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

Background: Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum 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 theta (PKC theta), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). Methods/Results: Using a PKC theta null allele mouse strain on a C57BL/6N background, we demonstrate that PKC theta deficiency significantly improves survival in Plasmodium berghei ANKA (PbA)-infected mice without altering parasite burdens in the blood or brain. Mechanistically, loss of PKC theta 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 PKC theta drives CD8(+) T cell-mediated brain injury in ECM. Conclusions: These results underscore the potential for repurposing clinically PKC theta inhibitors as host-targeted interventions to protect against cerebral injury and improve outcomes in patients with CM.