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

By Noël C. Derecki, Amber N. Cardani, C. Yang, Kayla Quinnies, Anastasia Crihfield, K. Lynch, Jonathan Kipnis. Journal of Experimental Medicine, 2010

764 citations recorded by the source corpus.

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.

Subfields: Biological Psychiatry, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/79489f9ca65efb038e945ac6f2a1ddcf70855e0b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. M. Schwartz
2. Zhiping Weng
3. G. Martino
4. S. Pluchino
5. Jonathan Kipnis

In Neurology

1. M. Schwartz
2. A. Louveau
3. Tajie H. Harris
4. Jonathan Kipnis

Citations in the corpus

• Immune modulation of learning, memory, neural plasticity and neurogenesis. (2011, neutral): “The meningeal spaces constitute an important location for T cell-based support of behavioral plasticity, providing an explanation for such effects of T cells without their presence in the CNS parenchyma (Derecki et al., 2010; Schwartz and Shechter, 2010).”
• The role of immune dysfunction in the pathophysiology of autism (2011, neutral): “IL-4 knock-out mice show impaired cognition, possibly as a result of loss of T cell function in the CNS (Derecki et al., 2010).”
• Revisiting the concept of CNS immune privilege (2015, background): “Interestingly, not only T cell deficiency but also acute depletion of T cells from wild-type mice or even inhibition of their migration into CNS tissue (by anti-VLA4 antibodies) resulted in impaired performance of mice in cognitive tasks [100,102].”
• Unexpected role of interferon-γ in regulating neuronal connectivity and social behavior (2016, background): “IFN-γ Signaling in Microglia is not Necessary for Normal Social Function Mice deficient for STAT1 in microglia have normal social preference (n = 9 mice per group; ANOVA for Cre F(1, 16) = 1.”
• Neuroinflammation: The Devil is in the Details (2016, neutral): “Furthermore, enhanced neuroinflammatory signaling between T-cells and resident CNS cells are implicated in normal memory and learning (Ziv et al. 2006; Derecki et al. 2010).”
• BRAIN REGENERATION IN PHYSIOLOGY AND PATHOLOGY: THE IMMUNE SIGNATURE DRIVING THERAPEUTIC PLASTICITY OF NEURAL STEM CELLS (2011, background): “As in the case of neurogenesis, this impairment in spatial learning and memory can be remedied by immune reconstitution (54, 104, 244).”