title: Fleet-footed soldiers
title: circulating memory CD8 T cells quickly enter the fray during malarial and bacterial infection of the liver
titleType: Subtitle
Creators: name: Lefebvre, Mitchell Neill
Publisher: name: University of Iowa
Year: 2023
Subjects: Circulating memory CD8 T cell
Listeria monocytogenes
Liver-stage malaria
Sporozoite
T cell recruitment
Vaccine
public abstract

description: The highly vascularized liver may coordinate immune responses to infection or inflammation, and this non-lymphoid tissue is also a key target of clinically relevant pathogens. Chief among these pathogens is Plasmodium, the causative parasite of malaria, a disease that causes hundreds of thousands of deaths annually. The Plasmodium parasite must productively infect the liver before it can progress to potentially deadly blood-stage infection. Other pathogens that may target the liver include the bacteria Listeria monocytogenes and commensal microbes that escape from the gastrointestinal tract to cause sepsis. Antigen-specific memory CD8 T cells may exert control over infectious diseases by killing pathogen-infected host cells. The mechanisms by which memory CD8 T cells clear liver-localized pathogens, however, remain incompletely characterized. These knowledge gaps hinder scientists’ and physicians’ ability to develop novel treatments for infectious diseases of the liver. My thesis work, therefore, focused on determining if and how subsets of phenotypically and functionally distinct memory CD8 T cells control liver-stage malaria and other infections.
description: Using mouse models of liver-stage malaria, Listeria monocytogenes, and sepsis infections, I demonstrate that antigen-specific circulating effector memory CD8 T cells rapidly enter the malaria- or bacterially infected liver to exert control over the respective pathogen. This T cell recruitment relied on T-cell expressed LFA-1, liver phagocytes, and chemokine signaling. These findings highlighted the importance of considering circulating memory CD8 T cells when developing malaria vaccines. Also apparent in the data were unique differences between memory CD8 T cell recruitment to the liver as compared to other non-lymphoid tissues. These findings suggest that studying CD8 T cell biology in the context of liver infection may offer additional possibilities for combating human disease.
description: I next set out to apply my findings about circulating memory CD8 T cell protective capacity in a translational context. To this end, I developed a murine vaccine strategy for malaria that both more accurately recapitulated human responses to parasite vaccination and generated large numbers of resident and circulating memory CD8 T cells. A mouse-human weight-normalized radiation attenuated sporozoite (RAS) vaccination dose in mice induced partial non-sterilizing immunity to liver-stage malaria, which is similar to a human response to single RAS vaccination. Mice boosted with subunit vaccines based on recombinant attenuated bacterial or viral pathogens expressing liver-stage protective CD8 T cell epitopes increased both the number of memory CD8 T cells and conferred sterilizing immunity to the mice. This immunity was maintained even when the subunit vaccines were delivered intramuscularly, which is more clinically deliverable route than intravenous injection. My findings therefore inform human malaria vaccine development by demonstrating (1) that circulating memory CD8 T cells are a potentially important target during human vaccination efforts and (2) that a single RAS vaccination can be optimized by following it with more readily producible and deliverable subunit booster immunizations.