Prolonged Antigen Presentation Is Required for Optimal CD8+ T Cell Responses against Malaria Liver Stage Parasites

PLoS Pathogens

Jason R. Lees¹  Donna L. Farber¹  Yun-Chi Chen²  Fidel Zavala²  Michael G. Overstreet²  Ian A. Cockburn²  Nico van Rooijen³ 

[1] Department of Surgery, University of Maryland at Baltimore, Baltimore, Maryland, United States of America;Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Baltimore, Maryland, United States of America;Vrije Universiteit, VUMC, Department of Molecular Cell Biology, Faculty of Medicine, Amsterdam, The Netherlands

关键词: T cells;    Sporozoites;    Antigen presentation;    Genetically modified animals;    Cytotoxic T cells;    Immune response;    Antigen-presenting cells;    Parasitic diseases;   

DOI  :  10.1371/journal.ppat.1000877

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Immunization with irradiated sporozoites is currently the most effective vaccination strategy against liver stages of malaria parasites, yet the mechanisms underpinning the success of this approach are unknown. Here we show that the complete development of protective CD8+ T cell responses requires prolonged antigen presentation. Using TCR transgenic cells specific for the malaria circumsporozoite protein, a leading vaccine candidate, we found that sporozoite antigen persists for over 8 weeks after immunization—a remarkable finding since irradiated sporozoites are incapable of replication and do not differentiate beyond early liver stages. Persisting antigen was detected in lymphoid organs and depends on the presence of CD11c+ cells. Prolonged antigen presentation enhanced the magnitude of the CD8+ T cell response in a number of ways. Firstly, reducing the time primed CD8+ T cells were exposed to antigen in vivo severely reduced the final size of the developing memory population. Secondly, fully developed memory cells expanded in previously immunized mice but not when transferred to naïve animals. Finally, persisting antigen was able to prime naïve cells, including recent thymic emigrants, to become functional effector cells capable of eliminating parasites in the liver. Together these data show that the optimal development of protective CD8+ T cell immunity against malaria liver stages is dependent upon the prolonged presentation of sporozoite-derived antigen.

【 授权许可】

CC BY