Targeting APC-Host Microbe interactions 2Robust control of a neurotropic parasite through MHC I presentation by infected neurons

Control of Central Nervous System (CNS) pathogens by CD8 T cells is pivotal to avoid fatal neuroinflammation. Yet the modalities of MHC I presentation in the brain are poorly understood. We analyzed the antigen presentation mechanisms underlying CD8 T cell-mediated brain restriction of Toxoplasma gondii, a neurotropic parasite that can chronically reside as cysts in the CNS and cause deadly encephalitis. First we engineered transgenic parasites expressing a model antigen that allows the establishment of latent toxoplasmosis in C57BL/6 mice, a mouse model that normally develops encephalitis following T. gondii infection. We show that MHC I presentation of that model antigen suffices to prevent encephalitis, even when restricted to the rapidly dividing tachyzoite stage. We find that improper parasite control in the context of encephalitis correlates with suboptimal MHC I presentation of T. gondii antigens by primary neuronal cultures. Using a new model of conditional MHC I-deficient mice, we finally demonstrate that brain parasite control requires neuronal MHC I presentation. Thus, MHC I presentation by CNS neurons is a crucial checkpoint that determines the clinical outcome of a prevalent and persisting brain infection.