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Varying Immunizations With Plasmodium Radiation-Attenuated Sporozoites Alter Tissue-Specific CD8(+) T Cell Dynamics

Whole sporozoite vaccines represent one of the most promising strategies to induce protection against malaria. However, the development of efficient vaccination protocols still remains a major challenge. To understand how the generation of immunity is affected by variations in vaccination dosage and...

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Detalles Bibliográficos
Autores principales: Frank, Roland, Gabel, Michael, Heiss, Kirsten, Mueller, Ann-Kristin, Graw, Frederik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985394/
https://www.ncbi.nlm.nih.gov/pubmed/29892289
http://dx.doi.org/10.3389/fimmu.2018.01137
Descripción
Sumario:Whole sporozoite vaccines represent one of the most promising strategies to induce protection against malaria. However, the development of efficient vaccination protocols still remains a major challenge. To understand how the generation of immunity is affected by variations in vaccination dosage and frequency, we systematically analyzed intrasplenic and intrahepatic CD8(+) T cell responses following varied immunizations of mice with radiation-attenuated sporozoites. By combining experimental data and mathematical modeling, our analysis indicates a reversing role of spleen and liver in the generation of protective liver-resident CD8(+) T cells during priming and booster injections: While the spleen acts as a critical source compartment during priming, the increase in vaccine-induced hepatic T cell levels is likely due to local reactivation in the liver in response to subsequent booster injections. Higher dosing accelerates the efficient generation of liver-resident CD8(+) T cells by especially affecting their local reactivation. In addition, we determine the differentiation and migration pathway from splenic precursors toward hepatic memory cells thereby presenting a mechanistic framework for the impact of various vaccination protocols on these dynamics. Thus, our work provides important insights into organ-specific CD8(+) T cell dynamics and their role and interplay in the formation of protective immunity against malaria.