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      Peripherally induced brain tissue-resident memory CD8 + T cells mediate protection against CNS infection

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          Abstract

          The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (Trm) CD8 + T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain Trm cells. We show that peripheral infections generate antigen-specific CD8 + memory T cells in the brain that adopt a unique Trm signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain Trm cells revealed by intravital imaging. Importantly, peripherally induced brain Trm cells showed evidence of rapid activation, enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain Trm cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.

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          Most cited references58

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          Structural and functional features of central nervous system lymphatics

          One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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            Is Open Access

            A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

            Aspelund et al. discover the presence of a lymphatic vessel network in the dura mater of the mouse brain and show that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
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              Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease

              Further information on research design is available in the Nature Research Reporting Summary linked to this paper.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                14 May 2020
                22 June 2020
                August 2020
                22 December 2020
                : 21
                : 8
                : 938-949
                Affiliations
                [1 ]Department of Pathology, Carver College of Medicine, University of Iowa
                [2 ]Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa
                [3 ]Center for Discovery and Innovation, Hackensack University Medical Center, NJ 07110
                [4 ]VA New Jersey Health Care System, East Orange, NJ 07018
                [5 ]Department of Microbiology and Immunology, University of Iowa
                Author notes

                Author Contributions

                S.L.U. and J.T.H. designed experiments, S.L.U. conducted experiments, S.L.U. and I.J.J. analyzed data, I.J.J., Q.S., and L.L.P. provided technical assistance, V.P.B. and H.-H.X. provided essential reagents and intellectual input and S.L.U. and J.T.H. wrote manuscript.

                [* ]Corresponding author: John T. Harty, john-harty@ 123456uiowa.edu , Department of Pathology, 3-501 Bowen Science Building, 51 Newton Road, University of Iowa, Iowa City, IA 52242-1109 , Lab: 319-335-9919
                Article
                NIHMS1594399
                10.1038/s41590-020-0711-8
                7381383
                32572242
                58523382-3242-4db8-bbad-3ede9c483e6d

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                Immunology
                Immunology

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