title: CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging.
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.
authors: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Kuti
authors: K
authors: Baruch
authors: Noga
authors: N
authors: Ron-Harel
authors: Hilah
authors: H
authors: Gal
authors: Aleksandra
authors: A
authors: Deczkowska
authors: Eric
authors: E
authors: Shifrut
authors: Wilfred
authors: W
authors: Ndifon
authors: Nataly
authors: N
authors: Mirlas-Neisberg
authors: Michal
authors: M
authors: Cardon
authors: Ilan
authors: I
authors: Vaknin
authors: Liora
authors: L
authors: Cahalon
authors: Tamara
authors: T
authors: Berkutzki
authors: Mark P
authors: MP
authors: Mattson
authors: Fernando
authors: F
authors: Gomez-Pinilla
authors: Nir
authors: N
authors: Friedman
authors: Michal
authors: M
authors: Schwartz
mesh_terms: D056704:Adaptive Immunity; D000375:Aging / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D049109:Cell Proliferation; D002831:Choroid Plexus / Q000276:immunology* / Q000473:pathology*; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015213:Neuroimmunomodulation; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology*; D000096743:Interferon gamma Receptor
chemical_list: D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor