Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites.
Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites.
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DOI：
10.1371/journal.ppat.1000998
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发表时间：
2010-07-15
期刊：
影响因子：
6.7
通讯作者：
Harty JT
中科院分区：
文献类型：
--
作者：
Schmidt NW;Butler NS;Badovinac VP;Harty JT
Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these “whole-parasite” vaccines are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines. Plasmodium infections are a global health crisis resulting in ∼300 million cases of malaria each year and ∼1 million deaths. Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccines that induce sterilizing anti-malarial immunity in humans. Importantly, “whole parasite” anti-malarial RAS vaccines are currently under evaluation in clinical trials. In rodents, RAS-induced protection is largely mediated by CD8 T cells. However, the quantitative and qualitative characteristics of RAS-induced protective CD8 T cell responses are unknown. Here, we used surrogate markers of T cell activation to reveal the magnitude and kinetics of Plasmodium-specific CD8 T cell responses following RAS-immunization in both inbred and outbred mice. Our data show that, independent of host genetic background, extremely large memory CD8 T cell responses were required, but not always sufficient for sterilizing protection. These data have broad implications for evaluating total T cell responses to attenuated pathogen-vaccines and direct relevance for efforts to translate attenuated whole-Plasmodium vaccines to humans.
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影响因子：
3.7
作者：
Kumar, Kota Arun;Baxter, Peter;Tarun, Alice S.;Kappe, Stefan H. I.;Nussenzweig, Victor
通讯作者：
Nussenzweig, Victor
影响因子：
64.5
作者：
Kaech, SM;Hemby, S;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
3.6
作者：
Aly, Ahmed S. I.;Mikolajczak, Sebastian A.;Rivera, Hilda Silva;Camargo, Nelly;Jacobs-Lorena, Vanessa;Labaied, Mehdi;Coppens, Isabelle;Kappe, Stefan H. I.
通讯作者：
Kappe, Stefan H. I.
影响因子：
6.7
作者：
Cockburn IA;Chen YC;Overstreet MG;Lees JR;van Rooijen N;Farber DL;Zavala F
通讯作者：
Zavala F
DOI：
10.4269/ajtmh.1975.24.397
发表时间：
1975-01-01
影响因子：
3.3
作者：
CLYDE, DF;MCCARTHY, VC;WOODWARD, WE
通讯作者：
WOODWARD, WE