CD8(+) T cells induce RIPK1-regulated brain endothelial cell death in cerebral malaria

07/11/2026

AI Summary

CD8+ T cells induce RIPK1-regulated death of brain endothelial cells in mouse cerebral malaria.
RIPK1 phosphorylation is increased in brain endothelial cells in human cerebral malaria.
RIPK1 kinase inhibition, genetic or pharmacological, prolongs survival in mouse CM without altering parasitaemia; combined RIPK1 and caspase inhibition protects endothelium in vitro.

TL;DR (AI Generated)

Here, we show that CD8+ T cells induce receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-regulated cell death of brain endothelial cells in mouse CM, while RIPK1 phosphorylation is increased in brain endothelial cells in human CM.

Using magnetic resonance imaging, three-dimensional tissue-cleared brain imaging, cross-species pathology, endothelial translatomics, immunocerebrovascular interactomics, and genetic association testing, we identify a CD8+ T cell-dependent, RIPK1-centered mouse endothelial cell death program.

Combined RIPK1 and caspase inhibition protected cross-presenting endothelial cells from CD8+ T cell-mediated death in vitro.

Basic summary

Sci Adv. 2026 Nov 6;12(45):eaej4381. doi: 10.1126/sciadv.aej4381. Epub 2026 Nov 6.

ABSTRACT

Cerebral malaria (CM) is a potentially lethal complication of Plasmodium falciparum infection characterized by blood-brain barrier disruption and brain hemorrhage. Although immune-mediated endothelial damage is central to CM pathology, the mechanisms linking cytotoxic immune responses to endothelial injury remain unclear. Here, we show that CD8⁺ T cells induce receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-regulated cell death of brain endothelial cells in mouse CM, while RIPK1 phosphorylation is increased in brain endothelial cells in human CM. Using magnetic resonance imaging, three-dimensional tissue-cleared brain imaging, cross-species pathology, endothelial translatomics, immunocerebrovascular interactomics, and genetic association testing, we identify a CD8⁺ T cell-dependent, RIPK1-centered mouse endothelial cell death program. Combined RIPK1 and caspase inhibition protected cross-presenting endothelial cells from CD8⁺ T cell-mediated death in vitro. In vivo, brain endothelial-specific genetic inactivation or systemic pharmacological inhibition of RIPK1 kinase activity prolonged survival in mouse CM without altering parasitemia. These findings support RIPK1 inhibition as a promising therapeutic strategy to counter CD8⁺ T cell-induced endothelial death in CM.

PMID:42993832 | DOI:10.1126/sciadv.aej4381

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