Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain

Anandasabapathy, Niroshana; Victora, Gabriel D.; Meredith, Matthew M.; Feder, Rachel; Dong, Bo‐Qing; Kluger, Courtney; Yao, Kai-Hui; Dustin, Michael L.; Nussenzweig, Michel C.; Steinman, Ralph M.; Liu, Kang

doi:10.1084/jem.20102657

Cited by 194 publications

(197 citation statements)

References 57 publications

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“…Here, we found that the CP, under physiological conditions, retains a broad repertoire of CNS-specific CD4 + T-cell clones. These T cells, upon recognition and reactivation by their cognate antigens, potentially presented to them by the Flt3 + dendritic cells found in the CP (39), either enter the CSF or remain in the CP (40,41). Although TCR-seq of the CP allowed us to identify CNS-specific clonotypic enrichment both in young and aged mice, other parameters of age-related changes of the TCR repertoire should not be ruled out.…”

Section: Discussionmentioning

confidence: 99%

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

Baruch¹,

Ron-Harel

Gal

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

251

197

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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...

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Section: Discussionmentioning

confidence: 99%

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

Baruch¹,

Ron-Harel

Gal

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

251

197

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“…The split between the two pathways was defined by Liu and Nussenzweig (64): Monocytes remain dependent upon M-CSF, and the dendritic cells remain dependent on flt-3L. The dendritic cell progenitor moves into lymphoid and nonlymphoid organs (64), the latest example being Kang Liu's research with the meninges of the brain (68). Niroshana Anandasabapathy is leading a new clinical study with Celldex Therapeutics to pursue flt-3L in people.…”

Section: Wwwannualreviewsorg • Decisions On Dendritic Cellsmentioning

confidence: 99%

Decisions About Dendritic Cells: Past, Present, and Future

Steinman

2012

Annu. Rev. Immunol.

Self Cite

1,071

843

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A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.

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“…Dendritic cells constitute approximately 1% of immune cells within the choroid plexus and meninges (87,88), but unlike the putative dendritic cells of the brain parenchyma, choroid plexus and meningeal dendritic cells are distinct from microglia and closely resemble classical dendritic cells that require FMSlike receptor tyrosine kinase 3 ligand for development (88). The CSF also contains a trafficking population of mononuclear cells, comprising T cells (90%), B cells (5%), monocytes (5%), and dendritic cells (Ͻ1%) (89).…”

Section: Immunosurveillance Of the Cnsmentioning

confidence: 99%

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

et al. 2014

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SUMMARY The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

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Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain

Abstract: As shown by analyses of morphology, gene expression, antigen-presenting function, and Flt3 dependence, the steady-state mouse brain contains a population of DCs that exhibits similarities to splenic DCs and differences from microglia.

Cited by 194 publications

References 57 publications

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

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

Decisions About Dendritic Cells: Past, Present, and Future

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

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