Journal article
CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging
Proceedings of the National Academy of Sciences of the United States of America, Vol.110(6), pp.2264-2269
Feb/2013
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-gamma, 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-gamma 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.
Details
- Title
- CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging
- Creators
- Kuti Baruch (null) - 972WIS_INST___123Harel, Noga Ron Harel (null) - 972WIS_INST___123Hilah Gal (null) - The Weizmann Institute of ScienceAleksandra Deczkowska (null) - 972WIS_INST___123Eric Shifrut (null) - 972WIS_INST___120Wilfred Ndifon (null) - The Weizmann Institute of ScienceNataly Mirlas-Neisberg (null)Michal Cardon (null) - 972WIS_INST___123Ilan Vaknin (null) - 972WIS_INST___123Liora Cahalon (null) - 972WIS_INST___123Tamara Berkutzki (null) - The Weizmann Institute of ScienceMark P. Mattson (null)Fernando Gomez-Pinilla (null)Nir Friedman (null) - 972WIS_INST___120Michal Schwartz (null) - 972WIS_INST___123
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences of the United States of America, Vol.110(6), pp.2264-2269; Feb/2013
- Number of pages
- 6
- Language
- English
- DOI
- https://doi.org/10.1073/pnas.1211270110
- Grant note
- European Research Council; National Institute on AgingWe thank Dr. Gilad Kunis for technical assistance, Dr. Shelley Schwarzbaum for editing the manuscript, Dr. Hillary Voet for statistical consultation, and Margalit Azoulay for animal handling. This research was supported by a European Research Council Grant Award, a Seventh Framework Programme HEALTH-2011 Grant (to M. S.), and by the Intramural Research Program of the National Institute on Aging (to M. P. M.). N.F. is the incumbent Pauline Recanati Career Development Chair of Immunology. M. S. holds The Maurice and Ilse Katz Professorial Chair in Neuroimmunology._ALMAME_DELIMITER_
- Record Identifier
- 993266979103596
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