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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900302v1 183/9/5870    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Trimnell, A. Articles by Wang, R. PubMed PubMed Citation Articles by Trimnell, A. Articles by Wang, R.

Genetically Attenuated Parasite Vaccines Induce Contact-Dependent CD8⁺ T Cell Killing of Plasmodium yoelii Liver Stage-Infected Hepatocytes¹

Adama Trimnell,^* Akihide Takagi,^* Megha Gupta,^* Thomas L. Richie, Stefan H. Kappe,^* and Ruobing Wang^2*

^*Seattle Biomedical Research Institute, Seattle, WA 98109; and Naval Medical Research Center, Silver Spring, MD 20910

The production of IFN- by CD8⁺ T cells is an important hallmark of protective immunity induced by irradiation-attenuated sporozoites against malaria. Here, we demonstrate that protracted sterile protection conferred by a Plasmodium yoelii genetically attenuated parasite (PyGAP) vaccine was completely dependent on CD8⁺ T lymphocytes but only partially dependent on IFN-. We used live cell imaging to document that CD8⁺ CTL from PyGAP-immunized mice directly killed hepatocyte infected with a liver stage parasite. Immunization studies with perforin and IFN- knockout mice also indicated that the protection was largely dependent on perforin-mediated effector mechanisms rather than on IFN-. This was further supported by our observation that both liver and spleen CD8⁺ T cells from PyGAP-immunized mice induced massive apoptosis of liver stage-infected hepatocytes in vitro without the release of detectable IFN- and TNF-. Conversely, CD8⁺ T cells isolated from naive mice that had survived wild-type P. yoelii sporozoite infection targeted mainly sporozoite-traversed and uninfected hepatocytes, revealing an immune evasion strategy that might be used by wild-type parasites to subvert host immune responses during natural infection. However, CTLs from wild-type sporozoite-challenged mice could recognize and kill infected hepatocytes that were pulsed with circumsporozoite protein. Additionally, protection in PyGAP-immunized mice directly correlated with the magnitude of effector memory CD8⁺ T cells. Our findings implicate CTLs as key immune effectors in a highly protective PyGAP vaccine for malaria and emphasize the critical need to define surrogate markers for correlates of protection, apart from IFN-.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a M. J. Murdock Trust and Seattle Biomedical Research Institute innovation grant.

² Address correspondence and reprint requests to Dr. Ruobing Wang, 307 Westlake Avenue N, Suite 500, Seattle Biomedical Research Institute, Seattle, WA 98109. E-mail address: ruobing.wang{at}sbri.org

³ Abbreviations used in this paper: spz, sporozoite; GAP, genetically attenuated parasite; KO, knockout; LS, liver stage; PCI, protection correlation index; PKO, perforin knockout; PyGAP, Plasmodium yoelii genetically attenuated parasite; T_CM, central memory T cell; T_EM, effector memory T cell; wt, wild type; CSP, circumsporozoite protein.

⁴ The online version of this article contains supplemental material.