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.blood-cerebrospinal fluid barrier | brain senescence | neuroinflammation C irculating immune cells have been repeatedly shown to be essential for central nervous system (CNS) maintenance (1-3). Specifically, T cells that recognize CNS antigens contribute to the functional integrity of the CNS under both normal and pathological conditions (2, 4-6), supporting hippocampus-dependent learning and memory, adult neurogenesis, and neurotrophic factor production (2).Under physiological conditions, T cells are rarely found in the brain parenchyma and are mainly observed at the borders of the CNS: the choroid plexus (CP) of the brain's ventricles, forming the blood-cerebrospinal fluid barrier (BCSFB), the meningeal spaces, and the cerebrospinal fluid (CSF) (7). T cells were shown to accumulate in these compartments in response to signals from the CNS, specifically in the meninges after performance of cognitive tasks (8) and in the CP after exposure to mental stress (9). In the meningeal spaces, these cells were further characterized as producing the cytokine interleukin 4 (IL-4), known for its beneficial role in CNS maintenance and neuroprotection (8, 10-13). However, the questions of why, where, and how T-cell specificity is needed for brain plasticity remained mysterious.The CP is strategically positioned at the lining between the CNS and the immune system and, in addition to its classically known role in generating the CSF, can enable bidirectional communication between the CNS parenchyma and blood circulation (14). Accordingly, we envisioned that T cells...

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Interestingly, choroid plexus stroma dendritic cells can also reside between choroid plexus epithelial cells and extend their dendrites into the CSF filled ventricles [133], where they might take up CSF antigens for presentation to T cells in the choroid plexus stroma [101]. This is supported by the observation that T cells found in the choroid plexus stroma are enriched for CNS-specific effector/memory CD4 + T cells [10] (Fig. 6).…”

“…6). In the absence of neuroinflammation local activation of CNS-specific Th1 and Th2 cells induces expression of the Th1 and Th2 signature cytokines, IFN-γ and IL-4, which may maintain expression of trafficking molecules at the choroid plexus allowing for limited T cell trafficking into the ventricles [10,75]. The choroidal endothelium, fenestrated and thus permissive to large molecules, does not display a BBB phenotype.…”

Th1 Polarization of T Cells Injected into the Cerebrospinal Fluid Induces Brain Immunosurveillance

“…In contrast, because activated T cells in the current study were injected directly into the lateral ventricle, no further activation was required prior to crossing the epithelial layer or the vasculature's glia limitans into the brain parenchyma, and, as such, the injected cells induced neither significant vascular pathology nor cellular apoptosis, but instead, similar to previous studies demonstrating the positive effects of T cells and IFN-g on neurogenesis (24, 27, 50, 51), slightly enhanced hippocampal neurogenesis in an age-dependent manner. Given recent observations pointing to age-related Th2 shift in the circulation (52) and at the brain compartment (53), it is possible that brain immunosurveillance and neural repair are impaired with aging and further in age-related neurodegenerative diseases. The migration capacity of IFN-g-expressing T cells secreting a variety of beneficial T cell proteins (such as cytokines, chemokines, and neurotrophic factors) that cannot be delivered into the brain at sufficient concentrations thus urges for further studies examining their safe therapeutic potential within the aged CNS milieu.…”

Learning and memory … and the immune system

“…Immune deficiency in mice is often accompanied by cognitive impairment (Kipnis et al 2004Cohen et al 2006;Ziv et al 2006;Brynskikh et al 2008;Lewitus and Schwartz 2009;Derecki et al 2010;Bailey et al 2011;Gadani et al 2012;Nautiyal et al 2012;Baruch et al 2013;Radjavi et al 2013). As with neurogenesis, replenishment of the immune system by adoptive transfer of wild-type splenocytes or by bone marrow reconstitution also improves the learning ability of SCID and nude mice in MWM, Barnes maze and radial arm water maze (Brynskikh et al 2008;Ron-Harel et al 2008;Derecki et al 2010;Bailey et al 2011).…”

“…Schwartz and colleagues have also identified the choroid plexus as an important site of neuroimmune interactions (Baruch et al 2013;Shechter et al 2013b). Interestingly, the T cell repertoire in the choroid plexus seems to be enriched in CNS-reactive cells (Baruch and Schwartz 2013), leading to the idea that autoimmune cells are important in modulating the nervous system milieu to support homeostasis Shechter et al 2013a). This argument is also supported by the fact that transgenic mice with CNSantigen specific T cells also show enhanced cognition, in addition to neurogenesis in subgranular and subventricular zones ).…”