Insights into the Subset, Antigen Specificity, and Localization of T Cells in Spatial Learning and Memory

Radjavi, Ali, Microbiology - Graduate School of Arts and Sciences, University of Virginia
Kipnis, Jonathan, Department of Neuroscience, University of Virginia

The notion of “immune privilege” in the central nervous system (CNS) has worked to perpetuate the impression that interactions between the brain and immune system are inherently detrimental. However, the view of the CNS as an ivory tower, insulated from the reach and influence of the immune system, has been considerably challenged in recent years. Indeed, many of the immune processes thought to be absent in the CNS have been observed in the meningeal structures that follow the contours, ventricles and vasculature of the brain parenchyma.
A large portion of this thesis is dedicated to T cell behavior in the meninges, which in spite of its profound influence on brain processes, immune surveillance, and neuropathology, remains poorly understood. Part of the original work herein attempts to elucidate the dynamics and the antigenic specificity of T cells within the meningeal space. By employing a parabiotic system of shared circulation we show that the CD4 turnover in the meninges to be slow relative to other tissues, dependent on a memory phenotype, and tightly coupled to the meninges draining deep cervical lymph node.
As our perception of absolute immune privilege has changed, so have our view on the outcomes of T cell-CNS crosstalk. Whereas neuroimmunology was once nearly synonymous with immune-mediated neuropathology, it now encompasses the emerging homeostatic roles of T cell-CNS interactions, including: hippocampal-dependent learning, stress response paradigms, and models of neurogenesis, neurodegeneration, and CNS injury.
This body of work aims to shed light on the observation that lymphopenic mice exhibit significant behavioral impairment in spatial learning and memory tasks. Employing several transgenic mouse models in combination with adoptive transfers, we evidence the necessity of an antigen-specific CD4 T cell compartment in normal special learning and memory in mice. Specifically we show that lymphopenic mice manifest with an impaired spatial learning and memory phenotype that can be rescued by adoptive transfer of wild-type CD4 T cells. We go on to show that a monoclonal T cell population reactive to CNS self-antigen is sufficient to improve cognitive task performance in otherwise learning impaired animals, and raise the possibility that rescue is mediated by a robust population of meninges infiltrating myeloid derived suppressor cells.

PHD (Doctor of Philosophy)
All rights reserved (no additional license for public reuse)
Issued Date: