Functional impact of MHC I presentation by CNS neurons during chronic toxoplasmosis A. Salvioni1, M. Belloy1, E. Bassot1, V. Vasseur1, S. Blanié1, E. Suberbielle1, R.S. Liblau1, E.A. Robey2, N. Blanchard1* 1Centre de Physiopathologie Toulouse-Purpan (CPTP), INSERM, CNRS, Université de Toulouse, France; 2Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA *Corresponding Author
In the brain, MHC I regulates synaptic plasticity and strong evidence suggest that CD8 T cells interact with virus-infected neurons. Yet little is known about the impact of neuronal MHC I presentation on the pathophysiology of infection by complex neurotropic parasites. The Toxoplasma gondii (T. gondii) parasite persists within bradyzoite-containing cysts that develop in CNS neurons. In rodents, T. gondii alters innate aversion towards feline urine and in humans, latent toxoplasmosis is linked to neuropsychiatric disorders. In both species, sub-optimal immune responses can result in impaired parasite control leading to a deadly Toxoplasmic Encephalitis (TE). TE is characterized by foci of parasite replication in the brain, formation of granuloma-like structures and glial cell activation. While CD8 T cells and MHC I are key determinants of TE resistance, the mechanisms of antigen presentation by neurons and its functional relevance during chronic T. gondii infection are unexplored. Here using a novel mouse model that allows cell type-specific deletion of H2-Ld, a MHC I molecule essential for resistance against TE, we show that MHC I presentation by neurons dramatically restricts the cyst burden at chronic stage without influencing parasite dissemination during acute stage. Absence of Ld expression by neurons did not perturb the accumulation of T. gondii-specific CD8 T cells in infected brains and modestly altered the activation of resident and recruited myeloid cells, indicating that neuronal MHC I presentation is pivotal for restricting parasites in brain but largely dispensable for the control of cerebral inflammation. On-going experiments aim to elucidate which form(s) of the parasite is/are targeted by CD8 T cells in the course of T. gondii infection. Harnessing CD8 T cells to remove cysts could be helpful in at-risk chronically infected individuals as there is currently no effective treatment against this stage. Our work provides critical insights on the mechanisms by which CD8 T cells recognize and control neurotropic persisting pathogens.
Funding: Idex Toulouse, FRM
Credits: None available.
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