Critical roles for T cells in regulating physiological and pathological events in the central nervous system have been defined in recent years. T cells modulate the post-injury survival and repair of neural tissue. In addition, T cells play an important role in neuronal plasticity, an essential substrate for spatial learning and memory. We showed that cognitive performance of immune-deficient mice is impaired relative to that of their wild-type counterparts, and is improved by passive transfer of T cells. These findings are consistent with the concept that the decline in immune activity associated with several mental disorders, such as age- and HIV-related dementia, """"""""chemo-brain"""""""" symptoms, contributes to cognitive dysfunction observed in these patients. The mechanism(s) underlying the beneficial T cell-mediated effect on cognition is (are) not fully understood. We hypothesize that cognitive task performance (or its associated stress response) results in migration and accumulation of T cells in the meningeal spaces. We posit that recruited T cells regulate meningeal myeloid cell phenotype and thus define the cytokine composition of the meninges. These cytokines, in turn, influence cognition either directly or through astrocyte-mediated synaptogenesis, regulating the astrocyte-derived synaptogenic factor, TSP1. This hypothesis predicts that the loss or inactivity of T cells would result in impaired synaptogenesis and lead to cognitive decline, whereas an enrichment of T cell-derived cytokines (primarily IL- 4) would improve cognitive function and conceivably circumvent the need for T cell activity. In the proposed project, we will address the types of T cells that affect learning and memory (aim #1), how do T cells get into the meninges (aim #2), and how do meningeal cytokines, controlled and produced by T cells, affect learning and memory (aim #3). Experiments in specific aim #1 are designed to determine which sub- populations of T cells are responsible for the mediated effect and how soon and for how long T cells mediate their protective effect on learning and memory. Experiments in specific aim #2 will examine the nature and the function of T cells that migrate to the meningeal spaces and accumulate there during performance of a cognitive task. The mechanism of T cell migration, their activation pattern and phenotype will be addressed. Experiments in specific aim #3 will aim to elucidate the mechanism underlying the beneficial role of T cell- derived IL-4 on learning and memory through either suppression of TNF, induction of TSP1, or though alternative pathway. Elucidation of the role of T cells in cognition and in their underlying cellular and molecular mechanism(s) of action will advance our understanding of cognitive deterioration in disorders characterized by impaired immune-system function. This enhanced understanding has the potential to define novel therapeutic targets for the improvement of several forms of cognitive decline.

Public Health Relevance

T cells modulate the post-injury survival and repair of neurons in the central nervous system. In addition, T cells play an important role in learning and memory.
The aim of this project is to elucidate cellular and molecular mechanism(s) underlying the role of T cells in cognitive function. This understanding has the potential to define novel therapeutic targets for several forms of cognitive decline.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034113-03
Application #
8279364
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Wagster, Molly V
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$300,553
Indirect Cost
$103,507
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Louveau, Antoine; Da Mesquita, Sandro; Kipnis, Jonathan (2016) Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer's Disease? Neuron 91:957-73
Filiano, Anthony J; Xu, Yang; Tustison, Nicholas J et al. (2016) Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535:425-9
Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan (2016) How Do Meningeal Lymphatic Vessels Drain the CNS? Trends Neurosci 39:581-6
Kipnis, Jonathan (2016) Multifaceted interactions between adaptive immunity and the central nervous system. Science 353:766-71
Filiano, Anthony J; Gadani, Sachin P; Kipnis, Jonathan (2015) Interactions of innate and adaptive immunity in brain development and function. Brain Res 1617:18-27
Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J et al. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337-41
Louveau, Antoine; Harris, Tajie H; Kipnis, Jonathan (2015) Revisiting the Mechanisms of CNS Immune Privilege. Trends Immunol 36:569-77
Radjavi, Ali; Smirnov, Igor; Kipnis, Jonathan (2014) Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav Immun 35:58-63
Radjavi, A; Smirnov, I; Derecki, N et al. (2014) Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol Psychiatry 19:531-3
Marin, Ioana; Kipnis, Jonathan (2013) Learning and memory ... and the immune system. Learn Mem 20:601-6

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