MHC I Ag presentation by Central nervous system-resident cells during Chronic infection of the Brain – MICCHROB

Rather than being ‘immune-privileged’, the brain is endowed with a unique immunological status, including innate and adaptive mechanisms that are essential for the detection and control of neurotropic infections. It is now established that Major Histocompatibility Complex class I (MHC I) molecules play key roles in regulating synaptic plasticity and there is also evidence that they drive antigen-specific interactions between CD8 T cells and virus-infected neurons. Yet, nothing is known about the pathways used by neurons to present antigens on MHC I and it is unclear how MHC I-restricted neuron-CD8 interactions affects neuronal activity and host behavior. More generally and beyond neurons, the roles of MHC I presentation by resident cells of the Central Nervous System (CNS) on the generation of brain memory CD8 T cells remain poorly understood.

The MICCHROB project aims to address these questions in the context of infection by the neurotropic apicomplexan parasite Toxoplasma gondii (T. gondii). In intermediate hosts, T. gondii co-exists as tachyzoites that disseminate throughout the organism and bradyzoites that chronically persist within cysts in muscles and the CNS. In the CNS, T. gondii interacts with a variety of cell types but neurons are the exclusive cells that support cyst development. Depending on the immune status of the host, infection may cause behavioral impairment and/or a deadly neuroinflammation named Toxoplasmic Encephalitis (TE). Behavioral impairment includes alteration of innate aversion towards feline urine in rodents and possibly a variety of neuropsychiatric disorders in humans, although no causal relationship has been proven for the latter. In mice and humans, T cell deficiency or dysfunction can lead to the development of TE, an inflammatory condition of the brain characterized by poor parasite control, immune infiltration and tissue damage. CD8 T cells and MHC I (in particular the H2-Ld MHC I allele in the mouse) are critical determinants of TE resistance. Nevertheless, how brain MHC I presentation underlies TE pathogenesis and potentially shapes innate behavior and/or cognitive functions remains unknown.

In this context, the overarching goal of our proposal is to unravel the functional consequences of MHC I presentation by CNS-resident cells on cerebral parasite control, generation of brain memory CD8 T cells and mouse behavior upon T. gondii infection. We also aim to investigate the molecular mechanisms of T. gondii MHC I presentation by neurons. To achieve these objectives, we will use (i) original mouse models allowing selective ablation of the MHC I allele associated with TE resistance in various CNS-resident cells, (ii) a panel of behavioral challenges assessing innate fear and cognitive functions (spatial and associative learning and memory), as well as (iii) antigen presentation assays with primary cultures of neurons.

The MICCHROB project will be undertaken by an interdisciplinary consortium, which brings together national and international academics with expertise in parasitology, behavioral neuroscience, cell biology and immunology.

Our results are expected to shed new light on the mechanisms whereby CD8 T cells control a brain-dwelling parasite via neuronal antigen presentation. They may uncover how MHC I presentation in the brain influences mouse behavior and formation of CD8 T cell memory. Beside the major fundamental interests of these questions, our data may be relevant from a prophylactic or therapeutic perspective as there is currently no drug effective on cysts and CD8 T cells have been proposed as a tool to clear them.