Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria

Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2008; 105(37):14017-22. DOI: 10.1073/pnas.0805452105
Source: PubMed


Infection of mice with sporozoites of Plasmodium berghei or Plasmodium yoelii has been used extensively to evaluate liver-stage protection by candidate preerythrocytic malaria vaccines. Unfortunately, repeated success of such vaccines in mice has not translated readily to effective malaria vaccines in humans. Thus, mice may be used better as models to dissect basic parameters required for immunity to Plasmodium-infection than as preclinical vaccine models. In turn, this basic information may aid in the rational design of malaria vaccines. Here, we describe a model of circumsporozoite-specific memory CD8 T cell generation that protects mice against multiple P. berghei sporozoite challenges for at least 19 months. Using this model we defined a threshold frequency of memory CD8 T cells in the blood that predicts long-term sterilizing immunity against liver-stage infection. Importantly, the number of Plasmodium-specific memory CD8 T cells required for immunity greatly exceeds the number required for resistance to other pathogens. In addition, this model allowed us to identify readily individual immunized mice that exceed or fall below the protective threshold before infection, information that should greatly facilitate studies to dissect basic mechanisms of protective CD8 T cell memory against liver-stage Plasmodium infection. Furthermore, the extremely large threshold in memory CD8 T cell frequencies required for long-term protection in mice may have important implications for development of effective malaria vaccines.

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    • "While the induction of sufficiently sized memory CD8+ T cell populations is necessary for providing protective immunity [53], another important consideration is the functionality of those cells [18], [19]. Our data demonstrate that while both VSV and LM can be used as effective vaccine vectors for inducing protective memory CD8+ T cell over the first 1–2 months, the protective quality of VSV-induced memory CD8+ T cells waned over time (Figure 1) while the magnitude of the memory CD8+ T cell population remained stable over time [14]. "
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    ABSTRACT: Intracellular pathogens are capable of inducing vigorous CD8+ T cell responses. However, we do not entirely understand the factors driving the generation of large pools of highly protective memory CD8+ T cells. Here, we studied the generation of endogenous ovalbumin-specific memory CD8+ T cells following infection with recombinant vesicular stomatitis virus (VSV) and Listeria monocytogenes (LM). VSV infection resulted in the generation of a large ovalbumin-specific memory CD8+ T cell population, which provided minimal protective immunity that waned with time. In contrast, the CD8+ T cell population of LM-ova provided protective immunity and remained stable with time. Agonistic CD40 stimulation during CD8+ T cell priming in response to VSV infection enabled the resultant memory CD8+ T cell population to provide strong protective immunity against secondary infection. Enhanced protective immunity by agonistic anti-CD40 was dependent on CD70. Agonistic anti-CD40 not only enhanced the size of the resultant memory CD8+ T cell population, but enhanced their polyfunctionality and sensitivity to antigen. Our data suggest that immunomodulation of CD40 signaling may be a key adjuvant to enhance CD8+ T cell response during development of VSV vaccine strategies.
    PLoS ONE 08/2014; 9(8):e106060. DOI:10.1371/journal.pone.0106060 · 3.23 Impact Factor
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    • "This intricate, self-regulatory mechanism exerted by activated CD8 + T cells may have implications for the development of malaria liver-stage vaccines, considering it has been demonstrated that a large threshold for memory CD8 + T cell frequencies is required for long-term protection. In these studies, the authors have developed a model of epitope-specific immunization regimes to induce a large memory CD8 + T cell response capable of protecting mice from sporozoite challenges (Schmidt et al., 2008). Although the issue concerning the persistence of parasite antigens for the maintenance of memory T cells still remains elusive as some studies have demonstrated that primaquine treatment of immunized mice with irradiated sporozoites does not affect the protective responses (Krzych et al., 2014). "
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    ABSTRACT: Plasmodium sporozoites and liver stages express antigens that are targeted to the MHC-Class I antigen-processing pathway. After the introduction of Plasmodium sporozoites by Anopheles mosquitoes, bone marrow-derived dendritic cells in skin-draining lymph nodes are the first cells to cross-present parasite antigens and elicit specific CD8(+) T cells. One of these antigens is the immunodominant circumsporozoite protein (CSP). The CD8(+) T cell-mediated protective immune response against CSP is dependent on the interleukin loop involving IL-4 receptor expression on CD8(+) cells and IL-4 secretion by CD4(+) T cell helpers. In a few days, these CD8(+) T cells re-circulate to secondary lymphoid organs and the liver. In the liver, the hepatic sinusoids are enriched with cells, such as dendritic, sinusoidal endothelial and Kupffer cells, that are able to cross-present MHC class I antigens to intrahepatic CD8(+) T cells. Specific CD8(+) T cells actively find infected hepatocytes and target intra-cellular parasites through mechanisms that are both interferon-γ-dependent and -independent. Immunity is mediated by CD8(+) T effector or effector-memory cells and, when present in high numbers, these cells can provide sterilizing immunity. Human vaccination trials with recombinant formulations or attenuated sporozoites have yet to achieve the high numbers of specific effector T cells that are required for sterilizing immunity. In spite of the limited number of specific CD8(+) T cells, attenuated sporozoites provided multiple times by the endovenous route provided a high degree of protective immunity. These observations highlight that CD8(+) T cells may be useful for improving antibody-mediated protective immunity to pre-erythrocytic stages of malaria parasites.
    Frontiers in Microbiology 08/2014; 5:440. DOI:10.3389/fmicb.2014.00440 · 3.99 Impact Factor
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    • "Thus CD8+ T cells specific for antigen presented on MHC-I of hepatocytes must find very few infected cells within a large excess of uninfected cells and combat them in a very narrow time-window. This was demonstrated in a study where different amounts of CSP-specific cells were transferred [43]. Using this approach a threshold of protection was defined. "
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    ABSTRACT: Regulatory T cells (Treg) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4+CD25+ Treg were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3+CD25- Treg. To obtain more insights in the specific function of Treg during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when Treg are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.
    PLoS ONE 08/2014; 9(8):e104627. DOI:10.1371/journal.pone.0104627 · 3.23 Impact Factor
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