Involvement of CD8+ T cell–mediated immune responses in LcrV DNA vaccine induced protection against lethal Y. pestis challenge

Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Vaccine (Impact Factor: 3.62). 09/2011; 29(39):6802-9. DOI: 10.1016/j.vaccine.2010.12.062
Source: PubMed


Yersinia pestis (Y. pestis) is the causative pathogen of plague, a highly fatal disease for which an effective vaccine, especially against mucosal transmission, is still not available. Like many bacterial infections, antigen-specific antibody responses have been traditionally considered critical, if not solely responsible, for vaccine-induced protection against Y. pestis. Studies in recent years have suggested the importance of T cell immune responses against Y. pestis infection but information is still limited about the details of Y. pestis antigen-specific T cell immune responses. In current report, studies are conducted to identify the presence of CD8+ T cell epitopes in LcrV protein, the leading antigen of plague vaccine development. Furthermore, depletion of CD8+ T cells in LcrV DNA vaccinated Balb/C mice led to reduced protection against lethal intranasal challenge of Y. pestis. These findings establish that an LcrV DNA vaccine is able to elicit CD8+ T cell immune responses against specific epitopes of this key plague antigen and that a CD8+ T cell immune response is involved in LcrV DNA vaccine-elicited protection. Future studies in plague vaccine development will need to examine if the presence of detectable T cell immune responses, in particular CD8+ T-cell immune responses, will enhance the protection against Y. pestis in higher animal species or humans.

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    • "After 72 h, the supernatants of cell cultures were collected for cytokine analysis using multiplex assay (Bio-Rad). The cells stained with CD4-phycoerythrin (PE) (clone RM4-5), CD8-allophycocyanin (APC) (clone 53-6.7) and then intracelullarly stained with IFN-fluorescein isothiocyanate (FITC) (clone XMG1.2) were analyzed by Flow cytometry as mentioned in a previous report [35]. Data was collected on a Beckman Coulter FC500 and analyzed using FCS Express 4 software. "
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    ABSTRACT: A Yersinia pseudotuberculosis PB1+ (Yptb PB1+) mutant strain combined with chromosome insertion of the caf1R-caf1A-caf1M-caf1 operon and deletions of yopJ and yopK, χ10068 [pYV-ω2 (ΔyopJ315 ΔyopK108) ΔlacZ044::caf1R-caf1M-caf1A-caf1] was constructed. Results indicated that gene insertion and deletion did not affect the growth rate of χ10068 compared to wild-type Yptb cultured at 26°C. In addition, the F1 antigen in χ10068 was synthesized and secreted on the surface of bacteria at 37°C (mammalian body temperature), not at ambient culture temperature (26°C). Immunization with χ10068 primed antibody responses and specific T-cell responses to F1 and YpL (Y. pestis whole cell lysate). Oral immunization with a single dose of χ10068 provided 70% protection against a subcutaneous (s.c.) challenge with ∼2.6×10(5) LD50 of Y. pestis KIM6+ (pCD1Ap) (KIM6+Ap) and 90% protection against an intranasal (i.n.) challenge with ∼500 LD50 of KIM6+Ap in mice. Our results suggest that χ10068 can be used as an effective precursor to make a safe vaccine to prevent plague in humans and to eliminate plague circulation among humans and animals.
    Vaccine 10/2015; DOI:10.1016/j.vaccine.2015.10.074 · 3.62 Impact Factor
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    • "Recently, the involvement of the CD8+ T cell-mediated immune response in protection against Y. pestis infection was demonstrated in mice immunized with the LcrV-based DNA vaccine. The unraveling of protective T-cell epitopes within the LcrV antigen is crucial for the creation of a vaccine that can elicit optimized humoral and cell-mediated immunities.67 "
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    Emerging Microbes and Infections 11/2012; 1(11). DOI:10.1038/emi.2012.34 · 2.26 Impact Factor
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    • "This is in contrast to B cells, which were found to be dispensable for protection, as shown by the effectiveness of anti-F1 therapy in ␮MT mice (Fig. 7). Several studies have recently demonstrated the contribution of CD4+ and CD8+ T cells to protection against plague following long-term immunization with either a live or an F1/LcrV-based vaccine [24] [39] [40]. In the current study, we extend these observations and report on the requirement for T cells for effective treatment with anti-F1 antibodies against Y. pestis infection. "
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    ABSTRACT: Plague, which is initiated by Yersinia pestis infection, is a fatal disease that progresses rapidly and leads to high mortality rates if not treated. Antibiotics are an effective plague therapy, but antibiotic-resistant Y. pestis strains have been reported and therefore alternative countermeasures are needed. In the present study, we assessed the potential of an F1 plus LcrV-based vaccine to provide protection shortly pre- or post-exposure to a lethal Y. pestis infection. Mice vaccinated up to one day before or even several hours after subcutaneous challenge were effectively protected. Mice immunized one or three days pre-challenge were protected even though their anti-F1 and anti-LcrV titers were below detection levels at the day of challenge. Moreover, using B-cell deficient μMT mice, we found that rapidly induced protective immunity requires the integrity of the humoral immune system. Analysis of the individual contributions of vaccine components to protection revealed that rF1 is responsible for the observed rapid antibody-mediated immunity. Applying anti-F1 passive therapy in the mouse model of bubonic plague demonstrated that anti-F1 F(ab')(2) can delay mortality, but it cannot provide long-lasting protection, as do intact anti-F1 molecules. Fc-dependent immune components, such as the complement system and (to a lesser extent) neutrophils, were found to contribute to mouse survival. Interestingly, T cells but not B cells were found to be essential for the recovery of infected animals following passive anti-F1 mediated therapy. These data extend our understanding of the immune mechanisms required for the development of a rapid and effective post-exposure therapy against plague.
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