Inhibition of PKCθ Abrogates CD8+ T Cell-Mediated Neurotoxicity in Murine Cerebral Malaria

<b>Background</b>: Cerebral malaria (CM) is a severe and often fatal complication of <i>Plasmodium falciparum</i> infection that causes devastating brain injury largely through immune-mediated mechanisms. Pathogenic brain-infiltrating CD8⁺ T cells are key drivers of CM pathology, yet the intracellular signals enabling their harmful autoimmune-like activity remain poorly defined. Here, we identify protein kinase C θ (PKCθ), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). <b>Methods/Results:</b> Using a PKCθ null allele mouse strain on a C57BL/6N background, we demonstrate that PKCθ deficiency significantly improves survival in <i>Plasmodium berghei</i> ANKA (<i>PbA</i>)-infected mice without altering parasite burdens in the blood or brain. Mechanistically, loss of PKCθ skews T cell differentiation towards central memory (Tcm) rather than effector memory (Tem) phenotypes, thereby reducing effector differentiation and sequestration of CD8⁺ T cells in the cerebral microvasculature. This prevents extensive neurovascular damage, preserves neural tissue integrity, and alleviates neurological signs and symptoms. Our findings provide genetic evidence that PKCθ drives CD8⁺ T cell-mediated brain injury in ECM. <b>Conclusions:</b> These results underscore the potential for repurposing clinically PKCθ inhibitors as host-targeted interventions to protect against cerebral injury and improve outcomes in patients with CM.