Immune mechanisms of experience induced brain plasticity: the contribution of brain resident T cells

T cells are part of the adaptive immune response. Breaking the dogma of the brain immune privilege I demonstrated the presence of T cells in the healthy brain. In the mouse brain they regulate neuronal morphology and behavior.

Surprisingly, brain T cells respond and proliferate upon exposure to an enriched environment (EE), suggesting a connection between neural activity and brain T cells. EE involves motoric, sensory and social stimulation.

Exposure of rodents to EE increases neurogenesis, enhances learning and memory, with proven beneficial effect in neuropathology. How brain T cells can respond to EE and eventually modify the brain is unknown.

I hypothesize that upon EE, T cells adapt their molecular profile and acquire an immunomodulatory phenotype to support the changes occurring in the brain.

My overarching goal is to understand how EE modulates immune-brain interactions and to harness emerging discoveries to develop novel therapeutic interventions for neurodevelopmental disorders, that mimic the beneficial effects of EE.

Currently, research into brain functions of T cells is limited by absence of research tools to deplete T cells in the brain only.

The proposed project will overcome these limitations by developing a novel gene therapy approach for depleting brain T cells . First, I will investigate how EE influences brain immunity.

Then I will take the opposite approach, investigating whether and how brain immune cells act as a necessary mediator of EE-induced brain plasticity, making use of the new nanobody-based tool to deplete brain T cells.

These complementary approaches will allow me to mechanistically decipher how experience influences interactions between the brain and the immune system.

Finally, using the Fragile X mouse model of Autism, I will translate the knowledge gained from brain resident T cells into impactful proof-of-concepts for treating neurological diseases and mimicking the benefits of environmental enrichment through immunotherapy