Meningeal Immunity, Learning and Memory, and IL-4: Do T cells Make You Smart? (87.35)

Abstract

Abstract T cells were recently shown to support learning and memory, although the underlying mechanisms for this phenomenon are yet unknown. Here, we show that severe combined immune deficient (SCID) mice, shown to be impaired in assays of learning and memory, display a pronounced pro-inflammatory (M1) skew of meningeal myeloid cells. Acute lymphopenia induced by FTY720, a sphingosine-phosphate receptor agonist, or blockade of T cell migration into the meninges using anti-VLA4 antibodies, results in similar cognitive impairment and M1-skewed meningeal myeloid phenotype in wild type mice. The role of IL-4 is critical: we show accumulation of IL-4+ CD4+ T cells in the meninges of wild type mice after MWM training. Moreover, IL-4 knockout mice exhibit profound cognitive impairment and M1 skew. Transfer of IL-4 knockout bone marrow to wild type mice results in meningeal myeloid inflammation and impaired learning, while transfer of wild type T lymphocytes to IL-4 knockout mice is sufficient to rescue both behavioral phenotype and M1 skew. Our results point to a critical role for meningeal T cells, and for IL-4 in particular, in the regulation of meningeal myeloid cells and concomitant cognitive function. These results might lead to development of new immune-based therapies for cognitive conditions associated with immune decline, such as HIV- and age-associated dementia.