CD8 T-cell-mediated protection against liver-stage malaria: Lessons from a mouse model

Article (PDF Available)inFrontiers in Microbiology 5:272 · June 2014with23 Reads
DOI: 10.3389/fmicb.2014.00272 · Source: PubMed
Abstract
Malaria is a major global health problem, with severe mortality in children living in sub-Saharan Africa, and there is currently no licensed, effective vaccine. However, vaccine-induced protection from Plasmodium infection, the causative agent of malaria, was established for humans in small clinical trials and for rodents in the 1960s. Soon after, a critical role for memory CD8 T cells in vaccine-induced protection against Plasmodium liver-stage infection was established in rodent models and is assumed to apply to humans. However, these seminal early studies have led to only modest advances over the ensuing years in our understanding the basic features of memory CD8 T cells required for protection against liver-stage Plasmodium infection, an issue which has likely impeded the development of effective vaccines for humans. Given the ethical and practical limitations in gaining mechanistic insight from human vaccine and challenge studies, animal models still have an important role in dissecting the basic parameters underlying memory CD8 T-cell immunity to Plasmodium. Here, we will highlight recent data from our own work in the mouse model of Plasmodium infection that identify quantitative and qualitative features of protective memory CD8 T-cell responses. Finally, these lessons will be discussed in the context of recent findings from clinical trials of vaccine-induced protection in controlled human challenge models.

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Available from: PubMed Central, Dec 22, 2014 · License: CC BY
    • "CD8 + T cells are important mediators of pathogen control during intracellular infections. Sufficient induction of these cells leads to pathogen elimination [1][2][3][4][5][6][7][8], whereas weak or exacerbated CD8 + T cell stimulation may lead to pathology [9][10][11][12][13][14][15][16][17]. Therefore, the proper induction of CD8 + T cells must be tightly regulated and may be co-opted in the development of new vaccines against intracellular pathogens [18][19][20][21][22]. Critical in the process of CD8 + T cell induction is the kinetics and efficiency of the provision of MHC class I-restricted epitopes recognized by these lymphocytes, which is linked to the degradation of mature proteins and defective ribosomal products in the cytosol by barrel-shaped structures denoted proteasomes, as recently reviewed [23, 24] . "
    Dataset · May 2016 · PLoS ONE
    • "CD8 + T cells are important mediators of pathogen control during intracellular infections. Sufficient induction of these cells leads to pathogen elimination [1][2][3][4][5][6][7][8], whereas weak or exacerbated CD8 + T cell stimulation may lead to pathology [9][10][11][12][13][14][15][16][17]. Therefore, the proper induction of CD8 + T cells must be tightly regulated and may be co-opted in the development of new vaccines against intracellular pathogens [18][19][20][21][22]. Critical in the process of CD8 + T cell induction is the kinetics and efficiency of the provision of MHC class I-restricted epitopes recognized by these lymphocytes, which is linked to the degradation of mature proteins and defective ribosomal products in the cytosol by barrel-shaped structures denoted proteasomes, as recently reviewed [23, 24] . "
    [Show abstract] [Hide abstract] ABSTRACT: The β1i, β2i and β5i immunoproteasome subunits have an important role in defining the repertoire of MHC class I-restricted epitopes. However, the impact of combined deficiency of the three immunoproteasome subunits in the development of protective immunity to intracellular pathogens has not been investigated. Here, we demonstrate that immunoproteasomes play a key role in host resistance and genetic vaccination-induced protection against the human pathogen Trypanosoma cruzi (the causative agent of Chagas disease), immunity to which is dependent on CD8+ T cells and IFN-γ (the classical immunoproteasome inducer). We observed that infection with T. cruzi triggers the transcription of immunoproteasome genes, both in mice and humans. Importantly, genetically vaccinated or T. cruzi-infected β1i, β2i and β5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8+ effector T cells (CD8+CD44highCD62Llow) specific for the previously characterized immunodominant (VNHRFTLV) H-2Kb-restricted T. cruzi epitope. Not only the quantity, but also the quality of parasite-specific CD8+ T cell responses was altered in TKO mice. Hence, the frequency of double-positive (IFN-γ+/TNF+) or single-positive (IFN-γ+) cells specific for the H-2Kb-restricted immunodominant as well as subdominant T. cruzi epitopes were higher in WT mice, whereas TNF single-positive cells prevailed among CD8+ T cells from TKO mice. Contrasting with their WT counterparts, TKO animals were also lethally susceptible to T. cruzi challenge, even after an otherwise protective vaccination with DNA and adenoviral vectors. We conclude that the immunoproteasome subunits are key determinants in host resistance to T. cruzi infection by influencing both the magnitude and quality of CD8+ T cell responses.
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    • "Experimental vaccination of humans and mice with attenuated sporozoites protects against challenge with wild-type sporozoites [3][4][5][6][7][8]. Antibodies can block hepatocyte invasion [9], while CD8 + cytotoxic T cells recognize parasite-infected hepatocytes [10][11][12]and can provide sterile protection in several mouse models [13] . Furthermore, CD8 + T cells play a role in protection in primates [14] and likely in humans as well [15] and are induced in humans experimentally immunized with attenuated sporozoites [16, 17]. "
    [Show abstract] [Hide abstract] ABSTRACT: Development of a subunit vaccine targeting liver-stage Plasmodium parasites requires the identification of antigens capable of inducing protective T cell responses. However, traditional methods of antigen identification are incapable of evaluating T cell responses against large numbers of proteins expressed by these parasites. This bottleneck has limited development of subunit vaccines against Plasmodium and other complex intracellular pathogens. To address this bottleneck, we are developing a synthetic minigene technology for multi-antigen DNA vaccines. In an initial test of this approach, pools of long (150 bp) antigen-encoding oligonucleotides were synthesized and recombined into vectors by ligation-independent cloning to produce two DNA minigene library vaccines. Each vaccine encoded peptides derived from 36 (vaccine 1) and 53 (vaccine 2) secreted or transmembrane pre-erythrocytic P. yoelii proteins. BALB/cj mice were vaccinated three times with a single vaccine by biolistic particle delivery (gene gun) and screened for interferon-.-producing T cell responses by ELISPOT. Library vaccination induced responses against four novel antigens. Naive mice exposed to radiation-attenuated sporozoites mounted a response against only one of the four novel targets (PyMDH, malate dehydrogenase). The response to PyMDH could not be recalled by additional homologous sporozoite immunizations but could be partially recalled by heterologous cross-species sporozoite exposure. Vaccination against the dominant PyMDH epitope by DNA priming and recombinant Listeria boosting did not protect against sporozoite challenge. Improvements in library design and delivery, combined with methods promoting an increase in screening sensitivity, may enable complex minigene screening to serve as a high-throughput system for discovery of novel T cell antigens.
    Full-text · Article · Apr 2016
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