| First Author | Trimnell A | Year | 2009 |
| Journal | J Immunol | Volume | 183 |
| Issue | 9 | Pages | 5870-8 |
| PubMed ID | 19812194 | Mgi Jnum | J:156626 |
| Mgi Id | MGI:4421099 | Doi | 10.4049/jimmunol.0900302 |
| Citation | Trimnell A, et al. (2009) Genetically attenuated parasite vaccines induce contact-dependent CD8+ T cell killing of Plasmodium yoelii liver stage-infected hepatocytes. J Immunol 183(9):5870-8 |
| abstractText | The production of IFN-gamma 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-gamma. 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-gamma knockout mice also indicated that the protection was largely dependent on perforin-mediated effector mechanisms rather than on IFN-gamma. 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-gamma and TNF-alpha. 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-gamma. |
