CD8+ T cells play a major protective role in immunity to malaria infection by inhibiting the development of liver stages. Vaccination studies using malaria sporozoites, and recombinant viral vectors as well as synthetic constructs such as DNA, have provided important new information regarding the protective role of these T cells. Our recent studies on CD8+ T cell responses against the CS protein of P. yoelii established that when sporozoites are delivered by mosquito bites, the T cell response is induced by dendritic cells (DCs) in skin draining lymph nodes (LN). Primed cells migrate to peripheral organs including the liver, where they develop memory CD8+ populations. Upon challenge these liver resident CD8+ T cells are able to eliminate malaria infection. To protect, T cells have to see antigen in the context of liver parenchymal cells - presumably infected hepatocytes - and need not be re-stimulated by bone-marrow derived DCs. Thus the processes of priming the CD8+ T cell response and eliciting effector function from those cells involve different cellular and molecular interactions. We propose to undertake studies aimed at characterizing some basic aspects of the in vivo CD8+ T cell responses against the liver stages of P. yoelii. These studies aim to define basic features of the key initial interactions that occur between sporozoites, DCs and pattern recognition receptors which lead to the acquisition and presentation of parasite antigen to CD8+ T cells in LN. We also propose studies on liver-resident memory CD8 cells which aim at characterizing the mechanisms that mediate their homing to the liver, at defining their functional properties and evaluating conditions that may modulate the permanence and anti-parasite activity of these memory cells. These studies will be facilitated by the availability of TCR transgenic mice and transgenic parasites expressing model CD8 epitopes developed in my laboratory. These enable us to track CD8 T cells throughout their differentiation in both normal and gene-knockout animals. Finally, we will develop research aimed at studying the functional properties and evolution of memory responses against the P. yoelii CS protein. We will evaluate the fate of these memory cells under continued antigen stimulation which normally occurs due to repeated parasite exposure and antigen persistence. We will study the renewal mechanisms of memory populations and the relationship between different memory cell subsets i.e., those residing in the liver (effector memory and those from lymph nodes (central memory).

Public Health Relevance

The proposal aims at investigating basic features of CD8+ T cell responses against Malaria liver stages. We propose to characterize the role of dendritic cell subsets in induction of this response, the role of adhesion molecule in homing and functional properties of liver-resident anti-Malaria memory T cells and study the mechanisms controlling the evolution and maintenance of protective memory CD8+ T cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Public Health
United States
Zip Code
Tse, Sze-Wah; Radtke, Andrea J; Espinosa, Diego A et al. (2014) The chemokine receptor CXCR6 is required for the maintenance of liver memory CD8? T cells specific for infectious pathogens. J Infect Dis 210:1508-16
Luo, Kun; Zhang, Hong; Zavala, Fidel et al. (2014) Fusion of antigen to a dendritic cell targeting chemokine combined with adjuvant yields a malaria DNA vaccine with enhanced protective capabilities. PLoS One 9:e90413
Cockburn, Ian A; Tse, Sze-Wah; Zavala, Fidel (2014) CD8+ T cells eliminate liver-stage Plasmodium berghei parasites without detectable bystander effect. Infect Immun 82:1460-4
Deal, Cailin; Balazs, Alejandro B; Espinosa, Diego A et al. (2014) Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice. Proc Natl Acad Sci U S A 111:12528-32
Sack, Brandon K; Miller, Jessica L; Vaughan, Ashley M et al. (2014) Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum. Infect Immun 82:808-17
Tse, S-W; Cockburn, I A; Zhang, H et al. (2013) Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites. Genes Immun 14:302-9
Sinnis, Photini; Zavala, Fidel (2008) The skin stage of malaria infection: biology and relevance to the malaria vaccine effort. Future Microbiol 3:275-8