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.