J Immunol. 2026 Nov 2;215(11):vkag295. doi: 10.1093/jimmun/vkag295.
ABSTRACT
Cerebral malaria (CM) is a life-threatening complication of Plasmodium infection driven in part by an overwhelming inflammatory response. No clinical therapies are approved that specifically prevent immunopathology during CM. In experimental cerebral malaria (ECM), vascular endothelial cells in the mouse brain cross-present malaria antigen and upregulate adhesion molecules in response to inflammation. This causes CD8 T-cell arrest, activation, and lethal disruption of the blood-brain barrier. We previously reported that treatment with IL-15 cytokine complex (IL-15C) prevents ECM by inducing natural killer (NK) cell secretion of IL-10. To further uncover the mechanisms underlying this immunotherapy, OT-I T cells were transferred into mice, followed by infection with ovalbumin-expressing Plasmodium berghei. Using intravital microscopy, we observed major areas of OT-I arrest within the brains of untreated mice experiencing ECM. IL-15C treatment reduced the number of arresting OT-I T cells, coinciding with an increased mean velocity when compared to untreated mice. To identify the target of NK cell-secreted IL-10, we used conditional knockouts of IL-10Rα and found that protection from ECM occurs through IL-10Rα on endothelial cells and not CD8 T cells. Coinciding with this, IL-15C reduced the expression of adhesion molecules, selectins, and MHC-I on brain endothelial cells. In summary, our studies support the mechanism that IL-15C treatment reduces the number of arrested CD8 T cells along the cerebral vasculature by modulating endothelial cells to prevent ECM. These insights demonstrate the potential for treatments that reduce T-cell arrest to improve outcomes of human CM.
PMID:42995426 | DOI:10.1093/jimmun/vkag295