Dissecting the molecular mechanisms of CD4+ T cell exhaustion during malaria

Abstract

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 during malaria. 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.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kevin Couper (Supervisor) & Andrew MacDonald (Supervisor)