PD-1 deficiency Enhances Humoral Immunity of Malaria infection-treated vaccine
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摘要
Objectives Vaccine against blood-stage is the most cost-effective strategy to reduce the morbidity and mortality caused by malaria parasite infection. However, there is still no effective blood-stage subunit vaccine available, due to the extensive antigenic variation and polymorphism of merozoites surface proteins. Recently, malaria infection-treatment vaccine(ITV) was reported to induce homologous and heterologous protective immunity against the blood stage of the parasite. However, the underlying mechanism of protection remains largely unknown. Here, we investigated the role of PD-1/PD-L signaling in the protective immunity induced by ITV. Methods Firstly, wild type and PD-1-/- BALB/c(Jackson laboratory) mice were immunized with 1×106 pR BC and challenged with 1×106 Plasmodium yoelii(P.y) 17 XL p RBC at 21 days post final immunization. Then, both parasitemia and survival rate in both immunized mice were determined. Secondly, the protection mechanisms of ITV were determined by serum adoptive transfer assay and in vivo depletion experiment. Finally, the level of malaria parasite-specific IgG, Ig G1, Ig G2a(Sigma-Aldrich) in serum and the spleen GC B cell, T_(FH) cell function were detected in both immunized mice by ELISA and FACS, respectively. Results In this study, we found that malaria-specific Ab could mediate the protective immunity of the ITV-immunized mice. Interestingly, PD-1 deficiency greatly elevated the levels of both malaria-specific total Ig G and subclass Ig G2 a and enhanced the protective efficacy of ITV-immunized mice against the blood-stage challenge. A serum adoptive transfer assay demonstrated that the increased Ab level contributed to the enhanced protective efficacy of the immunized PD-1-deficient mice. Further study showed that PD-1 deficiency could also promote the expansion of germinal center(GC) B cells and malaria parasite-specific T_(FH) cells in the spleens of the ITV-immunized mice. Conclusion we demonstrate that malaria parasite-specific Ab are capable of mediating the protective immunity of the ITV-immunized mice. Interestingly, PD-1 deficiency could confer sterile protective immunity to the ITV-immunized mice; this is an important step in the worldwide elimination of malaria. We also provide evidence that PD-1 signaling could greatly enhance the malaria specific B cells response and the expansion of T_(FH) cells, further supporting the negative role of PD-1 signaling in the modulation of humoral immunity. Thus, our findings have implications not only for the rational design of an effective blood-stage vaccine against malaria parasites through the induction of a robust B cells response but also further our understanding of the regulatory role of PD-1 signaling in the humoral immune response.
Objectives Vaccine against blood-stage is the most cost-effective strategy to reduce the morbidity and mortality caused by malaria parasite infection. However, there is still no effective blood-stage subunit vaccine available, due to the extensive antigenic variation and polymorphism of merozoites surface proteins. Recently, malaria infection-treatment vaccine(ITV) was reported to induce homologous and heterologous protective immunity against the blood stage of the parasite. However, the underlying mechanism of protection remains largely unknown. Here, we investigated the role of PD-1/PD-L signaling in the protective immunity induced by ITV. Methods Firstly, wild type and PD-1-/- BALB/c(Jackson laboratory) mice were immunized with 1×106 pR BC and challenged with 1×106 Plasmodium yoelii(P.y) 17 XL p RBC at 21 days post final immunization. Then, both parasitemia and survival rate in both immunized mice were determined. Secondly, the protection mechanisms of ITV were determined by serum adoptive transfer assay and in vivo depletion experiment. Finally, the level of malaria parasite-specific IgG, Ig G1, Ig G2a(Sigma-Aldrich) in serum and the spleen GC B cell, T_(FH) cell function were detected in both immunized mice by ELISA and FACS, respectively. Results In this study, we found that malaria-specific Ab could mediate the protective immunity of the ITV-immunized mice. Interestingly, PD-1 deficiency greatly elevated the levels of both malaria-specific total Ig G and subclass Ig G2 a and enhanced the protective efficacy of ITV-immunized mice against the blood-stage challenge. A serum adoptive transfer assay demonstrated that the increased Ab level contributed to the enhanced protective efficacy of the immunized PD-1-deficient mice. Further study showed that PD-1 deficiency could also promote the expansion of germinal center(GC) B cells and malaria parasite-specific T_(FH) cells in the spleens of the ITV-immunized mice. Conclusion we demonstrate that malaria parasite-specific Ab are capable of mediating the protective immunity of the ITV-immunized mice. Interestingly, PD-1 deficiency could confer sterile protective immunity to the ITV-immunized mice; this is an important step in the worldwide elimination of malaria. We also provide evidence that PD-1 signaling could greatly enhance the malaria specific B cells response and the expansion of T_(FH) cells, further supporting the negative role of PD-1 signaling in the modulation of humoral immunity. Thus, our findings have implications not only for the rational design of an effective blood-stage vaccine against malaria parasites through the induction of a robust B cells response but also further our understanding of the regulatory role of PD-1 signaling in the humoral immune response.
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