Dectin-2-Dependent NKT Cell Activation and Serotype-Specific Antibody Production in Mice Immunized with Pneumococcal Polysaccharide Vaccine

PLOS ONE, Dec 2019

Although thymus-independent type 2 antigens generally do not undergo Ig class switching from IgM to IgG, pneumococcal polysaccharide vaccine (PPV) induces the production of serotype-specific IgG. How this happens remains unclear, however. In the present study, PPV immunization induced production of IgG as well as IgM specific for a serotype 3-pneumococcal polysaccharide in the sera of wild-type (WT) mice, but this phenomenon was significantly reduced in Dectin-2 knockout (KO) mice. Immunization with PPV caused IL-12p40 production in WT mice, but this response was significantly reduced in Dectin-2KO mice. Likewise, immunization with PPV activated natural killer T (NKT) cells in WT mice but not in Dectin-2KO mice. Furthermore, administration of α-galactosylceramide, recombinant (r)IL-12 or rIFN-γ improved the reduced IgG levels in Dectin-2KO mice, and treatment with neutralizing anti-IFN-γ mAb resulted in the reduction of IgG synthesis in PPV-immunized WT mice. Transfer of spleen cells from PPV-immunized WT mice conferred protection against pneumococcal infection on recipient mice, whereas this effect was cancelled when the transferred spleen cells were harvested from PPV-immunized Dectin-2KO mice. These results suggest that the detection of PPV antigens via Dectin-2 triggers IL-12 production, which induces IFN-γ synthesis by NKT cells and subsequently the production of serotype-specific IgG.

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Dectin-2-Dependent NKT Cell Activation and Serotype-Specific Antibody Production in Mice Immunized with Pneumococcal Polysaccharide Vaccine

et al. (2013) Dectin-2-Dependent NKT Cell Activation and Serotype-Specific Antibody Production in Mice Immunized with Pneumococcal Polysaccharide Vaccine. PLoS ONE 8(10): e78611. doi:10.1371/journal.pone.0078611 Dectin-2-Dependent NKT Cell Activation and Serotype- Specific Antibody Production in Mice Immunized with Pneumococcal Polysaccharide Vaccine Tomomitsu Miyasaka 0 Yukiko Akahori 0 Masahiko Toyama 0 Namiko Miyamura 0 Keiko Ishii 0 Shinobu Saijo 0 Yoichiro Iwakura 0 Yuki Kinjo 0 Yoshitsugu Miyazaki 0 Kazunori Oishi 0 Kazuyoshi Kawakami 0 Anil Kumar Tyagi, University of Delhi, India 0 1 Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine , Sendai , Japan , 2 Division of Molecular Immunology, Medical Mycology Research Center, Chiba University , Chiba , Japan , 3 Division of Laboratory Animal, Research Institute for Biomedical Sciences, Tokyo University of Science , Tokyo , Japan , 4 Laboratory of Immune Regulation, Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases , Tokyo , Japan , 5 Infectious Disease Surveillance Center, National Institute of Infectious Diseases , Tokyo , Japan Although thymus-independent type 2 antigens generally do not undergo Ig class switching from IgM to IgG, pneumococcal polysaccharide vaccine (PPV) induces the production of serotype-specific IgG. How this happens remains unclear, however. In the present study, PPV immunization induced production of IgG as well as IgM specific for a serotype 3-pneumococcal polysaccharide in the sera of wild-type (WT) mice, but this phenomenon was significantly reduced in Dectin-2 knockout (KO) mice. Immunization with PPV caused IL-12p40 production in WT mice, but this response was significantly reduced in Dectin2KO mice. Likewise, immunization with PPV activated natural killer T (NKT) cells in WT mice but not in Dectin-2KO mice. Furthermore, administration of a-galactosylceramide, recombinant (r)IL-12 or rIFN-c improved the reduced IgG levels in Dectin-2KO mice, and treatment with neutralizing anti-IFN-c mAb resulted in the reduction of IgG synthesis in PPVimmunized WT mice. Transfer of spleen cells from PPV-immunized WT mice conferred protection against pneumococcal infection on recipient mice, whereas this effect was cancelled when the transferred spleen cells were harvested from PPVimmunized Dectin-2KO mice. These results suggest that the detection of PPV antigens via Dectin-2 triggers IL-12 production, which induces IFN-c synthesis by NKT cells and subsequently the production of serotype-specific IgG. - Funding: This work was supported in part by a Grant from the Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Challenging Exploratory Research: 23659841 to K.K.), Grants from the Ministry of Health, Labor and Welfare of Japan (22-SHINKOU-IPPAN-014 to K.K.; H22-SEISAKUSOUYAKUIPPAN-012 to Y.K.: H25-SHINKOU-WAKATE-005 to Y.K.) and aid funding from Takeda Science Foundation to Y.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Streptococcus pneumoniae is a leading causative bacterium of community-acquired pneumonia [1-3]. The risk of serious S. pneumoniae infection is increased in patients with a deficiency of IgG against pneumococcal capsular polysaccharides and phosphorylcholine, which facilitates opsonophagocytic killing by neutrophils [4,5]. Immunization with 23-valent pneumococcal polysaccharide vaccine (PPV) results in a protective IgG response in vaccinated individuals who have a high risk of pneumococcal infection [68]. Thus, IgG production against pneumococcal polysaccharides is a key factor in protecting hosts from pneumococcal infection. However, it remains to be clarified how PPV causes the production of IgG. Recently, C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) for pathogen-derived polysaccharides, have garnered much attention from many investigators with respect to their role in host defense against fungal infection [9]. DCassociated C-type lectin-2 (Dectin-2), one of the CLRs, possesses a carbohydrate recognition domain (CRD) for the Ca++-dependent recognition of mannose [10,11]. The triggering of Dectin-2mediated stimulation by fungal hyphae or specific Ab leads to the activation of NF-kB and the production of proinflammatory cytokines [12,13]. Capsular polysaccharide of S. pneumoniae is classified as a thymus-independent type 2 (TI-2) antigen, which does not require T cell help for the activation of B cells. TI-2 antigens generally fail to induce Ig class switching from IgM to IgG, affinity maturation and memory B cell response because of the lack of a cognate CD40/CD40L interaction between T and B cells [14,15]. One notable exception to this is the fact that serotype-specific IgG2 is produced in individuals who receive (...truncated)


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Tomomitsu Miyasaka, Yukiko Akahori, Masahiko Toyama, Namiko Miyamura, Keiko Ishii, Shinobu Saijo, Yoichiro Iwakura, Yuki Kinjo, Yoshitsugu Miyazaki, Kazunori Oishi, Kazuyoshi Kawakami. Dectin-2-Dependent NKT Cell Activation and Serotype-Specific Antibody Production in Mice Immunized with Pneumococcal Polysaccharide Vaccine, PLOS ONE, 2013, Volume 8, Issue 10, DOI: 10.1371/journal.pone.0078611