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

Introduction

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

Connection Between T Cells and Enriched Environment

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 stimulation
• Sensory stimulation
• Social stimulation

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

Hypothesis

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.

Research Limitations

Currently, research into the brain functions of T cells is limited by the 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.

Research Objectives

1. Investigate how EE influences brain immunity.
2. Take the opposite approach by investigating whether and how brain immune cells act as a necessary mediator of EE-induced brain plasticity, utilizing 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.

Application of Research

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.