Dendritic Cell (DC)-Based Protection Against an Intracellular Pathogen Is Dependent Upon DC-Derived IL-12 and Can Be Induced by Molecularly Defined Antigens

Berberich, Christof; Ramírez-Pineda, José R.; Hambrecht, Christine; Alber, Gottfried; Skeiky, Yasir A. W.; Moll, Heidrun

doi:10.4049/jimmunol.170.6.3171

Cited by 109 publications

(95 citation statements)

References 58 publications

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“…The differentiation of naïve CD4 + T cells into IFN-γ-producing Th1 cells is regulated in part by the nature of costimulatory molecules expressed on APCs and their cytokine milieu [27,28]. Indeed, the production of IL-12 by infected DCs and the degree of responsiveness of T cells to IL-12 critically affects the outcome of L. major infection in mice [29,30]. We found that BMDCs from PIP-deficient mice showed lower expression of CD40, CD80, CD86, and MHC class II ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

Liu

Mou

et al. 2015

Eur J Immunol

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Although the strategic production of prolactin-inducible protein (PIP) at several ports of pathogen entry into the body suggests it might play a role in host defense, no study has directly implicated it in immunity against any infectious agent. Here, we show for the first time that PIP deficiency is associated with reduced numbers of CD4 + T cells in peripheral lymphoid tissues and impaired CD4 + Th1-cell differentiation in vitro. In vivo, CD4+ T cells from OVA-immunized, PIP-deficient mice showed significantly impaired proliferation and IFN-γ production following in vitro restimulation. Furthermore, PIPdeficient mice were highly susceptible to Leishmani major infection and failed to control lesion progression and parasite proliferation. This susceptibility was associated with impaired NO production and leishmanicidal activity of PIP KO macrophages following IFN-γ and LPS stimulation. Collectively, our findings implicate PIP as an important regulator of CD4 + Th1-cell-mediated immunity. Keywords: IFN-γ r Leishmania r Macrophages r Protozoan r Th1 cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe mouse prolactin-inducible protein (PIP), also known as the mouse submaxillary gland protein, is a 14 kDa protein present in the saliva of mice. The function of PIP is not known, but it is suspected to play a role in host defense against pathogens [1][2][3][4][5][6] because it is expressed in tissues strategically located at several Correspondence: Dr. Jude E. Uzonna e-mail: jude.uzonna@med.umanitoba.ca ports of pathogen entry, including the skin, eyes, and mouth [7]. Although a definitive evidence showing a role for PIP in host immunity is lacking, its ability to potentially bind with several important host molecules including CD4 + T-cell receptor, IgG, actin, zinc α2-glycoprotein, fibronectin, and enamel pellicle suggests it may have important biological functions [8][9][10][11][12][13]. Indeed, it has been shown that PIP is a ligand of the CD4 molecule and a potent inhibitor of * These authors contributed equally to this manuscript.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1082-1091 Immunity to infection 1083 T-cell apoptosis induced by sequential CD4/T-cell receptor triggering, which in part modulates the immune response during viral infection by interfering with the functions mediated by the CD4 molecule [5,6,14]. Furthermore, PIP has been reported to exhibit a mitogenic effect for both normal and malignant breast epithelial cells [15], strongly suggesting that it might play a critical role in differentiation, proliferation, and function of immune cells.Our previous studies show that PIP KO mice have enlarged submandibular lymph nodes and thymic medulla [16]. However, to date, no studies have addressed the contributions of PIP in T-cell responses to either model Ags or infectious agents. Our major aim in the present study is to investigate whether PIP has immunoregulatory function...

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Section: Discussionmentioning

confidence: 99%

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

Liu

Mou

et al. 2015

Eur J Immunol

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“…34 The availability of DC-derived IL-12 is a requirement for the development of protective immunity. 38,39 So in our study, the efficacy of HAF-pulsed and/or AdmIL-12-transduced DCs for controlling aspergillosis in vivo was examined. Firstly, our results showed that HAF-pulsed DCs could induce an Aspergillus Ag-specific Th1 response in vivo; this immune response can bear the function for protection against Aspergillus infection.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells transduced with an adenovirus vector encoding interleukin-12 are a potent vaccine for invasive pulmonary aspergillosis

Shao

et al. 2005

Genes Immun

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Invasive pulmonary aspergillosis (IPA) is a common and devastating pneumonia. We developed a novel antiinfective vaccine that couples the potent Ag-presenting capacity of dendritic cells (DCs) with paracrine delivery of interleukin-12 (IL-12) to local immune response sites. Our results showed that DCs engulfed Aspergillus conidia through coiling phagocytosis. Transfection of DCs with adenovirus encoding the cDNA of IL-12 did not affect their morphology and capacity to engulf conidia. The transduced DCs secreted IL-12, which was biologically active, to induce the production of gamma interferon (IFN-g) from spleen cells. Adoptive transfer of DCs pulsed with heat-inactivated Aspergillus fumigatus (HAF) to naïve mice induced the Ag-specific production of IFN-g; the transduced HAF-pulsed DCs augmented this immune response further. Animals receiving HAF-pulsed DCs had lower fungal burdens, a more than three-fold higher survival rate at day 3. This protection was associated with a pronounced enhancement in the Aspergillus-specific IFN-g response. IL-12-engineered DCs augmented this protection strikingly as judged by a higher survival, and almost no Aspergillus could be detected in the lung of mice that had received IL-12-transduced HAF-pulsed DCs. These results suggest that antigen-pulsed DCs and IL-12 gene therapy could be used as adjunct therapy for aspergillosis.

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“…Recently, DCs have been examined for their capacity to serve as adjuvants and vaccine carriers mediating protection against bacterial, viral, parasitic or fungal pathogens (Moll & Berberich, 2001a, b). For example, DC-based vaccination improved immunity to malaria (Pouniotis et al, 2004), human immunodeficiency virus (Brown et al, 2003), Candida albicans (d 'Ostiani et al, 2000) and Leishmania major (Berberich et al, 2003;Ramirez-Pineda et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

Huang

Xiang

et al. 2006

Journal of General Virology

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Infections with Hepatitis C virus (HCV) pose a serious health problem worldwide. In this study, the hypothesis that adoptive transfer of dendritic cells (DCs) pulsed with HCV NS3 protein and matured with an oligodeoxynucleotide (ODN) containing CpG motifs (CpG) ex vivo would initiate potent HCV-specific protective immune responses in vivo was tested. NS3 protein was efficiently transduced into DCs and treatment of DCs with CpG ODN induced phenotypic maturation and specifically increased the expression of CD40. DCs matured with CpG ODN produced higher interleukin 12 levels and a stronger allogeneic T-cell response compared with untreated DCs. Notably, there were no differences between NS3-pulsed DCs and DCs pulsed with a control protein with respect to phenotype, cytokine production or mixed lymphocyte reaction, indicating that transduction with NS3 protein did not impair DC functions. Compared with the untreated NS3-pulsed DCs, the NS3-pulsed DCs matured with CpG ODN induced stronger cellular immune responses including enhanced cytotoxicity, higher interferon-c production and stronger lymphocyte proliferation. Upon challenge with a recombinant vaccinia virus expressing NS3, all mice immunized with NS3-pulsed DCs showed a significant reduction in vaccinia virus titres when compared with mock-immunized mice. However, the NS3-pulsed DCs matured with CpG ODN induced higher levels of protection compared with the untreated NS3-pulsed DCs. These data are the first to show that NS3-pulsed DCs induce specific immune responses and provide protection from viral challenge, and also demonstrate that CpG ODNs, which have a proven safety profile, would be useful in the development of DC vaccines. INTRODUCTIONInfections with Hepatitis C virus (HCV) pose a serious health problem worldwide. An estimated 170 million people are currently infected, which amounts to 3 % of the world population. About 80 % of infected people remain chronic carriers and are at high risk of developing severe liver disease including cirrhosis and hepatocellular carcinoma (WHO, 1999). Treatment with interferon-a (IFN-a) and ribavirin is the only effective therapy against HCV infection, but the overall response rate is only 40-50 % (Fried et al., 2002;Manns et al., 2001). Currently, there is no licensed vaccine against HCV; therefore, developing strategies for vaccination as well as for treatment of HCV infection is of great importance.Dendritic cells (DCs) are the most potent type of antigen presenting cells (APCs) and are responsible for the initiation and maintenance of immune responses. Situated in peripheral tissues and in lymphoid organs, DCs are uniquely suited to detect and capture pathogens. They express members of the recently identified Toll-like receptor (TLR) family, which bind common chemical moieties associated with microbial organisms. TLR ligands include bacterial lipopolysaccharide, lipopeptides, hypomethylated CpG DNA motifs, dsRNA and flagellin (Akira et al., 2001;Iwasaki & Medzhitov, 2004). TLR signalling triggers a maturation program...

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Dendritic Cell (DC)-Based Protection Against an Intracellular Pathogen Is Dependent Upon DC-Derived IL-12 and Can Be Induced by Molecularly Defined Antigens

Cited by 109 publications

References 58 publications

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

Dendritic cells transduced with an adenovirus vector encoding interleukin-12 are a potent vaccine for invasive pulmonary aspergillosis

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

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