Abstract
Efficient induction of effector and long-term protective antigen-specific CD8+ T memory response by vaccination is essential to eliminate malignant and pathogen-infected cells. Intracellular infectious bacteria, including Listeria monocytogenes, have been considered potent vectors to carry multiple therapeutic proteins and generate antigen-specific CD8+ T cell responses. Although the role of molecules involved in inflammatory cell death pathways, such as necroptosis (RIPK3-mediated) and pyroptosis (Caspase-1/11-mediated), as effectors of immune response against intracellular bacteria are relatively well understood, their contribution to the adjuvant effect of recombinant bacterial vectors in the context of antigen-specific CD8+ T cell response remained obscure. Therefore, we evaluated the impact of RIPK3 and Caspase-1/11 (Casp-1/11) individual and combined deficiencies on the modulation of antigen-specific CD8+ T cell response during vaccination of mice with ovalbumin-expressing L. monocytogenes (LM-OVA). We observed that Casp-1/11 but not RIPK3 deficiency negatively impacts the capacity of mice to clear LM-OVA. Importantly, both RIPK3 and Casp-1/11 are necessary for optimal LM-OVA-mediated antigen-specific CD8+ T cell response, as measured by in vivo antigen-specific CD8+ T cell proliferation, target cell elimination, and cytokine production. Furthermore, Casp-1/11 and Casp-1/11/RIPK3 combined deficiencies restrict the early initiation of antigen-specific CD8+ T cell memory response. Taken together, our findings demonstrate that RIPK3 and Casp-1/11 influence the quality of CD8+ T cell responses induced by recombinant L. monocytogenes vectors.
Highlights
CD8+ cytotoxic T lymphocytes (CTLs) are key cells in host immune defense against pathogens and cancer [1]
Our results demonstrate that RIPK3 and Casp-1/11 deficiencies directly impact the clearance of Listeria monocytogenes (LM)-OVA infection
Mice in comparison to WT (Figure 1C). At this time point, bacterial burden was only detected in Casp1/11−/− and Casp-1/11−/−/RIPK3−/− DKO mice, suggesting that Casp-1/11 but not RIPK3 is essential to clear LM-OVA infection (Figure 1D)
Summary
CD8+ cytotoxic T lymphocytes (CTLs) are key cells in host immune defense against pathogens and cancer [1]. Preferential accumulation of LM into the cytoplasm of infected cells potentiates the presentation of LM-expressing antigens through MHC-I restricted pathway for CD8+ T cell priming [10,11,12,13]. This results in a strong antigen-specific CD8+ T cell response [2], which peaks at 7–10 days after primary infection [14, 15]. As LM-based vaccines hold promise, it is important to develop a better understanding of immune response triggered by recombinant LM in preclinical settings [19]
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