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

TL;DR

Blocking PKCθ reduces brain damage caused by CD8+ T cells in a mouse model of cerebral malaria.

Contribution

This study identifies PKCθ as a key driver of CD8+ T cell-mediated brain injury in cerebral malaria.

Findings

PKCθ deficiency improves survival in Plasmodium-infected mice without affecting parasite levels.

Loss of PKCθ shifts T cell differentiation toward central memory, reducing brain infiltration.

Inhibiting PKCθ prevents neurovascular damage and preserves neural tissue integrity.

Abstract

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 θ (PKCθ), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). Methods/Results: Using a PKCθ null allele mouse strain on a C57BL/6N background, we demonstrate that PKCθ deficiency significantly improves survival in Plasmodium berghei ANKA (PbA)-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. Conclusions: 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.

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