Robust Control of a Neurotropic Parasite Through MHC I Presentation by Infected Neurons

Abstract

Inadequate immune control of Central Nervous System (CNS) pathogens may result in fatal neuroinflammation. CD8 T cells are instrumental for CNS pathogen control but the functions of brain-resident antigen-presenting cells remain poorly understood. Here, we analyzed the modalities of MHC I presentation of Toxoplasma gondii, a parasite chronically residing in the CNS. Using transgenic parasites with stage-restricted expression of a protective antigen, we show that MHC I presentation of the rapidly dividing tachyzoites prevents encephalitis and that improper parasite control during encephalitis correlates with sub-optimal MHC I presentation of T. gondii by neurons. Thanks to conditional MHC I-deficient mice, we demonstrate that neuronal MHC I presentation is dispensable for brain CD8 T cell accumulation but is required for durable pathogen control. Thus, MHC I presentation of parasite antigens by CNS neurons is a pivotal checkpoint that determines the clinical outcome of a prevalent and chronic brain infection.