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: 9.81). 10/2008; 105(37):14017-22. DOI: 10.1073/pnas.0805452105
Source: PubMed

ABSTRACT 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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    ABSTRACT: Although CD8(+) T cells are shown to mediate the protective immunity against the liver stages of malaria parasites in mice, whether the direct presentation of malaria antigen by major histocompatibility complex (MHC) class I molecules expressed on the liver of infected host is required for anti-plasmodial activity of CD8(+) T cells is still unknown. Presently, there is only one CD8(+) epitope, SYVPSAEQI, derived from the circumsporozoite protein of Plasmodium yoelii (PyCS), that mediates anti-malarial protection and is presented in the context of a K(d) molecule. Therefore, to investigate the mode of anti-plasmodial activity of CD8+ T cells, we have previously generated C57BL/6 transgenic (Tg) mice, in which a K(d) molecule is expressed only on hepatocyte (Alb-K(d)) or dendritic cell (DC; CD11c-K(d)), by using albumin promoter or CD11c promoter, respectively. We have also generated MHC-I-K(d) Tg mice, which express the K(d) molecule under the MHC class I (MHC-I) promoter, as a positive control. From splenocytes collected from CD11c-K(d) Tg mice immunized with a synthetic peptide, SYVPSAEQI, which corresponds to the CD8(+) T-cell epitope of PyCS, emulsified in incomplete Freund's adjuvant , a PyCS-specific CD8(+) T-cell line was generated. This PyCS-specific CD8(+)T-cell line was then adoptively transferred into a cohort of either MHC-K(d) Tg or Alb-K(d) Tg mice listed above, as well as wild-type C57BL/6 mice. Then both transferred and non-transferred mice were challenged with live malaria parasites. We found that the adoptive transfer of a PyCS-specific CD8(+) T-cell line resulted in a significant inhibition of the parasite burden in the liver of Alb-K(d) Tg, as well as MHC-I-K(d) Tg mice, but not of C57BL/6 mice. These results indicate that the K(d) molecule expressed by hepatocytes is sufficient in mediating the anti-plasmodial activity of PyCS-specific CD8(+) T cells in vivo.

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