Resolving the spatiotemporal events controlling effector T cell responses during malaria

Malaria remains one of the most important diseases in the world, responsible for hundreds of thousands of deaths and significant morbidity and suffering in many millions of people, each year. CD4+ T cells are essential for control of malaria, through helping macrophages kill parasites and promoting antibody production. However, it is well known that CD4+ T cell effector responses become suppressed during blood-stage malaria (a phenomenon called T cell exhaustion) and this directly impairs parasite control, contributes to chronicity of infection, and promotes susceptibility to reinfection. At present the pathways that promote T cell exhaustion during malaria are poorly understood.

The project will dissect the processes that provoke T cell exhaustion during malaria. In the labs of Dr Kevin Couper and Prof Andrew MacDonald at the University of Manchester, cutting-edge imaging mass cytometry will be used (which allows the multiplex and concurrent detection of 40 molecules in a tissue section) to identify the complex spatiotemporal cellular choreography that occurs within the spleen during the course of malaria.

This will define, for the first time, the T cellular phenotypic, positional and interactional events that combine to regulate T cell function during malaria. Utilising complementary two-photon imaging approaches (a modality that allows us to look deep within intact tissues in live animals), the changing dynamic behaviour of antigen-specific CD4+ T cells, and their interactions with dendritic cells and tissue components will be assessed during the course of malaria, associated with alterations in T cell function.

In the lab of Prof Bill Heath at the Peter Doherty Institute at the University of Melbourne, in vivo murine models of malaria will be employed as well as novel approaches to perturb the activity of specific dendritic cell populations and immune and tissue factors (such as stromal cells) identified during experiments in Manchester.

The project will examine how these targeted manipulations influence CD4+ T cell effector function and establishment of cellular exhaustion during malaria. Combined, the results from this collaborative project will transform our understanding of the pathways and cellular events that promote T cell exhaustion within a physiological tissue environment during malaria. This will directly lead to new strategies to therapeutically reinvigorate CD4+ T cells during malaria, and other human diseases characterised by T cell exhaustion, such as cancer.

Prof William Heath, Faculty of Medicine, Dentistry and Health Sciences (Doherty Institute), The University of Melbourne

Dr Kevin Couper, The University of Manchester