Regulation of learning and memory by meningeal immunity: a key role for IL-4

• DOI: 10.1084/jem.20091419
• Publication Date: 2010-05-04T01:36:57Z
• Authors: Noël C. Derecki; Amber N. Cardani; Chun Hui Yang; Kayla M. Quinnies; Anastasia Crihfield; Kevin R. Lynch; Jonathan Kipnis
• Keywords: Mice, Knockout; 0301 basic medicine; Mice, Inbred BALB C; Fingolimod Hydrochloride; T-Lymphocytes; Article; Lymphocyte Depletion; 3. Good health; Mice; 03 medical and health sciences; Meninges; Propylene Glycols; Sphingosine; Animals; Learning; Interleukin-4; Cognition Disorders; Immunosuppressive Agents; Bone Marrow Transplantation

Proinflammatory cytokines have been shown to impair cognition; consequently, immune activity in the central nervous system was considered detrimental to cognitive function. Unexpectedly, however, T cells were recently shown to support learning and memory, though the underlying mechanism was unclear. We show that one of the steps in the cascade of T cell–based support of learning and memory takes place in the meningeal spaces. Performance of cognitive tasks led to accumulation of IL-4–producing T cells in the meninges. Depletion of T cells from meningeal spaces skewed meningeal myeloid cells toward a proinflammatory phenotype. T cell–derived IL-4 was critical, as IL-4−/− mice exhibited a skewed proinflammatory meningeal myeloid cell phenotype and cognitive deficits. Transplantation of IL-4−/− bone marrow into irradiated wild-type recipients also resulted in cognitive impairment and proinflammatory skew. Moreover, adoptive transfer of T cells from wild-type into IL-4−/− mice reversed cognitive impairment and attenuated the proinflammatory character of meningeal myeloid cells. Our results point to a critical role for T cell–derived IL-4 in the regulation of cognitive function through meningeal myeloid cell phenotype and brain-derived neurotrophic factor expression. These findings might lead to the development of new immune-based therapies for cognitive impairment associated with immune decline.