[Thesis]. Manchester, UK: The University of Manchester; 2019.
Malaria is a global life-threatening disease responsible for 400,000 deaths each year.
Chronic infection with Plasmodium species drives CD4+ T cell exhaustion, which is
characterised by the inability of effector CD4+ T cells to produce effector cytokines,
proliferate and increased T cell apoptosis. T cell exhaustion significantly impairs
parasite control during blood stage malaria. However, the molecular mechanisms promoting
CD4+ T cell exhaustion during malaria are poorly understood.
Using a model antigen-specific CD4+ T cell system, we have shown that effector CD4+
T cells rapidly become functionally exhausted during P.yoelii infection. The degradation
of the effector CD4+ T cell response appeared to relate to the loss of MHC II-TCR
signalling, as blockade of MHC II signalling, post priming, did not exacerbate effector
T cell dysfunction and attrition during malaria. However, apparent loss of MHC II
activation during infection was not due to alterations in CD4+ T cell compartmentalisation,
or inability of effector CD4+ T cells to interact with antigen presenting cells (APC)
during infection. Instead, we propose that negative signals from co-inhibitory receptors
subvert peptide MHC II-TCR signals in effector CD4+ T cells, contributing to T cell
exhaustion during blood stage malaria.
To further investigate the role of co-inhibitory receptors in promoting CD4+ T cell
exhaustion during malaria, we administered antagonistic antibodies against TIGIT and
PD-L1. Dual blockade of TIGIT and PD-L1 significantly enhanced parasite control, which
correlated with an increased level of systemic interferon gamma (IFNg) and an enhanced
T follicular helper response during infection. Surprisingly, however, dual blockade
of TIGIT and PD-L1 did not significantly improve effector CD4+ T cell function. Thus,
blockade of TIGIT and PD-1 signalling pathways cannot prevent CD4+ T cell exhaustion
We also investigated the synergistic role of Tim3 and PD-1 in promoting CD4+ T cell
exhaustion during malaria. Interestingly, Tim3 was transiently expressed on effector
CD4+ T cells and was downregulated as T cell exhaustion was established during infection.
In agreement, co-blockade of Tim3 and PD-L1 failed to improve CD4+ T cell functionality
during P.yoelii infection, suggesting that Tim3 does not contribute to CD4+ T cell
exhaustion during malaria.
Collectively, this thesis has shown that effector CD4+ T cell exhaustion is not associated
with the inability of T cells to form stable interactions with APC during infection,
but instead we propose that multiple immunoregulatory pathways act in parallel to
orchestrate T cell exhaustion during blood stage malaria.