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 Kd 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 Kd molecule is expressed only on hepatocyte (Alb-Kd) or dendritic cell (DC; CD11c-Kd), by using albumin promoter or CD11c promoter, respectively. We have also generated MHC-I-Kd Tg mice, which express the Kd molecule under the MHC class I (MHC-I) promoter, as a positive control. From splenocytes collected from CD11c-Kd 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-Kd Tg or Alb-Kd 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-Kd Tg, as well as MHC-I-Kd Tg mice, but not of C57BL/6 mice. These results indicate that the Kd molecule expressed by hepatocytes is sufficient in mediating the anti-plasmodial activity of PyCS-specific CD8+ T cells in vivo.
Highlights
Malaria is a severe disease that ranks among the most prevalent infections in tropical areas throughout the world
Splenocytes from peptide-immunized CD11c-Kd Tg mice were collected for the expansion of a PyCS-specific CD8+ T-cell line in vitro, which was achieved by stimulating the cells for a few times with irradiated major histocompatibility complex class I (MHC-I)-Kd Tg mouse-derived splenocytes pulsed with the SYVPSAEQI peptide in a 10–14-day interval, as performed previously (Rodrigues et al, 1991)
The role of major histocompatibility complex (MHC)-I molecules in mediating CD8+ T celldependent immunity against the liver stages of rodent malaria parasites has been shown by a few studies as described in the introduction section (White et al, 1996; Chakravarty et al, 2007)
Summary
Malaria is a severe disease that ranks among the most prevalent infections in tropical areas throughout the world. Using transgenic (Tg) mice that express a Tcell receptor (TCR), based on the TCR sequence of CD8+ T cells that recognize an immunodominant T-cell epitope of the PyCS protein, SYVPSAEQI, a recent study showed that the Tg T cells do not require bone marrow-derived antigen-presenting cells (APCs) for protection upon adoptive transfer; instead, they recognize antigen on parenchymal cells, presumably parasitized hepatocytes (Chakravarty et al, 2007). These studies all together strongly suggest that MHC-I molecules expressed by malaria-infected hepatocytes play a key role in mediating the anti-plasmodial activity of CD8+ T cells in vivo. It is still unknown to which extent MHC-I molecules expressed by hepatocytes mediate the anti-plasmodial activity of CD8+ T cells in vivo
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