Cytokine regulation of IL-12 receptor β2 expression: differential effects on human T and NK cells

Wu, Changyou; Gadina, Massimo; Wang, Kening; O’Shea, John J.; Seder, Robert A.

doi:10.1002/(sici)1521-4141(200005)30:5<1364::aid-immu1364>3.0.co;2-u

Cited by 58 publications

(38 citation statements)

References 19 publications

(29 reference statements)

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“…Results from the current report indicate that the expression of the IL-12R␤2 component of the IL-12R is absent on CD8 ϩ and CD4 ϩ T cells from sensitized mice, but is up-regulated by administration of rIL-12. Recent in vitro studies by Wu and co-workers showed that IL-12R␤2 expression on human CD4 ϩ and CD8 ϩ T cells is up-regulated by IL-12 (22). Administration of rIL-12 during sensitization also increased the number of hapten-specific, IFN-␥-producing CD8 ϩ T cells in the skin draining lymph nodes 2-to 3-fold.…”

Section: Discussionmentioning

confidence: 95%

IL-12 Augments CD8+ T Cell Development for Contact Hypersensitivity Responses and Circumvents Anti-CD154 Antibody-Mediated Inhibition

Gorbachev¹,

DiIulio

Fairchild

2001

The Journal of Immunology

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During sensitization with dinitrofluorobenzene for contact hypersensitivity (CHS) responses, hapten-specific CD8+ T cells develop into IFN-γ-producing cells, and CD4+ T cells develop into IL-4/IL-5-producing cells. Administration of IL-12 during sensitization skews CD4+ T cell development to IFN-γ-producing cells, resulting in exaggerated CHS responses. In the current report we tested the role of IL-12 on CD8+ T cell development during sensitization and elicitation of CHS to dinitrofluorobenzene. Administration of IL-12 during hapten sensitization induced the expression of IL-12Rβ2 on both CD4+ and CD8+ T cells, augmented IFN-γ production by these T cell populations, and increased the magnitude and duration of the CHS response to hapten challenge. CHS responses were virtually identical in wild-type and IL-12 p40−/− mice. Since engagement of CD40 on APC may stimulate IL-12 production, we also tested the role of CD40-CD154 interactions on the development of IFN-γ-producing CD4+ and CD8+ T cells following hapten sensitization. Development of IFN-γ-producing CD4+ T cells during hapten sensitization was absent in wild-type mice treated with anti-CD154 mAb or in CD154−/− mice. In contrast, the absence of CD40-CD154 signaling had little or no impact on the development of IFN-γ-producing CD8+ T cells. These results demonstrate that the development of hapten-specific Th1 effector CD4+ T cells in CHS requires both CD40-CD154 interactions and IL-12, whereas the development of IFN-γ-producing effector CD8+ T cells can occur independently of these pathways.

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Section: Discussionmentioning

confidence: 95%

IL-12 Augments CD8+ T Cell Development for Contact Hypersensitivity Responses and Circumvents Anti-CD154 Antibody-Mediated Inhibition

Gorbachev¹,

DiIulio

Fairchild

2001

The Journal of Immunology

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“…RNase protection assay (RPA) was performed using the Riboquant system (Pharmingen, San Diego, Calif.) per the manufacturer's instructions. Briefly, radiolabeled RNA probes were synthesized from DNA template sets using T7 RNA polymerase, 32 P-UTP, and pooled nonradiolabeled nucleotides. Isolated mRNAs (10 g of total RNA/sample) were hybridized with purified riboprobes and subjected to RNase digestion.…”

Section: Methodsmentioning

confidence: 99%

Cellular Mechanisms That Cause Suppressed Gamma Interferon Secretion in Endotoxin-Tolerant Mice

Varma¹,

Toliver‐Kinsky

Chen³

et al. 2001

Infect Immun

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Endotoxin (lipopolysaccharide [LPS]) tolerance is a state of altered immunity characterized, in part, by suppression of LPS-induced gamma interferon (IFN-γ) expression. However, the cellular mediators regulating LPS-induced production of IFN-γ in normal mice and the effect of LPS tolerance on these mediators has not been well characterized. Our studies show that macrophage dysfunction is the primary factor causing suppressed IFN-γ expression in LPS-tolerant mice. Specifically, LPS-tolerant macrophages have a markedly impaired ability to induce IFN-γ secretion by T cells and NK cells obtained from either control or LPS-tolerant mice. However, T cells and NK cells isolated from LPS-tolerant mice produce normal levels of IFN-γ when cocultured with control macrophages or exogenous IFN-γ-inducing factors. Assessment of important IFN-γ-regulating factors showed that interleukin-12 (IL-12) and costimulatory signals provided by IL-15, IL-18, and CD86 are largely responsible for LPS-induced IFN-γ expression in control mice. IL-10 is an inhibitor of IFN-γ production in both the control and LPS-tolerant groups. Expression of IL-12 and the IL-12 receptor β1 (IL-12Rβ1) and IL-12Rβ2 subunits are suppressed in the spleens of LPS-tolerant mice. LPS-tolerant splenocytes also exhibit decreased production of IL-15 and IL-15Rα. However, expression of IL-18 and the B7 proteins CD80 and CD86 are unchanged or increased compared to controls after induction of LPS tolerance. CD28, a major receptor for B7 proteins, is also increased in the spleens of LPS-tolerant mice. Expression of the inhibitory cytokine IL-10 and the IL-10R are sustained after induction of LPS tolerance. These data show that suppression of IFN-γ production in LPS-tolerant mice is largely due to macrophage dysfunction and provide insight into the cellular alterations that occur in LPS tolerance. This study also better defines the factors that mediate LPS-induced IFN-γ production in normal mice

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“…Ligation of the TCR induces IL-12R␤2 expression rendering T cells responsive to IL-12. 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).…”

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

107

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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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Cytokine regulation of IL-12 receptor β2 expression: differential effects on human T and NK cells

Cited by 58 publications

References 19 publications

IL-12 Augments CD8+ T Cell Development for Contact Hypersensitivity Responses and Circumvents Anti-CD154 Antibody-Mediated Inhibition

IL-12 Augments CD8+ T Cell Development for Contact Hypersensitivity Responses and Circumvents Anti-CD154 Antibody-Mediated Inhibition

Cellular Mechanisms That Cause Suppressed Gamma Interferon Secretion in Endotoxin-Tolerant Mice

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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