ag-independent survival of Th1 cells may participate in an innate inflammatory loop with monocytes at the sites of chronic inflammation. In addition, p38 MAP kinase inhibition of this cytokine-regulated pathway may be a unique mechanism to inhibit chronic inflammation without disruption of Ag-driven activation and function of naive T cells.

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“…Although IL-18 alone does not appear to be sufficient for Th1 development (10 -11), T cells primed in the presence of IL-12 will subsequently respond to both IL-12 and IL-18 in a paracrine fashion by secreting large amounts of IFN-␥ (12)(13)(14). High levels of IL-18R␣ expression correlate with the ability of IL-18 to induce, as well as synergize with IL-12 for significant IFN-␥ production (7). This synergistic effect of IL-12 and IL-18 occurs in the absence of TCR ligation and may represent an alternative pathway for production of IFN-␥ during ongoing inflammatory responses.…”

Section: Role Of Ifn-␥ In Th1 Differentiation: Ifn-␥ Regulates Il-18rmentioning

confidence: 94%

“…Binding of IL-12 leads to IFN-␥ production and further enhancement of IL-12R␤2 expression (2)(3)(4)(5)(6). In addition to IL-12R␤2, IL-12 up-regulates IL-18R␣ expression (7)(8)(9). Although IL-18 alone does not appear to be sufficient for Th1 development (10 -11), T cells primed in the presence of IL-12 will subsequently respond to both IL-12 and IL-18 in a paracrine fashion by secreting large amounts of IFN-␥ (12)(13)(14).…”

Section: Role Of Ifn-␥ In Th1 Differentiation: Ifn-␥ Regulates Il-18rmentioning

confidence: 99%

Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression

Smeltz

Chen

Ehrhardt

et al. 2002

The Journal of Immunology

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109

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Two key events occur during the differentiation of IFN-γ-secreting Th1 cells: up-regulation of IL-12Rβ2 and IL-12-driven up-regulation of IL-18Rα. We previously demonstrated that IL-12-driven up-regulation of IL-18Rα expression is severely impaired in IFN-γ−/− mice. However, it was unclear from these studies how IFN-γ influenced IL-18Rα since IFN-γ alone had no direct effect on IL-18Rα expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Rα/IL-12Rβ2 was independent of IFN-γ. However, in the presence of IL-4, IFN-γ functions to limit the negative effects of IL-4 on both IL-18Rα and IL-12Rβ2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18Rα/IL-12Rβ2 in an IFN-γ-independent fashion. In the absence of both IL-12 and IL-4, IFN-γ up-regulates IL-12β2 expression and primes IFN-γ-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Rα or the IL-12Rβ2 and the capacity of these cells to produce IFN-γ, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-γ in regulation of IL-18Rα/IL-12Rβ2 during both IL-12-dependent and IL-12-independent Th1 differentiation.

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Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

Cited by 92 publications

References 36 publications

IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells

IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells

Regulation and Phenotype of an Innate Th1 Cell: Role of Cytokines and the p38 Kinase Pathway

Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression

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