Induction Of Protective CD8 Research Articles

The roles of CD4+ T cell help, sex, and dose in the induction of protective CD8+ T cells against a lethal poxvirus by mRNA-LNP vaccines

The role of CD4+ T-cells in the induction of protective CD8+ T-cells by mRNA Lipid Nanoparticle (LNP) vaccines is unknown. We used B6 or Tlr9-/- mice depleted or not of CD4+ T-cells and LNP vaccines loaded with mRNAs encoding the ectromelia virus (ECTV) MHC Class I H-2 Kb-restricted immunodominant CD8+ T-cell epitope TSYKFESV (TSYKFESV mRNA-LNP) or the ECTV EVM158 protein, which contains TSYKFESV (EVM-158 mRNA-LNP). Following prime and boost with 10 μg of either vaccine, Kb-TSYKFESV-specific CD8+ T-cells fully protected male and female mice from ECTV at 29- (both mRNA-LNPs) or 90-days (EVM158 mRNA-LNP) post boost (dpb) independently of CD4+ T-cells. However, at 29 dpb with 1 μg mRNA-LNPs, males had lower frequencies of Kb-TSYKFESV-specific CD8+ T-cells and were much less well protected than females from ECTV, also independently of CD4+ T-cells. At 90 dpb with 1 μg EVM158 mRNA-LNPs, the frequencies of Kb-TSYKFESV-specific CD8+ T-cells in males and females were similar, and both were similarly partially protected from ECTV, independently of CD4+ T-cells. Therefore, at optimal or suboptimal doses of mRNA-LNP vaccines, CD4+ T-cell help is unnecessary to induce protective anti-poxvirus CD8+ T-cells specific to a dominant epitope. At suboptimal doses, protection of males requires more time to develop.

Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains1. The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells1–4. Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fcγ receptor FcγRIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8+ T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.

Enhancement of CD8+ T Cell Immunity in the Lung by CpG Oligodeoxynucleotides Increases Protective Efficacy of a Modified Vaccinia Ankara Vaccine against Lethal Poxvirus Infection Even in a CD4-Deficient Host

Immunostimulatory CpG oligodeoxynucleotides (ODN) have proven effective as adjuvants for protein-based vaccines, but their impact on immune responses induced by live viral vectors is not known. We found that addition of CpG ODN to modified vaccinia Ankara (MVA) markedly improved the induction of longer-lasting adaptive protective immunity in BALB/c mice against intranasal pathogenic vaccinia virus (Western Reserve; WR). Protection was mediated primarily by CD8(+) T cells in the lung, as determined by CD8-depletion studies, protection in B cell-deficient mice, and greater protection correlating with CD8(+) IFN-gamma-producing cells in the lung but not with those in the spleen. Intranasal immunization was more effective at inducing CD8(+) T cell immunity in the lung, and protection, than i.m. immunization. Addition of CpG ODN increased the CD8(+) response but not the Ab response. Depletion of CD4 T cells before vaccination with MVA significantly diminished protection against pathogenic WR virus. However, CpG ODN delivered with MVA was able to substitute for CD4 help and protected CD4-depleted mice against WR vaccinia challenge. This study demonstrates for the first time a protective adjuvant effect of CpG ODN for a live viral vector vaccine that may overcome CD4 deficiency in the induction of protective CD8(+) T cell-mediated immunity.

Induction of protective CD8+ T lymphocytes by an attenuated Listeria monocytogenes actA mutant.

We tested the ability of an attenuated actA mutant of Listeria monocytogenes to induce protective immunity in mice. This mutant can enter and multiply in the cytosol of the infected host cell, but is deficient in actin-dependent cell-to-cell spread. It was found to be of attenuated virulence for inbred C3H mice: the LD50 after i.v. injection was 1000-fold higher than that of the wild-type strain. Mutant bacteria multiplied up to the fourth day in the liver, but only for 1 day in the spleen. A single infection with the maximum sublethal dose of the actA mutant induced long-lasting immunity; the LD50 of virulent wild-type L. monocytogenes increased 100-fold and growth of wild-type L. monocytogenes was controlled in liver and spleen of these mice. The presence of Listeria-reactive T cells in spleen of C3H mice infected 7 days previously with the actA mutant was monitored, through their ability to protect naive syngeneic recipients against wild-type L. monocytogenes. Protection was mainly conferred by Thy-1+ CD8+ T lymphocytes; depletion of CD4+ T cells had no significant effect on the level of transferred protection. Such attenuated mutants may be used to develop live vector vaccines for delivery of heterologous proteins into the cytosol, thereby favoring the induction of a CD8+ T cell response.