9. 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)(11)(12)(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...

Towards early diagnosis of Alzheimer’s disease: advances in immune-related blood biomarkers and computational approaches

“…Additionally, the proposed framework introduces a new category for biomarkers associated with inflammatory and immune processes, reflecting the reactivity of astrocytes and microglia. This adjustment addresses developments in recent years, highlighting the increasingly apparent cross-talk between the immune cells of the central nervous system and those in the periphery (19)(20)(21)(22)(23)(24). Moreover, there has been a notable increase in research findings related to AD and immune system-related genes over the last decades, with a significant portion falling into the biomarkers category (see Supplementary Figure 1).…”

“…2 Brain-immune system crosstalk in Alzheimer's disease Recent anatomical and functional discoveries of ways by which the immune system interacts with the brain have shaped the longheld dogma of the brain as an immune privileged organ. Instead of being considered as solely secluded behind the blood-brain-barrier from having any interaction with the peripheral immune system, it is becoming increasingly clear that the central nervous system (CNS) is in constant dialogue with immune cells, and that these interactions are taking place at unique anatomical barriers, such as the choroid plexus (22,25) and the meningeal spaces (26,27).…”