RIPK3 and Caspase-1/11 Are Necessary for Optimal Antigen-Specific CD8 T Cell Response Elicited by Genetically Modified Listeria monocytogenes

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 antigenspecific 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.

Variation in CD8 T cell IFNγ differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16

“…Necroptosis is a programed cell death response that is mediated by the RIPK3/RIPK1 signaling complex ( Pasparakis and Vandenabeele, 2015 ), and in certain contexts is initiated by IFN-STAT1 signaling ( Thapa et al., 2013 ). Several studies have demonstrated that RIPK3-dependent necroptosis is potent at inducing CD8 T cell activation in vitro and in vivo ( Yatim et al., 2015 ; Ren et al., 2017 ; Rana et al., 2020 ; Aaes and Vandenabeele, 2021 ). Hence the role of RIPK3 was explored.…”

Type I Interferon Signaling on Antigen-Presenting Cells Blunts Cell-Mediated Immunity TowardListeria monocytogenes

“…Our results contrast with Rana et. al (2020) who observed that Caspase-1 was necessary for optimal T-cell responses to L. monocytogenes 34 . Our strain is deficient for the host-actin assembly protein ActA to attenuate its virulence and is cleared in 2-3 days 20 while Rana et al (2020) utilized WT L. monocytogenes which persisted for nearly 7 days-post immunization and is not suitable as a vaccine strain.…”

From Eberthella typhi to Salmonella Typhi: The Fascinating Journey of the Virulence and Pathogenicity of Salmonella Typhi

“…IL-18 influences the activation of CD4 + T lymphocytes, resulting in the secretion of IFN-γ and the clearance of S. Typhimurium infection from the spleen of mice in a MHC-II-independent manner . CD8 + T lymphocytes are essential in clearing the infection caused by cytosolic bacteria such as Listeria monocytogenes . , However, the same is unknown during the infection of vacuolar pathogens such as S. Typhimurium. , The successful onset of typhoid fever in humans by S. Typhi depends on its ability to evade and eventually establish an intracellular proliferating niche in phagocytes. In the following part of this Review, we discuss the intelligent approaches employed by S. Typhi and S. Typhimurium to deceive the immune system and initiate systemic infections in humans and mice.…”

“… 197 CD8 + T lymphocytes are essential in clearing the infection caused by cytosolic bacteria such as Listeria monocytogenes . 198 , 199 However, the same is unknown during the infection of vacuolar pathogens such as S. Typhimurium. 200 , 201 The successful onset of typhoid fever in humans by S. Typhi depends on its ability to evade and eventually establish an intracellular proliferating niche in phagocytes.…”