Augmentation of Antigen-Presenting and Th1-Promoting Functions of Dendritic Cells by WSX-1(IL-27R) Deficiency

Wang, Sen; Miyazaki, Y.; Shinozaki, Yukari; Yoshida, Hiroki

doi:10.4049/jimmunol.179.10.6421

Cited by 85 publications

(95 citation statements)

References 32 publications

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“…[33][34][35] Through this IL-10 production and a direct suppressive mechanism as yet to be determined, IL-27 also has a suppressive effect on immune cells other than T cells, such as NK/NKT cells, 29,30 macrophages, 31 and DCs. 13 WSX-1 2/2 DCs lacking IL-27-mediated suppression were more potent than WT DCs in generation of Th1-biased anti-protozoan immunity. 13 As expected, WSX-1 2/2 DCs were more potent in generation of tumor-specific CTLs when pulsed with specific peptide and transferred in vivo (Fig.…”

Section: Discussionmentioning

confidence: 90%

“…13 WSX-1 2/2 DCs lacking IL-27-mediated suppression were more potent than WT DCs in generation of Th1-biased anti-protozoan immunity. 13 As expected, WSX-1 2/2 DCs were more potent in generation of tumor-specific CTLs when pulsed with specific peptide and transferred in vivo (Fig. 3).…”

Section: Discussionmentioning

confidence: 90%

“…For example, Wang et al reported up regulation of antigen-presenting function of WSX-1-deficient DCs. 13 IL-27 thus has 2 roles during immune responses; one as an initiator of Th1 responses and the other as an attenuator of immune and inflammatory responses.…”

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confidence: 99%

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Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

Shinozaki

Wang

Miyazaki

et al. 2008

Intl Journal of Cancer

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Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor a chain)-deficient (WSX-1 2/2 ) mice. In WSX-1 2/2 mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1 2/2 mice than in WT mice. CTL induction in WSX-1 2/2 mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumorbearing mice, WSX-1 2/2 DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8 1 T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8 1 T cells were also the highest in the combination of WT CD81 T cells and WSX-1 2/2 DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

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Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

Shinozaki

Wang

Miyazaki

et al. 2008

Intl Journal of Cancer

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“…IL-27R-deficient DCs are hyperresponsive to LPS, with increased expression of CD80 and CD86 compared with wild-type (WT) DCs (32). In addition, administration of rIL-27 suppresses production of reactive oxygen intermediates, TNF-a and IL-12, by activated macrophages in vitro (30,33).…”

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confidence: 99%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

109

123

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Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R–deficient (WSX-1−/−) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4+ T cells—but not CD8+ T cells—prevented liver pathology in infected WSX-1−/− mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4+ T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1−/− mice, indicating that additional, IL-10–independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.

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“…135,136 However, the role of IL-27 signaling in DCs during CNS autoimmunity is unknown. We recently found increased IL-27Ra expression in cDCs than in pDCs.…”

Section: Regulation Of DC Function By Il-27mentioning

confidence: 99%

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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Augmentation of Antigen-Presenting and Th1-Promoting Functions of Dendritic Cells by WSX-1(IL-27R) Deficiency

Cited by 85 publications

References 32 publications

Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

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