CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging

Kuti Baruch, Noga Ron-Harel, Hilah Gal, Aleksandra Deczkowska, Eric Shifrut, Wilfred Ndifon, Nataly Mirlas-Neisberg, Michal Cardon, Ilan Vaknin, Liora Cahalon, Tamara Berkutzki, Mark P. Mattson, Fernando Gomez-Pinilla, Nir Friedman, Michal Schwartz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4+ effector memory cells with a T-cell receptor repertoire specific to CNS antigens. With age, whereas CNS specificity in this compartment was largely maintained, the cytokine balance shifted in favor of the T helper type 2 (Th2) response; the Th2-derived cytokine IL-4 was elevated in the CP of old mice, relative to IFN-γ, which decreased. We found this local cytokine shift to critically affect the CP epithelium, triggering it to produce the chemokine CCL11 shown to be associated with cognitive dysfunction. Partial restoration of cognitive ability in aged mice, by lymphopenia-induced homeostasis-driven proliferation of memory T cells, was correlated with restoration of the IL-4:IFN-γ ratio at the CP and modulated the expression of plasticity-related genes at the hippocampus. Our data indicate that the cytokine milieu at the CP epithelium is affected by peripheral immunosenescence, with detrimental consequences to the aged brain. Amenable to immunomodulation, this interface is a unique target for arresting age-related cognitive decline.

Original languageEnglish
Pages (from-to)2264-2269
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number6
DOIs
StatePublished - 5 Feb 2013
Externally publishedYes

Keywords

  • Blood-cerebrospinal fluid barrier
  • Brain senescence
  • Neuroinflammation

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