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Meningeal Lymphatics: From to Central Immune Surveillance

This information is current as Zachary Papadopoulos, Jasmin Herz and Jonathan Kipnis of September 27, 2021. J Immunol 2020; 204:286-293; ; doi: 10.4049/jimmunol.1900838 http://www.jimmunol.org/content/204/2/286 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Meningeal Lymphatics: From Anatomy to Immune Surveillance Zachary Papadopoulos, Jasmin Herz, and Jonathan Kipnis At steady state, the CNS parenchyma has few to no from the CNS to the cervical nodes had been reported and less potent Ag-presentation capability using a variety of tracers in animal and cadaver studies, al- compared with other organs. However, the meninges though this was speculated on mainly as a fluid reabsorption surrounding the CNS host diverse populations of im- process rather than from an immunological perspective mune cells that influence how CNS-related immune (6–10). Studies would go on to show that Ag delivered to the responses develop. Interstitial and cerebrospinal fluid CNS could induce a robust humoral response via the cervi- produced in the CNS is continuously drained, and cal lymph nodes and the (11–13). Notably, the recent advances have emphasized that this process is CNS-lymphatic connection has recently been demonstrated in Downloaded from largely taking place through the . vivo in humans through contrast magnetic resonance imaging (14). Thus, the immune privilege of the CNS cannot be as To what extent this fluid process mobilizes CNS- simple as a lack of lymphatic immune surveillance nor isolation derived Ags toward meningeal immune cells and sub- from peripheral immune responses but rather depends on dy- sequently the peripheral through the namic physiological processes and cellular interactions. network is a question of significant A new challenge in understanding fluid drainage of the brain http://www.jimmunol.org/ clinical importance for autoimmunity, tumor immu- erupted in 2015, with the publication of studies describing nology, and infectious disease. Recent advances in un- an intracranial lymphatic network in mouse meninges that derstanding the role of meningeal lymphatics as a absorb tracer from the cerebrospinal fluid (15, 16). Analogous communicator between the brain and peripheral im- structures were found also in post mortem human meninges munity are discussed in this review. The Journal of (15) and were later visualized in vivo by means of magnetic Immunology, 2020, 204: 286–293. resonance imaging in humans and nonhuman primates (17). A large body of literature around fluid dynamics in the CNS

developed prior to these discoveries, and it is essential that we by guest on September 27, 2021 he CNS is often described as an immune-privileged acquire a detailed understanding of the mechanisms that with tolerance to normally rejected stimuli underlie exchange of fluids in the CNS. Furthermore, the T such as grafts. Over the last century the precise immunologic implications of direct intracranial lymph for- meaning of this term has evolved, diverging from its meaning mation, as discussed in this review, require extensive investi- in other tissues with unique immunological regulation, such as gation. After describing the dialogue established between cells the testis and eye (1–4). Immune privilege could be enacted of the nervous and immune systems, we summarize recent through lenient immune surveillance, through the modula- studies of the CNS–lymphatic network physiology and its tion of the immune response itself or a combination of the immunological implications as we understand them today. two. A foundational experiment by P. B. Medawar disclosed that whereas allografts in the brain were not rejected APC populations of the CNS initially, a subsequent peripheral allograft would induce The parenchyma of the brain is continuously surveyed by its priming and cause rejection of both grafts (5). This led to the only resident leukocyte, microglia. These cells form a highly long-held conclusion that whereas an immune response can specialized population of innate sentinels that is self-renewing be mounted effectively within the brain parenchyma, immune and not reliant on hematopoietic replacement (18, 19). Al- surveillance must be limited such that Ags can escape immune though microglia have been ascribed many homeostatic roles, detection. This model was in line with the consensus that their capacity as APC remains in question. They have been because the brain (unlike almost all other tissues) does not reported to express MHC class II in inflammatory conditions, contain lymphatic vessels, the immune system would not have such as , viral , and Alzheimer’s the access to CNS Ags that it would need to develop a re- disease (20–23), and thus could present Ag to adjacent sponse. However, the existence of a functional connection lymphocytes. There is still much to be learned about the way

Center for Brain Immunology and Glia, Graduate Program, Department Address correspondence and reprint requests to Dr. Jasmin Herz and Dr. Jonathan of Neuroscience, University of Virginia, Charlottesville, VA 22908 Kipnis, Center for Brain Immunology and Glia, Neuroscience Graduate Program, De- partment of Neuroscience, University of Virginia, 409 Lane Road, Charlottesville, VA ORCID: 0000-0002-3714-517X (J.K.). 22908. E-mail addresses: [email protected] (J.H.) and [email protected] (J.K.) Received for publication July 17, 2019. Accepted for publication November 15, 2019. Abbreviations used in this article: AQP4, aquaporin-4 water channel; DC, ; This work was supported by grants from the National Institutes of Health (AG034113, EAE, experimental autoimmune encephalomyelitis; ISF, interstitial fluid. AG057496, and NS096967) to J.K. Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900838 The Journal of Immunology 287 microglia might influence local immune responses, and more which occupies the ventricles and subarachnoid space, and the recent studies suggest that microglial MHC class II expression interstitial fluid (ISF), which perfuses the brain parenchyma. is dispensable for the induction of experimental autoim- There is net fluid production in both compartments (47–51) that mune encephalomyelitis (EAE) (24). Because microglia ultimately provides both a drainage pathway for waste products do not appear capable of migrating from the parenchyma and a site for sensing antigenic material within the brain and to the vascular system, their role in the induction of an meninges. Reuptake of ISF occurs through the cerebrospinal adaptive immune response would be constrained to local fluid presumably directly to the blood and through the lym- (re)activation of infiltrating lymphocytes (23) rather than phatic system. Although the relative contributions of each re- initial Ag processing. Although we can exclude microglia mains controversial, the role of lymphatic drainage is increasingly from being long-distance messengers from the CNS, studies appreciated in recent studies (52–54). Physiologically, this in the skin illustrate the importance of this cellular com- reuptake is necessary to balance fluid influx to the CNS from ponent of the immune response. It has been demonstrated the blood as cerebrospinal fluid and ISF. Immunologically, that skin-resident APCs (Langerhans cells) migrate from a however, lymphatic drainage of the CNS is a powerful mech- site of infection to the draining for the induction anism for remote immune surveillance of the CNS and leaves of a systemic immune response but are not directly respon- open questions. To what extent is Ag collected and delivered to sible for the presentation of foreign Ag to lymphocytes in the the immune system in the process of CNS fluid circulation? lymph node and instead are most likely transporting Ag to The brain is separated from the periphery by an intricate lymph node-resident APCs (25, 26). system of barriers that provide the context for its unique in- Downloaded from At present, the brain parenchyma seems to differ from other teractions with the immune system. Starting from the cranium, tissues as it is devoid of a professional resident APC during the three meningeal layers surrounding the brain are the dura steady state (27). However, following closer examination, mater, the arachnoid mater, and the pia mater. Whereas the significant populations of dendritic cells (DC) are present dura and arachnoid membranes are in contact with one an- among the immune cells found in the meninges and other other, the pia is separated from the arachnoid by the sub-

CNS barrier structures that interact with cerebrospinal fluid. arachnoid space. This space is filled with cerebrospinal fluid http://www.jimmunol.org/ Whereas conventional DC1s are mainly located in the cho- and is bridged by the arachnoid trabeculae, a dense network of roid plexus, layers of the meninges harbor predominantly connective filaments. Underneath the pia mater begins the conventional DC2s (28), including a subpopulation of mi- brain parenchyma with a layer of glial processes known as the glia gratory (CCR7-expressing) DCs. Nevertheless, numerous limitans.AdditionalCNSstructures that are important from a studies have reported that meningeal DCs survey the brain cerebrospinal fluid efflux perspective are cerebral ventricles. The parenchyma and promote or constrain CNS immunity. ventricles are cerebrospinal fluid–filled cavities that are connected This occurs through migration to the with each other and the subarachnoid space. They contain the

and reactivation of T cells following their infiltration into choroid plexus, a unique, well-vascularized organ with a distinct by guest on September 27, 2021 the CNS (29–35). Tissue-resident DCs normally serve as that secretes cerebrospinal fluid from the selective , but once activated, they process the Ag and carry filtration of blood plasma (47, 48, 50, 55). Once blood vessels it to lymph nodes where they function as potent APCs (36). cross the arachnoid matter into the brain, they maintain a Meningeal DCs are well positioned to access cerebrospinal stricter barrier function than elsewhere in the body, decreasing fluid–filled spaces and surveil material crossing the blood– water conductivity and passive permeability to most solutes cerebrospinal fluid or blood–brain barrier to ensure detection (56, 57) to restrict the access of molecules from circulation into of a variety of insults, including injury and infection (37–41). surrounding neural tissue and vice versa. For many solutes, the Although migratory DCs, monocytes, and resident DCs ro- existence of this barrier has shifted focus for removal to distal tate through most tissues, there is less evidence for the turn- sites such as the dural venous sinuses and lymphatic networks. over of this population in the CNS. They appear to be in part For some specific solutes, including amyloid b,however,higher a specialized self-renewing population, but their homeostatic exchange rates are achieved at the vasculature through active role is not fully understood (42–44). Interestingly, DCs transport (58–60), and a decreased rate of removal through all lacking migratory capacity (through depletion of CCR7) are routes is implicated in Alzheimer’s disease (61). retained in the CNS and worsen the outcome of EAE (45). In In addition, the cerebrovasculature allows minimal entry of addition, meningeal DCs may also serve as inducers of pe- peripheral immune cells to the brain parenchyma at steady ripheral tolerance by engaging regulatory or effector T cells state compared with other organs. The vascular endothelial locally (46). Fluid flow from the parenchyma to the menin- cells of the brain exhibit low expression of adhesion molecules, geal spaces and dural sinuses has the potential to make pa- including selectins, VCAM-1, and ICAM-1 at rest, but can renchymal Ag available for meningeal DCs and therefore upregulate adhesion molecules during inflammation (62, 63). interact with multiple layers of immune surveillance. Having At the resting state, this barrier enforces isolation of the specialized APCs scan the CNS microenvironment and ini- specialized brain-resident immune cell populations from cir- tiate or prevent an immune response in draining lymph nodes culating cell types (64). The specialization of CNS immune and the meninges may have evolved as a strategy to balance cells as well as apparent spatial separation of immune sur- the need for immune surveillance with the lower tolerance for veillance is likely related to the low tolerance of the brain for inflammation in the brain. inflammation and poor regenerative capacity.

Barriers and pathways for efflux from the nervous system Cerebrospinal fluid and ISF circulation Two distinct but communicating extracellular fluid com- The pia mater, which is the largest interface between ISF and partments are found within the CNS: the cerebrospinal fluid, cerebrospinal fluid, is not an absolute barrier, and permeability 288 BRIEF REVIEWS: MENINGES AS A NEUROIMMUNE INTERFACE to macromolecules is dependent on concentration gradient, Routes of fluid drainage from the CNS size, and solubility in cerebrospinal fluid but is not com- Afferent to the cervical lymph nodes, several lymphatic net- pletely characterized (65–67). Several groups have published works have been proposed to collect both cerebrospinal fluid compelling evidence that diffusion across this boundary alone and interstitial macromolecules. Although the CNS paren- does not fully account for the movement of interstitial chyma does not have a conventional lymphatic drainage sys- macromolecules from the parenchyma to the cerebrospinal tem, an extensive lymphatic network has been discovered in the fluid (53, 68–71). Rather, parenchymal solutes appear to dura mater along the transverse and superior sagittal sinuses move as a consequence of bulk flow, carried by the (15, 16). True to their acknowledged function, these vessels movement of the surrounding fluid. This is apparent from assist in the drainage of cerebrospinal fluid and facilitate the rates of tracer influx and efflux from the parenchyma T and DC movement. The vessels run alongside and the rapid distribution throughout perivascular spaces the venous sinuses and exit together with the jugular (52, 71–73). (16). Lymphatic vessels in the meninges are broadly similar to In traditional models of cerebrospinal fluid flow, the lym- initial lymphatic vessels described in other tissues with subtle phatic collection of cerebrospinal fluid is not sufficient to exceptions. As with other initial lymphatics, they are not constitute immune surveillance of the brain as freshly produced ensheathed by cells and lack lymphatic valves cerebrospinal fluid from the choroid plexus would not contain (15, 16, 74, 84). As noted previously, these vessels do not parenchymal Ag, such as myelin proteins. In this model, most penetrate the brain parenchyma, which subsequently brings us of the cerebrospinal fluid is produced at the choroid plexuses, to the question of how dural lymphatic vessels access paren- Downloaded from flows through the ventricular system, and exits into the sub- chymal macromolecules (Fig. 1). arachnoid space via the foramen of Magendie and the foramina The arachnoid mater features tight junctions and is con- of Luschka with relatively little crossing into the interstitium of sidered to demarcate the boundary between cerebrospinal the brain parenchyma (15, 70). However, small fluorescent fluid–filled spaces and dura and thus plays a major role in tracers introduced into the subarachnoid cerebrospinal fluid compartmentalizing the CNS (42, 85, 86). Injection of demonstrate more complex movements along perivascular fluorescent tracer into the cerebrospinal fluid reveals bilateral http://www.jimmunol.org/ spaces into the parenchyma (70) and are removed from the “hot spots” in the lateral portions of the vessels along the CNS through lymph or blood (15, 16, 54, 74). These studies transverse sinus that appear to be the first sites of cerebro- suggest an extensive exchange of cerebrospinal fluid and ISF spinal fluid uptake (74). These regions possess increased vessel solutes, which is consistent with studies showing that inter- density and complexity, including short loops and terminal stitial metabolites and Ags accumulate in the cerebrospinal sprouts. Importantly, photodynamic ablation targeting this fluid (75–77). The formation of brain ISF, whether through lymphatic vasculature was found to decrease drainage to the cerebrospinal fluid influx, vascular extravasation, or meta- deep cervical lymph nodes of fluorescently labeled OVA, bolism, is balanced by fluid efflux suggested to occur through polystyrene beads, and T cells (61, 74). Recently, another by guest on September 27, 2021 multiple routes, including return to cerebrospinal fluid before study reported that these regions of increased vascular com- being taken up as lymph or blood (52, 64, 65). Lymphatic plexity and apparent uptake capacity extend further ven- transport is essentially an advective process, and therefore, a trolaterally along the transverse sinus as it splits into the fluid source is needed to account for the observed drainage of sigmoid and petrosquamosal sinuses before exiting the cra- CNS tracers. Currently, we know very little about how APCs nium (87). Ags have been suggested to move from the cere- respond to the dynamics of this process to access and extract brospinal fluid compartment to CNS-draining lymph nodes information from the CNS to maintain equilibrium or in- through perineural routes as well (74, 88), but only ablation stigate inflammation. of dural lymphatic vessels, and not ablation of nasal networks, The mechanisms driving fluid dynamics in the brain resulted in a delay in onset and a decrease in the severity of are extremely complex and challenging to measure non- EAE (74). Furthermore, the impairment of meningeal lym- invasively. In mice, a genetic model of disrupted fluid phatic drainage impeded both the influx of cerebrospinal fluid dynamics is the deletion of the aquaporin-4 water channel tracer to the perivascular spaces and the brain parenchyma as (AQP4). AQP4 is abundantly expressed on astrocytes, in well as intraparenchymal tracer clearance (61). which it is polarized to the cellular endfeet that form the glia Within the cranium, vessels have also been found along the limitans (78–81). AQP4-deficient mice show a decreased middle meningeal , but in contrast to dural meningeal influx of cerebrospinal fluid tracers to the parenchyma and lymphatics, tracer studies do not support their role in the impaired clearance of intracortically injected tracer (70, uptake of molecules from the cerebrospinal fluid (74, 84). 82) as well as decreased drainage to the draining lymph These potential two networks of lymphatic vasculature were nodes (75). Apart from these fluid tracing experiments, it suggested to have different efferent routes at the base of the is particularly interesting that changes in mounting an , with the middle meningeal artery–associated vessels active immune response to a CNS-derived Ag occur when appearing to exit along the internal carotid (16). Given ISF movement is disrupted. Previous immunization stud- the lack of cerebrospinal fluid tracer uptake, it has been ies of AQP4-deficient mice have suggested decreased im- proposed that these vessels drain the dura (74), but the mune surveillance of the CNS, and the knockout mice complete network of collecting lymphatics and their con- present with delayed and less severe EAE (83). Although nections to lymph nodes in the are not fully understood the complete mechanisms underlying these changes are not (54, 87). yet clear, it appears that the dynamics of the brain ISF and Several other routes of cerebrospinal fluid efflux and col- cerebrospinal fluid modulate Ag availability from the brain lection from the CNS have been studied and been suggested to parenchyma. follow a perivascular or perineural exit route from the cranial The Journal of Immunology 289 Downloaded from http://www.jimmunol.org/ by guest on September 27, 2021

FIGURE 1. Routes of fluid and solute passage through the brain. Fluid continuously enters the CNS from blood either (a) directly to ISF at the cere- brovasculature or (b) as cerebrospinal fluid (CSF) via secretion at the choroid plexus. Fluid exits to lymph through (c) meningeal lymphatic vessels or (d) directly back to the blood at the dural venous sinuses. This movement mobilizes solutes, including CNS Ag as well as cytokines, toward the immune cell populations of the meninges. The cervical lymph nodes (e) can receive solutes either in lymph or in draining meningeal APCs for sampling and processing. Ultimately, these routes all reconvene in the blood, which is in turn subject to immune surveillance by the spleen and . cavity into a peripheral lymphatic network (54, 89–92). These territories of lymph nodes are not definitively mapped in pathways generally describe movement through a series of humans nor model species. Tracers introduced into spinal connected interstitia until they reach extracranial lymphatic cerebrospinal fluid drain through lymph nodes that differ networks. The exact transition from ISF to lymph, however, from those draining cranial cerebrospinal fluid tracers, and the is not well demarcated. The most recent studies have rapidly spine possesses additional lymphatic vasculature (74, 84, 102– expanded the known extent of intracranial and transcranial 104). Connectivity between the different sets of lymph nodes lymphatic vasculature, in part because of the identification has been described differently in different studies, and the of lymphatic markers and the development of reporter mice relative involvement of superficial and deep nodes as well as and rats (93–95). Given recent descriptions of meningeal the vascular connections between nodes remain controversial lymphatic vessels sharing many of the vascular and neural (54, 74). The consequences of different drainage patterns foramina, the possibility that lymphatic uptake occurs in- from the CNS require detailed studies. Experiments in the tracranially in locations other than the hot spots merits intestinal system have shown that the immune surveillance further scrutiny (74, 96–98). carried out by different lymph nodes produces differently orchestrated responses in their respective territories (105, Lymph node microenvironment and lymph composition 106). In cases of spontaneous EAE in mice, the deep cervical In mice, tracers from the CNS accumulate mainly in two sets of lymph nodes express activation markers prior to the superfi- lymph nodes: the superficial cervical lymph nodes, which are cial cervical lymph nodes (107). Even in immunization- generally thought to drain from the face and the oronasal induced EAE, in which adjuvant and Ag are processed in tissues, and the deep cervical lymph nodes, which show more the periphery, the main site of CNS autoimmune reaction specific accumulation of tracers introduced into the cerebro- appears to be the deep cervical lymph nodes (74). It is im- spinal fluid (15, 54, 74, 99–101). However, the drainage portant to note that other laboratory animals, and also 290 BRIEF REVIEWS: MENINGES AS A NEUROIMMUNE INTERFACE humans, have additional lymph nodes in the head and neck, During inflammation, however, changes in the expression of making the networks more complex. The past several de- chemoattractants and migration of APCs through the lym- cades have seen periods of immense interest in mapping phatic system affect the nature of the immune response. CCR7 the drainage territories of individual lymph nodes, al- upregulation on DCs increases mobility and initial lymphatic though recently, this research field has become smaller, CCL21–CCR7 interactions, encouraging DCs to enter the focusing on sentinel nodes for and dis- lymphatic vasculature. As discussed, this cellular transport of tribution of (99, 108). In species with more nodes, Ag can result in Ag transfer to node-resident APCs or direct drainage territories may be further subdivided, or more stimulation of lymphocytes. For free Ag, however, changes in nodes may occur along a given network if the area that the node during inflammation will have an impact as well. needstobesurveilledislarger. The structural characteristics of the node change, along with cellular activities to increase the retention and processing of Immune processing of brain-derived lymph Ag (119, 120), which suggests that some factors in specialized Although lymphatic drainage is needed for fluid and lipid CNS immunity may originate distally from the inflammatory homeostasis and removal of waste, the immunological func- state of the draining lymph nodes. Studying this further will, tions of this elaborate system are of interest in both homeostasis however, require definitive understanding of the drainage and in disease. Adaptive immune surveillance revolves largely territories of individual nodes and vascular networks. Simi- around the lymph nodes, which maintain a substantial subset larly, the stromal cells of the meninges have the ability to of the T and repertoire and facilitate cognate–Ag en- respond to the inflammatory state and shape the immune cell Downloaded from counters. Because the lymph node is distant from the tissue, dynamics of the CNS in ways that we are only beginning to contextual information must be transferred to the lymph node understand (121). Our understanding of the immune re- along with Ag. Evidence of tissue injury or innate immune sponse in other peripheral tissues has advanced rapidly in activation has to be relayed through the proper processing of recent years, but there are still many mechanistic details that Ag and immune cell trafficking via lymphatic vessels. Subse- need to be addressed in the CNS. quent migration to the draining cervical lymph nodes is en- http://www.jimmunol.org/ abled by CCR7 expression; however, the relocation route Conclusions leading to stimulation of B and T lymphocytes has not been Immune surveillance of the CNS differs from surveillance of ultimately defined. As discussed previously, continuous CNS other organs, and (contrary to historical viewpoints) lym- immune surveillance is vital for responses to self-, phatic collection of Ags from the CNS is an active part of its both tolerogenic and inflammatory (109–111). A selection homeostasis. In general, the priming of immune cells toward of additional mechanisms has been suggested for Ag sorting brain-derived Ags requires the ability of Ag to move from the and processing peripherally, and the interplay of different parenchyma to the cerebrospinal fluid–filled space and mechanisms remains incompletely understood with even less across the arachnoid mater. Limited access through specific by guest on September 27, 2021 known in the CNS specifically. lymphatic protrusions (hot spots) and the existence of a In the healthy CNS, as in other tissues, a substantial fraction sophisticated barrier system can regulate peripheral immune of Ag drains in the fluid itself rather than carried by APCs. This traffic to and from the CNS differently than in other tissues. balance is maintained through a low expression of CCR7 by Nonetheless, memory responses to Ags derived from the APCs, low CCL19/21 by the initial lymphatic brain are comparable to those in peripheral tissues. Un- vessels, and the absence of high levels of cytokine signaling. derstanding what contributestotheseuniqueimmunere- When an Ag arrives in the lymph node without a cellular sponses and how these mechanisms predispose the brain to chaperone, it is still processed and rarely reaches the blood autoimmune attacks or protect it may uncover new insights unimpeded. In the absence of inflammation, this Ag may be into multiple sclerosis and many other neuroinflammatory used to maintain self-tolerance (112–115). The use of brain- conditions. derived Ags for negative selection in the lymph node provides an interesting alternative to negative selection in the , Acknowledgments where the promiscuous gene expression creating a library of We thank S. Smith for editing the manuscript. We thank all the members of the peripheral epitopes seems to fall short of depleting myelin- Kipnis laboratory for valuable comments during discussions of the manuscript. reactive T cells (116). Although the endogenous proteome of brain-derived lymph is not well characterized yet, proteins are Disclosures expected to follow similar patterns to the tracers, which have J.K. is an adviser to PureTech Health. The other authors have no financial clearly demonstrated that solutes from the CNS, in healthy conflicts of interest. animals and in disease contexts, reaches professional APCs and the cervical lymph nodes. Recent studies generally in- References troduce a fluorescent tracer to the cerebrospinal fluid via in- 1. Zhao, S., W. Zhu, S. Xue, and D. Han. 2014. Testicular defense systems: immune jection into the cisterna magna or lateral ventricles and have privilege and innate immunity. Cell. Mol. Immunol. 11: 428–437. shown drainage to cervical lymphatics as well as active cere- 2. Tung, K. S. K., J. Harakal, H. Qiao, C. Rival, J. C. H. Li, A. G. A. Paul, K. Wheeler, P. Pramoonjago, C. M. Grafer, W. Sun, et al. 2017. Egress of sperm brospinal fluid–ISF exchange (15, 17, 61, 70, 74, 117). autoantigen from seminiferous tubules maintains systemic tolerance. J. Clin. Invest. Furthermore, because autoreactive T cells are present in au- 127: 1046–1060. 3. Streilein, J. W. 2003. Ocular immune privilege: therapeutic opportunities from an toimmunity as well as healthy subjects (118), the specific experiment of nature. Nat. Rev. Immunol. 3: 879–889. processing of Ag and mobilization to draining lymph nodes 4. Aspelund, A., T. Tammela, S. Antila, H. Nurmi, V.-M. Leppa¨nen, G. Zarkada, L. Stanczuk, M. Francois, T. Ma¨kinen, P. Saharinen, et al. 2014. The Schlemm’s via lymphatic vessels appears to be crucial to the suppression canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J. Clin. Invest. 124: of CNS autoimmunity. 3975–3986. The Journal of Immunology 291

5. Medawar, P. B. 1948. Immunity to homologous grafted skin; the fate of skin reveals distinct populations of brain myeloid cells in mouse neuroinflammation homografts transplanted to the brain, to , and to the anterior and models. Nat. Neurosci. 21: 541–551. chamber of the eye. Br. J. Exp. Pathol. 29: 58–69. 33. McMenamin, P. G., R. J. Wealthall, M. Deverall, S. J. Cooper, and B. Griffin. 6. Hill, L. 1896. The Physiology and of the Cerebral Circulation: An 2003. and dendritic cells in the rat meninges and choroid plexus: Experimental Research. J. & A. Churchill, London. three-dimensional localisation by environmental scanning electron microscopy and 7. 1913. The late professor Edwin Goldmann’s investigations on the central nervous confocal microscopy. Cell Tissue Res. 313: 259–269. system by vital staining. Br. Med. J. 2: 871–873. 34. Dando, S. J., R. Kazanis, H. R. Chinnery, and P. G. McMenamin. 2019. Regional 8. Weed, L. H. 1914. Studies on cerebro-spinal fluid. No. III: the pathways of escape and functional heterogeneity of presenting cells in the mouse brain and from the subarachnoid spaces with particular reference to the arachnoid villi. J. meninges. Glia 67: 935–949. Med. Res. 31: 51–91. 35. O’Brien, C. A., C. Overall, C. Konradt, A. C. O’Hara Hall, N. W. Hayes, 9. Weed, L. H. 1922. The cerebrospinal fluid. Physiol. Rev. 2: 171–203. S. Wagage, B. John, D. A. Christian, C. A. Hunter, and T. H. Harris. 2017. 10. Brierley, J. B., and E. J. Field. 1948. The connexions of the spinal sub-arachnoid CD11c-expressing cells affect regulatory behavior in the meninges during space with the lymphatic system. J. Anat. 82: 153–166. central nervous system infection. J. Immunol. 198: 4054–4061. 11. Harling-Berg, C., P. M. Knopf, J. Merriam, and H. F. Cserr. 1989. Role of 36. Karman, J., C. Ling, M. Sandor, and Z. Fabry. 2004. Initiation of immune re- cervical lymph nodes in the systemic humoral immune response to human serum sponses in brain is promoted by local dendritic cells. J. Immunol. 173: 2353–2361. albumin microinfused into rat cerebrospinal fluid. J. Neuroimmunol. 25: 185–193. 37. Fischer, H. G., U. Bonifas, and G. Reichmann. 2000. Phenotype and functions of 12. Cserr, H. F., C. J. Harling-Berg, and P. M. Knopf. 1992. Drainage of brain ex- brain dendritic cells emerging during chronic infection of mice with Toxoplasma tracellular fluid into blood and deep cervical lymph and its immunological gondii. J. Immunol. 164: 4826–4834. significance. Brain Pathol. 2: 269–276. 38. Fischer, H. G., and G. Reichmann. 2001. Brain dendritic cells and macrophages/ 13. Knopf, P. M., H. F. Cserr, S. C. Nolan, T. Y. Wu, and C. J. Harling-Berg. 1995. microglia in central nervous system inflammation. J. Immunol. 166: 2717–2726. Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal 39. Kostulas, N., H.-L. Li, B.-G. Xiao, Y.-M. Huang, V. Kostulas, and H. Link. 2002. fluid from the brain. Neuropathol. Appl. Neurobiol. 21: 175–180. Dendritic cells are present in ischemic brain after permanent middle cerebral artery 14. Eide, P. K., S. A. S. Vatnehol, K. E. Emblem, and G. Ringstad. 2018. Magnetic occlusion in the rat. Stroke 33: 1129–1134. resonance imaging provides evidence of glymphatic drainage from to 40. Walsh, J. T., J. Zheng, I. Smirnov, U. Lorenz, K. Tung, and J. Kipnis. 2014. cervical lymph nodes. Sci. Rep. 8: 7194. Regulatory T cells in central nervous system injury: a double-edged sword. J. 15. Louveau, A., I. Smirnov, T. J. Keyes, J. D. Eccles, S. J. Rouhani, J. D. Peske, Immunol. 193: 5013–5022. Downloaded from N. C. Derecki, D. Castle, J. W. Mandell, K. S. Lee, et al. 2015. Structural and 41. Walsh, J. T., S. Hendrix, F. Boato, I. Smirnov, J. Zheng, J. R. Lukens, S. Gadani, functional features of central nervous system lymphatic vessels. [Published erratum D. Hechler, G. Go¨lz, K. Rosenberger, et al. 2015. MHCII-independent CD4+ appears in 2016 Nature 533: 278.] Nature 523: 337–341. T cells protect injured CNS neurons via IL-4. J. Clin. Invest. 125: 699–714. 16. Aspelund, A., S. Antila, S. T. Proulx, T. V. Karlsen, S. Karaman, M. Detmar, 42. Rua, R., and D. B. McGavern. 2018. Advances in meningeal immunity. Trends H. Wiig, and K. Alitalo. 2015. A dural lymphatic vascular system that drains brain Mol. Med. 24: 542–559. interstitial fluid and macromolecules. J. Exp. Med. 212: 991–999. 43. Rua, R., J. Y. Lee, A. B. Silva, I. S. Swafford, D. Maric, K. R. Johnson, and 17. Absinta, M., S.-K. Ha, G. Nair, P. Sati, N. J. Luciano, M. Palisoc, A. Louveau, D. B. McGavern. 2019. Infection drives meningeal engraftment by inflammatory

K. A. Zaghloul, S. Pittaluga, J. Kipnis, and D. S. Reich. 2017. Human and monocytes that impairs CNS immunity. Nat. Immunol. 20: 407–419. http://www.jimmunol.org/ nonhuman primate meninges harbor lymphatic vessels that can be visualized 44. Herz, J., A. J. Filiano, A. Smith, N. Yogev, and J. Kipnis. 2017. Myeloid cells in noninvasively by MRI. Elife 6: e29738. the central nervous system. Immunity 46: 943–956. 18. Ginhoux, F., M. Greter, M. Leboeuf, S. Nandi, P. See, S. Gokhan, M. F. Mehler, 45. Clarkson, B. D., A. Walker, M. G. Harris, A. Rayasam, M. Hsu, M. Sandor, and S. J. Conway, L. G. Ng, E. R. Stanley, et al. 2010. Fate mapping analysis reveals Z. Fabry. 2017. CCR7 deficient inflammatory dendritic cells are retained in the that adult microglia derive from primitive macrophages. Science 330: 841–845. central nervous system. Sci. Rep. 7: 42856. 19. Huang, Y., Z. Xu, S. Xiong, F. Sun, G. Qin, G. Hu, J. Wang, L. Zhao, Y.- 46. Sage, P. T., F. A. Schildberg, R. A. Sobel, V. K. Kuchroo, G. J. Freeman, and X. Liang, T. Wu, et al. 2018. Repopulated microglia are solely derived from the A. H. Sharpe. 2018. Dendritic cell PD-L1 limits autoimmunity and follicular proliferation of residual microglia after acute depletion. Nat. Neurosci. 21: 530– T cell differentiation and function. J. Immunol. 200: 2592–2602. 540. 47. Hladky, S. B., and M. A. Barrand. 2014. Mechanisms of fluid movement into, 20. Hayes, G. M., M. N. Woodroofe, and M. L. Cuzner. 1987. Microglia are the through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11: major cell type expressing MHC class II in human white matter. J. Neurol. Sci. 80: 26.

25–37. 48. Hladky, S. B., and M. A. Barrand. 2016. Fluid and ion transfer across the blood- by guest on September 27, 2021 21. McGeer, P. L., S. Itagaki, and E. G. McGeer. 1988. Expression of the histo- brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms compatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. 76: and roles. Fluids Barriers CNS 13: 19. 550–557. 49. Pollay, M. 2010. The function and structure of the cerebrospinal fluid outflow 22. Perlmutter, L. S., S. A. Scott, E. Barro´n, and H. C. Chui. 1992. MHC class II- system. Cerebrospinal Fluid Res. 7: 9. positive microglia in human brain: association with Alzheimer lesions. J. Neurosci. 50. Brinker, T., E. Stopa, J. Morrison, and P. Klinge. 2014. A new look at cerebro- Res. 33: 549–558. spinal fluid circulation. Fluids Barriers CNS 11: 10. 23. Herz, J., K. R. Johnson, and D. B. McGavern. 2015. Therapeutic antiviral T cells 51. Johanson, C. E., J. A. Duncan, III, P. M. Klinge, T. Brinker, E. G. Stopa, and noncytopathically clear persistently infected microglia after conversion into G. D. Silverberg. 2008. Multiplicity of cerebrospinal fluid functions: new chal- antigen-presenting cells. J. Exp. Med. 212: 1153–1169. lenges in health and disease. Cerebrospinal Fluid Res. 5: 10. 24. Wolf, Y., A. Shemer, L. Levy-Efrati, M. Gross, J.-S. Kim, A. Engel, E. David, 52. Hladky, S. B., and M. A. Barrand. 2018. Elimination of substances from the brain L. Chappell-Maor, J. Grozovski, R. Rotkopf, et al. 2018. Microglial MHC class II parenchyma: efflux via perivascular pathways and via the blood-brain barrier. is dispensable for experimental autoimmune encephalomyelitis and cuprizone- Fluids Barriers CNS 15: 30. induced demyelination. Eur. J. Immunol. 48: 1308–1318. 53. Cserr, H. F., D. N. Cooper, P. K. Suri, and C. S. Patlak. 1981. Efflux of radio- 25. Allan, R. S., C. M. Smith, G. T. Belz, A. L. van Lint, L. M. Wakim, W. R. Heath, labeled polyethylene glycols and albumin from rat brain. Am. J. Physiol. 240: and F. R. Carbone. 2003. Epidermal viral immunity induced by CD8alpha+ F319–F328. dendritic cells but not by Langerhans cells. Science 301: 1925–1928. 54. Ma, Q., B. V. Ineichen, M. Detmar, and S. T. Proulx. 2017. Outflow of cere- 26. Allan, R. S., J. Waithman, S. Bedoui, C. M. Jones, J. A. Villadangos, Y. Zhan, brospinal fluid is predominantly through lymphatic vessels and is reduced in aged A. M. Lew, K. Shortman, W. R. Heath, and F. R. Carbone. 2006. Migratory mice. Nat. Commun. 8: 1434. dendritic cells transfer antigen to a lymph node-resident dendritic cell population 55. Steffensen, A. B., E. K. Oernbo, A. Stoica, N. J. Gerkau, D. Barbuskaite, for efficient CTL priming. Immunity 25: 153–162. K. Tritsaris, C. R. Rose, and N. MacAulay. 2018. Cotransporter-mediated water 27. Hart, D. N., and J. W. Fabre. 1981. Demonstration and characterization of Ia- transport underlying cerebrospinal fluid formation. Nat. Commun. 9: 2167. positive dendritic cells in the interstitial connective tissues of rat and other 56. Dolman, D., S. Drndarski, N. J. Abbott, and M. Rattray. 2005. Induction of tissues, but not brain. J. Exp. Med. 154: 347–361. aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel 28. Van Hove, H., L. Martens, I. Scheyltjens, K. De Vlaminck, A. R. Pombo Antunes, endothelial cells in culture. J. Neurochem. 93: 825–833. S. De Prijck, N. Vandamme, S. De Schepper, G. Van Isterdael, C. L. Scott, et al. 57. Oshio, K., H. Watanabe, Y. Song, A. S. Verkman, and G. T. Manley. 2005. 2019. A single-cell atlas of mouse brain macrophages reveals unique transcriptional Reduced cerebrospinal fluid production and intracranial pressure in mice lacking identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22: 1021– choroid plexus water channel Aquaporin-1. FASEB J. 19: 76–78. 1035. 58. Shibata, M., S. Yamada, S. R. Kumar, M. Calero, J. Bading, B. Frangione, 29. Anandasabapathy, N., G. D. Victora, M. Meredith, R. Feder, B. Dong, C. Kluger, D. M. Holtzman, C. A. Miller, D. K. Strickland, J. Ghiso, and B. V. Zlokovic. K. Yao, M. L. Dustin, M. C. Nussenzweig, R. M. Steinman, and K. Liu. 2011. 2000. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL Flt3L controls the development of radiosensitive dendritic cells in the meninges receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest. 106: 1489– and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208: 1695–1705. 1499. 30. Mundt, S., D. Mrdjen, S. G. Utz, M. Greter, B. Schreiner, and B. Becher. 2019. 59. Deane, R., Z. Wu, A. Sagare, J. Davis, S. Du Yan, K. Hamm, F. Xu, M. Parisi, Conventional DCs sample and present myelin antigens in the healthy CNS and B. LaRue, H. W. Hu, et al. 2004. LRP/amyloid beta-peptide interaction mediates allow parenchymal T cell entry to initiate neuroinflammation. Sci. Immunol. 4: differential brain efflux of Abeta isoforms. Neuron 43: 333–344. eaau8380. 60. Storck, S. E., A. M. S. Hartz, J. Bernard, A. Wolf, A. Kachlmeier, A. Mahringer, 31. Greter, M., F. L. Heppner, M. P. Lemos, B. M. Odermatt, N. Goebels, T. Laufer, S. Weggen, J. Pahnke, and C. U. Pietrzik. 2018. The concerted amyloid-beta R. J. Noelle, and B. Becher. 2005. Dendritic cells permit immune invasion of the clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by CNS in an animal model of multiple sclerosis. Nat. Med. 11: 328–334. PICALM. Brain Behav. Immun. 73: 21–33. 32. Ajami, B., N. Samusik, P. Wieghofer, P. P. Ho, A. Crotti, Z. Bjornson, M. Prinz, 61. Da Mesquita, S., A. Louveau, A. Vaccari, I. Smirnov, R. C. Cornelison, W. J. Fantl, G. P. Nolan, and L. Steinman. 2018. Single-cell mass cytometry K. M. Kingsmore, C. Contarino, S. Onengut-Gumuscu, E. Farber, D. Raper, et al. 292 BRIEF REVIEWS: MENINGES AS A NEUROIMMUNE INTERFACE

2018. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s dis- 88. Walter, B. A., V. A. Valera, S. Takahashi, and T. Ushiki. 2006. The olfactory route ease. [Published erratum appears in 2018 Nature 564: E7.] Nature 560: 185–191. for cerebrospinal fluid drainage into the peripheral lymphatic system. Neuropathol. 62. Coisne, C., L. Dehouck, C. Faveeuw, Y. Delplace, F. Miller, C. Landry, Appl. Neurobiol. 32: 388–396. C. Morissette, L. Fenart, R. Cecchelli, P. Tremblay, and B. Dehouck. 2005. 89. Szentistva´nyi, I., C. S. Patlak, R. A. Ellis, and H. F. Cserr. 1984. Drainage of Mouse syngenic in vitro blood-brain barrier model: a new tool to examine in- interstitial fluid from different regions of rat brain. Am. J. Physiol. 246: F835– flammatory events in cerebral . Lab. Invest. 85: 734–746. F844. 63. Coisne, C., C. Faveeuw, Y. Delplace, L. Dehouck, F. Miller, R. Cecchelli, and 90. Goldmann, J., E. Kwidzinski, C. Brandt, J. Mahlo, D. Richter, and I. Bechmann. B. Dehouck. 2006. Differential expression of selectins by mouse brain 2006. T cells traffic from brain to cervical lymph nodes via the cribroid plate and endothelial cells in vitro in response to distinct inflammatory stimuli. Neurosci. the nasal mucosa. J. Leukoc. Biol. 80: 797–801. Lett. 392: 216–220. 91. Carare, R. O., M. Bernardes-Silva, T. A. Newman, A. M. Page, J. A. R. Nicoll, 64. Mastorakos, P., and D. McGavern. 2019. The anatomy and immunology of V. H. Perry, and R. O. Weller. 2008. Solutes, but not cells, drain from the brain vasculature in the central nervous system. Sci. Immunol. 4: eaav0492. parenchyma along basement membranes of and : significance for 65. Weller, R. O., M. M. Sharp, M. Christodoulides, R. O. Carare, and K. Møllga˚rd. cerebral amyloid angiopathy and . Neuropathol. Appl. Neurobiol. 2018. The meninges as barriers and facilitators for the movement of fluid, cells and 34: 131–144. related to the rodent and human CNS. Acta Neuropathol. 135: 363– 92. Clapham, R., E. O’Sullivan, R. O. Weller, and R. O. Carare. 2010. Cervical 385. lymph nodes are found in direct relationship with the internal carotid artery: 66. Hutchings, M., and R. O. Weller. 1986. Anatomical relationships of the pia mater significance for the lymphatic drainage of the brain. Clin. Anat. 23: 43–47. to cerebral blood vessels in man. J. Neurosurg. 65: 316–325. 93. Bianchi, R., A. Teijeira, S. T. Proulx, A. J. Christiansen, C. D. Seidel, T. Rulicke,€ 67. Abbott, N. J., M. E. Pizzo, J. E. Preston, D. Janigro, and R. G. Thorne. 2018. The T. Ma¨kinen, R. Ha¨gerling, C. Halin, and M. Detmar. 2015. A transgenic Prox1- role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Cre-tdTomato reporter mouse for lymphatic vessel research. PLoS One 10: Acta Neuropathol. 135: 387–407. e0122976. 68. Abbott, N. J. 2004. Evidence for bulk flow of brain interstitial fluid: significance 94. Wilting, J., M. Papoutsi, B. Christ, K. H. Nicolaides, C. S. von Kaisenberg, for physiology and pathology. Neurochem. Int. 45: 545–552. J. Borges, G. B. Stark, K. Alitalo, S. I. Tomarev, C. Niemeyer, and J. Ro¨ssler. 69. Cserr, H. F., D. N. Cooper, and T. H. Milhorat. 1977. Flow of cerebral interstitial 2002. The transcription factor Prox1 is a marker for lymphatic endothelial cells in fluid as indicated by the removal of extracellular markers from rat caudate nucleus. normal and diseased human tissues. FASEB J. 16: 1271–1273. Exp. Eye Res. 25(Suppl.): 461–473. 95. Jung, E., D. Gardner, D. Choi, E. Park, Y. Jin Seong, S. Yang, J. Castorena- Downloaded from 70.Iliff,J.J.,M.Wang,Y.Liao,B.A.Plogg,W.Peng,G.A.Gundersen, Gonzalez, A. Louveau, Z. Zhou, G. K. Lee, et al. 2017. Development and char- H. Benveniste, G. E. Vates, R. Deane, S. A. Goldman, et al. 2012. A par- acterization of a novel Prox1-EGFP lymphatic and schlemm’s canal reporter rat. avascular pathway facilitates CSF flow through the brain parenchyma and the Sci. Rep. 7: 5577. clearance of interstitial solutes, including amyloid b. Sci. Transl. Med. 4: 96. Hsu, M., A. Rayasam, J. A. Kijak, Y. H. Choi, J. S. Harding, S. A. Marcus, 147ra111. W. J. Karpus, M. Sandor, and Z. Fabry. 2019. Neuroinflammation-induced 71. Ray, L., J. J. Iliff, and J. J. Heys. 2019. Analysis of convective and diffusive near the cribriform plate contributes to drainage of CNS- transport in the brain interstitium. Fluids Barriers CNS 16: 6. derived antigens and immune cells. Nat. Commun. 10: 229.

72. Bedussi, B., M. Almasian, J. de Vos, E. VanBavel, and E. N. Bakker. 2018. 97. Cai, R., C. Pan, A. Ghasemigharagoz, M. I. Todorov, B. Fo¨rstera, S. Zhao, http://www.jimmunol.org/ Paravascular spaces at the brain surface: low resistance pathways for cerebrospinal H. S. Bhatia, A. Parra-Damas, L. Mrowka, D. Theodorou, et al. 2019. Panoptic fluid flow. [Published erratum appears in 2018 J. Cereb. Blood Flow Metab. 38: imaging of transparent mice reveals whole-body neuronal projections and skull- 746.] J. Cereb. Blood Flow Metab. 38: 719–726. meninges connections. Nat. Neurosci. 22: 317–327. 73. Rennels, M. L., T. F. Gregory, O. R. Blaumanis, K. Fujimoto, and P. A. Grady. 98. Herisson, F., V. Frodermann, G. Courties, D. Rohde, Y. Sun, K. Vandoorne, 1985. Evidence for a ‘paravascular’ fluid circulation in the mammalian central G. R. Wojtkiewicz, G. S. Masson, C. Vinegoni, J. Kim, et al. 2018. Direct vascular nervous system, provided by the rapid distribution of tracer protein throughout the channels connect skull marrow and the brain surface enabling myeloid cell brain from the subarachnoid space. Brain Res. 326: 47–63. migration. Nat. Neurosci. 21: 1209–1217. 74. Louveau, A., J. Herz, M. N. Alme, A. F. Salvador, M. Q. Dong, K. E. Viar, 99. Kawashima, Y., M. Sugimura, Y.-C. Hwang, and N. Kudo. 1964. The lymph S. G. Herod, J. Knopp, J. C. Setliff, A. L. Lupi, et al. 2018. CNS lymphatic system in mice. Jpn. J. Vet. Res. 12: 69–78. drainage and neuroinflammation are regulated by meningeal lymphatic vascula- 100. Van den Broeck, W., A. Derore, and P. Simoens. 2006. Anatomy and nomen- ture. Nat. Neurosci. 21: 1380–1391. clature of murine lymph nodes: descriptive study and nomenclatory standardiza-

75. Plog, B. A., M. L. Dashnaw, E. Hitomi, W. Peng, Y. Liao, N. Lou, R. Deane, and tion in BALB/cAnNCrl mice. J. Immunol. Methods 312: 12–19. by guest on September 27, 2021 M. Nedergaard. 2015. Biomarkers of traumatic injury are transported from brain 101. Lohrberg, M., and J. Wilting. 2016. The lymphatic vascular system of the mouse to blood via the glymphatic system. J. Neurosci. 35: 518–526. head. Cell Tissue Res. 366: 667–677. 76.Lundgaard,I.,M.L.Lu,E.Yang,W.Peng,H.Mestre,E.Hitomi,R.Deane, 102. Kwon, S., C. F. Janssen, F. C. Velasquez, and E. M. Sevick-Muraca. 2017. and M. Nedergaard. 2017. Glymphatic clearance controls state-dependent Fluorescence imaging of lymphatic outflow of cerebrospinal fluid in mice. J. changes in brain lactate concentration. J. Cereb. Blood Flow Metab. 37: Immunol. Methods 449: 37–43. 2112–2124. 103. Jacob, L., L. Boisserand, J. Pestel, S. Antila, J.-M. Thomas, M.-S. Aigrot, 77. Holth, J. K., S. K. Fritschi, C. Wang, N. P. Pedersen, J. R. Cirrito, T. E. Mahan, T. Mathivet, S. Lee, K. Alitalo, N. Renier, et al. 2019. Anatomy of the vertebral M. B. Finn, M. Manis, J. C. Geerling, P. M. Fuller, et al. 2019. The sleep-wake column lymphatic network in mice. Nat. Commun. 10: 4594. cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 104. Ma, Q., Y. Decker, A. Muller,€ B. V. Ineichen, and S. T. Proulx. 2019. Clearance 363: 880–884. of cerebrospinal fluid from the sacral spine through lymphatic vessels. J. Exp. Med. 78. Rash, J. E., T. Yasumura, C. S. Hudson, P. Agre, and S. Nielsen. 1998. Direct 216: 2492–2502. immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependy- 105. Esterha´zy, D., M. C. C. Canesso, L. Mesin, P. A. Muller, T. B. R. de Castro, mocyte plasma membranes in rat brain and . Proc. Natl. Acad. Sci. USA A. Lockhart, M. ElJalby, A. M. C. Faria, and D. Mucida. 2019. Compartmen- 95: 11981–11986. talized gut lymph node drainage dictates adaptive immune responses. Nature 569: 79. Verkman, A. S. 2002. Physiological importance of aquaporin water channels. Ann. 126–130. Med. 34: 192–200. 106. Houston, S. A., V. Cerovic, C. Thomson, J. Brewer, A. M. Mowat, and 80. Nicchia, G. P., M. Srinivas, W. Li, C. F. Brosnan, A. Frigeri, and D. C. Spray. S. Milling. 2016. The lymph nodes draining the and colon are 2005. New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and anatomically separate and immunologically distinct. Mucosal Immunol. 9: functional relationship with connexin43. FASEB J. 19: 1674–1676. 468–478. 81. Mathiisen, T. M., K. P. Lehre, N. C. Danbolt, and O. P. Ottersen. 2010. The 107. Furtado, G. C., M. C. G. Marcondes, J.-A. Latkowski, J. Tsai, A. Wensky, and perivascular astroglial sheath provides a complete covering of the brain micro- J. J. Lafaille. 2008. Swift entry of myelin-specific T lymphocytes into the central vessels: an electron microscopic 3D reconstruction. Glia 58: 1094–1103. nervous system in spontaneous autoimmune encephalomyelitis. J. Immunol. 181: 82. Mestre, H., L. M. Hablitz, A. L. Xavier, W. Feng, W. Zou, T. Pu, H. Monai, 4648–4655. G. Murlidharan, R. M. Castellanos Rivera, M. J. Simon, et al. 2018. Aquaporin-4- 108. Suami, H., and M. F. Scaglioni. 2017. Lymphatic territories (lymphosomes) in the dependent glymphatic solute transport in the rodent brain. Elife 7: e40070. rat: an anatomical study for future lymphatic research. Plast. Reconstr. Surg. 140: 83. Li, L., H. Zhang, and A. S. Verkman. 2009. Greatly attenuated experimental 945–951. autoimmune encephalomyelitis in aquaporin-4 knockout mice. BMC Neurosci. 10: 109. Zozulya, A. L., S. Ortler, J. Lee, C. Weidenfeller, M. Sandor, H. Wiendl, 94. and Z. Fabry. 2009. Intracerebral dendritic cells critically modulate en- 84. Antila, S., S. Karaman, H. Nurmi, M. Airavaara, M. H. Voutilainen, T. Mathivet, cephalitogenic versus regulatory immune responses in the CNS. J. Neurosci. D. Chilov, Z. Li, T. Koppinen, J.-H. Park, et al. 2017. Development and plasticity 29: 140–152. of meningeal lymphatic vessels. J. Exp. Med. 214: 3645–3667. 110. Yogev, N., F. Frommer, D. Lukas, K. Kautz-Neu, K. Karram, D. Ielo, E. von 85. Yasuda, K., C. Cline, P. Vogel, M. Onciu, S. Fatima, B. P. Sorrentino, Stebut, H.-C. Probst, M. van den Broek, D. Riethmacher, et al. 2012. Dendritic R. K. Thirumaran, S. Ekins, Y. Urade, K. Fujimori, and E. G. Schuetz. 2013. cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 Drug transporters on arachnoid barrier cells contribute to the blood-cerebrospinal receptor(+) regulatory T cells. Immunity 37: 264–275. fluid barrier. Drug Metab. Dispos. 41: 923–931. 111. Giles, D. A., P. C. Duncker, N. M. Wilkinson, J. M. Washnock-Schmid, and 86. Balin, B. J., R. D. Broadwell, M. Salcman, and M. el-Kalliny. 1986. Avenues for B. M. Segal. 2018. CNS-resident classical DCs play a critical role in CNS auto- entry of peripherally administered protein to the central nervous system in mouse, immune disease. J. Clin. Invest. 128: 5322–5334. rat, and squirrel monkey. J. Comp. Neurol. 251: 260–280. 112. Hirosue, S., and J. Dubrot. 2015. Modes of by lymph node 87. Ahn, J. H., H. Cho, J.-H. Kim, S. H. Kim, J.-S. Ham, I. Park, S. H. Suh, stromal cells and their immunological implications. Front. Immunol. 6: 446. S. P. Hong, J.-H. Song, Y.-K. Hong, et al. 2019. Meningeal lymphatic vessels at 113. Fletcher, A. L., S. E. Acton, and K. Knoblich. 2015. Lymph node fibroblastic the skull base drain cerebrospinal fluid. Nature 572: 62–66. reticular cells in health and disease. Nat. Rev. Immunol. 15: 350–361. The Journal of Immunology 293

114. Santambrogio, L., S. J. Berendam, and V. H. Engelhard. 2019. The antigen pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. processing and presentation machinery in lymphatic endothelial cells. Front. Transl. Med. 11: 107. Immunol. 10: 1033. 118. Danke, N. A., D. M. Koelle, C. Yee, S. Beheray, and W. W. Kwok. 2004. Au- 115. Alonso, R., H. Flament, S. Lemoine, C. Sedlik, E. Bottasso, I. Pe´guillet, toreactive T cells in healthy individuals. J. Immunol. 172: 5967–5972. V. Pre´mel, J. Denizeau, M. Salou, A. Darbois, et al. 2018. Induction of anergic or 119. Roozendaal, R., R. E. Mebius, and G. Kraal. 2008. The conduit system of the regulatory tumor-specific CD4+ T cells in the tumor-draining lymph node. Nat. lymph node. Int. Immunol. 20: 1483–1487. Commun. 9: 2113. 120. Lin, Y., D. Louie, A. Ganguly, D. Wu, P. Huang, and S. Liao. 2018. Elastin 116. Handel, A. E., S. R. Irani, and G. A. Holla¨nder. 2018. The role of thymic tol- shapes small molecule distribution in lymph node conduits. J. Immunol. 200: erance in CNS . Nat. Rev. Neurol. 14: 723–734. 3142–3150. 117. Yang, L., B. T. Kress, H. J. Weber, M. Thiyagarajan, B. Wang, R. Deane, 121. Pikor, N. B., J. Cupovic, L. Onder, J. L. Gommerman, and B. Ludewig. 2017. Stromal H. Benveniste, J. J. Iliff, and M. Nedergaard. 2013. Evaluating glymphatic cell niches in the inflamed central nervous system. J. Immunol. 198: 1775–1781. Downloaded from http://www.jimmunol.org/ by guest on September 27, 2021