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Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell–Mediated Neuroinflammation

Carmen Gonzalez-Fierro,Coralie Fonte,Eloïse Dufourd,Vincent Cazaentre,Sidar Aydin,B. Engelhardt,R. Caspi,Biying C Xu,G. Martin-Blondel,J. Spicer,J. Trapani,J. Bauer,R. Liblau,C. Bost

Published 2023 in Neurology: Neuroimmunology & Neuroinflammation

ABSTRACT

Background and Objectives Alteration of the blood-brain barrier (BBB) at the interface between blood and CNS parenchyma is prominent in most neuroinflammatory diseases. In several neurologic diseases, including cerebral malaria and Susac syndrome, a CD8 T cell–mediated targeting of endothelial cells of the BBB (BBB-ECs) has been implicated in pathogenesis. Methods In this study, we used an experimental mouse model to evaluate the ability of a small-molecule perforin inhibitor to prevent neuroinflammation resulting from cytotoxic CD8 T cell–mediated damage of BBB-ECs. Results Using an in vitro coculture system, we first identified perforin as an essential molecule for killing of BBB-ECs by CD8 T cells. We then found that short-term pharmacologic inhibition of perforin commencing after disease onset restored motor function and inhibited the neuropathology. Perforin inhibition resulted in preserved BBB-EC viability, maintenance of the BBB, and reduced CD8 T-cell accumulation in the brain and retina. Discussion Therefore, perforin-dependent cytotoxicity plays a key role in the death of BBB-ECs inflicted by autoreactive CD8 T cells in a preclinical model and potentially represents a therapeutic target for CD8 T cell–mediated neuroinflammatory diseases, such as cerebral malaria and Susac syndrome.

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