Regulation of learning and memory by meningeal immunity: a key role for IL-4.
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.
Derecki
Noël C
NC
Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Cardani
Amber N
AN
Yang
Chun Hui
CH
Quinnies
Kayla M
KM
Crihfield
Anastasia
A
Lynch
Kevin R
KR
Kipnis
Jonathan
J
D000818:Animals; D016026:Bone Marrow Transplantation; D003072:Cognition Disorders / Q000235:genetics; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008212:Lymphocyte Depletion; D008578:Meninges / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011409:Propylene Glycols / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D015847:Interleukin-4; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine