1932

Abstract

Neuroimmunology, albeit a relatively established discipline, has recently sparked numerous exciting findings on microglia, the resident macrophages of the central nervous system (CNS). This review addresses meningeal immunity, a less-studied aspect of neuroimmune interactions. The meninges, a triple layer of membranes—the pia mater, arachnoid mater, and dura mater—surround the CNS, encompassing the cerebrospinal fluid produced by the choroid plexus epithelium. Unlike the adjacent brain parenchyma, the meninges contain a wide repertoire of immune cells. These constitute meningeal immunity, which is primarily concerned with immune surveillance of the CNS, and—according to recent evidence—also participates in postinjury CNS recovery, chronic neurodegenerative conditions, and even higher brain function. Meningeal immunity has recently come under the spotlight owing to the characterization of meningeal lymphatic vessels draining the CNS. Here, we review the current state of our understanding of meningeal immunity and its effects on healthy and diseased brains.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-102319-103410
2020-04-26
2024-06-25
Loading full text...

Full text loading...

/deliver/fulltext/immunol/38/1/annurev-immunol-102319-103410.html?itemId=/content/journals/10.1146/annurev-immunol-102319-103410&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Herculano-Houzel S. 2017. What modern mammals teach about the cellular composition of early brains and mechanisms of brain evolution. Evolution of Nervous Systems JH Kaas 153–80 Amsterdam: Elsevier
    [Google Scholar]
  2. 2. 
    Klimovich AV, Bosch TCG. 2018. Rethinking the role of the nervous system: lessons from the Hydra holobiont. BioEssays 40:91800060
    [Google Scholar]
  3. 3. 
    Holland LZ. 2017. Invertebrate origins of vertebrate nervous systems. Evolution of Nervous Systems JH Kaas 3–23 Amsterdam: Elsevier
    [Google Scholar]
  4. 4. 
    Taylor EW, Jordan D, Coote JH 1999. Central control of the cardiovascular and respiratory systems and their interactions in vertebrates. Physiol. Rev. 79:3855–916
    [Google Scholar]
  5. 5. 
    Bucher D, Anderson PAV. 2015. Evolution of the first nervous systems—what can we surmise?. J. Exp. Biol. 218:4501–3
    [Google Scholar]
  6. 6. 
    Dando SJ, Mackay-Sim A, Norton R, Currie BJ, St. John JA et al. 2014. Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin. Microbiol. Rev. 27:4691–726
    [Google Scholar]
  7. 7. 
    Ghannam JY, Al Kharazi KA 2019. Neuroanatomy, cranial meninges. StatPearls Treasure Island, FL: StatPearls
    [Google Scholar]
  8. 8. 
    Decimo I, Fumagalli G, Berton V, Krampera M, Bifari F 2012. Meninges: from protective membrane to stem cell niche. Am. J. Stem Cells 1:292–105
    [Google Scholar]
  9. 9. 
    Wilkins RH. 1964. Neurosurgical Classic—XVII. J. Neurosurg. 21:3240–44
    [Google Scholar]
  10. 10. 
    Aurboonyawat T, Suthipongchai S, Pereira V, Ozanne A, Lasjaunias P 2007. Patterns of cranial venous system from the comparative anatomy in vertebrates: Part I, introduction and the dorsal venous system. Interv. Neuroradiol. 13:4335–44
    [Google Scholar]
  11. 11. 
    Michael-Titus A, Revest P, Shortland P 2010. Infection in the central nervous system. The Nervous System227–36 Amsterdam: Elsevier
    [Google Scholar]
  12. 12. 
    Louveau A, Herz J, Alme MN, Salvador AF, Dong MQ et al. 2018. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 21:101380–91
    [Google Scholar]
  13. 13. 
    Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC et al. 2018. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560:7717185–91
    [Google Scholar]
  14. 14. 
    Ahn JH, Cho H, Kim J-H, Kim SH, Ham J-S et al. 2019. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572:776762–66
    [Google Scholar]
  15. 15. 
    Kisler K, Nelson AR, Montagne A, Zlokovic BV 2017. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18:7419–34
    [Google Scholar]
  16. 16. 
    Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV 2015. Establishment and dysfunction of the blood-brain barrier. Cell 163:51064–78
    [Google Scholar]
  17. 17. 
    Achrol AS, Rennert RC, Anders C, Soffietti R, Ahluwalia MS et al. 2019. Brain metastases. Nat. Rev. Dis. Primer. 5:15
    [Google Scholar]
  18. 18. 
    Lun MP, Monuki ES, Lehtinen MK 2015. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat. Rev. Neurosci. 16:8445–57
    [Google Scholar]
  19. 19. 
    Ribatti D, Nico B, Crivellato E, Artico M 2006. Development of the blood-brain barrier: a historical point of view. Anat. Rec. B 289B:13–8
    [Google Scholar]
  20. 20. 
    Rubin LL, Staddon JM. 1999. The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22:11–28
    [Google Scholar]
  21. 21. 
    Engelhardt B, Vajkoczy P, Weller RO 2017. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18:2123–31
    [Google Scholar]
  22. 22. 
    Balin BJ, Broadwell RD, Salcman M, El-Kalliny M 1986. Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J. Comp. Neurol. 251:2260–80
    [Google Scholar]
  23. 23. 
    JAMA. Immunologically privileged? 1964. JAMA 190:2150
    [Google Scholar]
  24. 24. 
    Medawar PB. 1948. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29:158–69
    [Google Scholar]
  25. 25. 
    Scheinberg LC, Edelman FL, Levy A 1964. Is the brain “an immunologically privileged site”?: 1. Studies based on intracerebral tumor homotransplantation and isotransplantation to sensitized hosts. Arch. Neurol. 11:3248–64
    [Google Scholar]
  26. 26. 
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ et al. 2015. Structural and functional features of central nervous system lymphatic vessels. Nature 523:7560337–41
    [Google Scholar]
  27. 27. 
    Antila S, Karaman S, Nurmi H, Airavaara M, Voutilainen MH et al. 2017. Development and plasticity of meningeal lymphatic vessels. J. Exp. Med. 214:123645–67
    [Google Scholar]
  28. 28. 
    Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S et al. 2015. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212:7991–99
    [Google Scholar]
  29. 29. 
    Sandrone S, Moreno-Zambrano D, Kipnis J, van Gijn J 2019. A (delayed) history of the brain lymphatic system. Nat. Med. 25:4538–40
    [Google Scholar]
  30. 30. 
    Key A, Retzius MG. 1903. Studien in der Anatomie des Nervensystems und des Bindegewebes Stockholm: Norstedt & Söner
    [Google Scholar]
  31. 31. 
    Lukić IK, Glunčić V, Ivkić G, Hubenstorf M, Marušić A 2003. Virtual dissection: a lesson from the 18th century. Lancet 362:94012110–13
    [Google Scholar]
  32. 32. 
    Lecco V. 1953. Di una probabile modificazione delle fissure linfatiche della della parte dei seni venosi della dura madre [Probable modification of the lymphatic fissures of the walls of the venous sinuses of the dura mater]. Arch. Ital. Otol. Rinol. Laringol. 64:3287–96
    [Google Scholar]
  33. 33. 
    Földi M, Gellért A, Kozma M, Poberai M, Zoltán OT, Csanda E 1966. New contributions to the anatomical connections of the brain and the lymphatic system. Acta Anat 64:4498–505
    [Google Scholar]
  34. 34. 
    Li J, Zhou J, Shi Y 1996. Scanning electron microscopy of human cerebral meningeal stomata. Ann. Anat. 178:3259–61
    [Google Scholar]
  35. 35. 
    Absinta M, Ha S-K, Nair G, Sati P, Luciano NJ et al. 2017. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6:e29738
    [Google Scholar]
  36. 36. 
    Bower NI, Koltowska K, Pichol-Thievend C, Virshup I, Paterson S et al. 2017. Mural lymphatic endothelial cells regulate meningeal angiogenesis in the zebrafish. Nat. Neurosci. 20:6774–83
    [Google Scholar]
  37. 37. 
    Jung E, Gardner D, Choi D, Park E, Jin Seong Y et al. 2017. Development and characterization of a novel Prox1-EGFP lymphatic and Schlemm's canal reporter rat. Sci. Rep. 7:15577
    [Google Scholar]
  38. 38. 
    Wang J, Murray M, Grafstein B 1995. Cranial meninges of goldfish: age-related changes in morphology of meningeal cells and accumulation of surfactant-like multilamellar bodies. Cell Tissue Res 281:2349–58
    [Google Scholar]
  39. 39. 
    Alitalo K. 2011. The lymphatic vasculature in disease. Nat. Med. 17:111371–80
    [Google Scholar]
  40. 40. 
    Aspelund A, Robciuc MR, Karaman S, Makinen T, Alitalo K 2016. Lymphatic system in cardiovascular medicine. Circ. Res. 118:3515–30
    [Google Scholar]
  41. 41. 
    Levick JR, Michel CC. 2010. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87:2198–210
    [Google Scholar]
  42. 42. 
    Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J 2017. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J. Clin. Investig. 127:93210–19
    [Google Scholar]
  43. 43. 
    Cserr HF, Harling-Berg CJ, Knopf PM 1992. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:4269–76
    [Google Scholar]
  44. 44. 
    Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF 1984. Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. Ren. Physiol. 246:6F835–44
    [Google Scholar]
  45. 45. 
    Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA 1985. Evidence for a ‘Paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 326:147–63
    [Google Scholar]
  46. 46. 
    Rennels ML, Blaumanis OR, Grady PA 1990. Rapid solute transport throughout the brain via paravascular fluid pathways. Adv. Neurol. 52:431–39
    [Google Scholar]
  47. 47. 
    Jessen NA, Munk ASF, Lundgaard I, Nedergaard M 2015. The glymphatic system: a beginner's guide. Neurochem. Res. 40:122583–99
    [Google Scholar]
  48. 48. 
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W et al. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid. Sci. Transl. Med. 4:147147ra111
    [Google Scholar]
  49. 49. 
    Plog BA, Nedergaard M. 2018. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. Mech. Dis. 13:379–94
    [Google Scholar]
  50. 50. 
    Yang L, Kress BT, Weber HJ, Thiyagarajan M, Wang B et al. 2013. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11:1107
    [Google Scholar]
  51. 51. 
    Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA et al. 2013. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 33:4618190–99
    [Google Scholar]
  52. 52. 
    Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M et al. 2014. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 34:4916180–93
    [Google Scholar]
  53. 53. 
    Plog BA, Dashnaw ML, Hitomi E, Peng W, Liao Y et al. 2015. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J. Neurosci. 35:2518–26
    [Google Scholar]
  54. 54. 
    Preston JE. 2001. Ageing choroid plexus-cerebrospinal fluid system. Microsc. Res. Tech. 52:131–37
    [Google Scholar]
  55. 55. 
    Silverberg GD, Heit G, Huhn S, Jaffe RA, Chang SD et al. 2001. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type. Neurology 57:101763–66
    [Google Scholar]
  56. 56. 
    Weed LH. 1923. The absorption of cerebrospinal fluid into the venous system. Am. J. Anat. 31:3191–221
    [Google Scholar]
  57. 57. 
    Upton ML, Weller RO. 1985. The morphology of cerebrospinal fluid drainage pathways in human arachnoid granulations. J. Neurosurg. 63:6867–75
    [Google Scholar]
  58. 58. 
    Kida S, Pantazis A, Weller RO 1993. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat: anatomy, histology and immunological significance. Neuropathol. Appl. Neurobiol. 19:6480–88
    [Google Scholar]
  59. 59. 
    Bradbury MW, Westrop RJ. 1983. Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J. Physiol. 339:1519–34
    [Google Scholar]
  60. 60. 
    Kaminski M, Bechmann I, Pohland M, Kiwit J, Nitsch R, Glumm J 2012. Migration of monocytes after intracerebral injection at entorhinal cortex lesion site. J. Leukoc. Biol. 92:131–39
    [Google Scholar]
  61. 61. 
    Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I 2006. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J. Leukoc. Biol. 80:4797–801
    [Google Scholar]
  62. 62. 
    Mohammad MG, Tsai VWW, Ruitenberg MJ, Hassanpour M, Li H et al. 2014. Immune cell trafficking from the brain maintains CNS immune tolerance. J. Clin. Investig. 124:31228–41
    [Google Scholar]
  63. 63. 
    Kipnis J. 2016. Multifaceted interactions between adaptive immunity and the central nervous system. Science 353:6301766–71
    [Google Scholar]
  64. 64. 
    Herz J, Filiano AJ, Smith A, Yogev N, Kipnis J 2017. Myeloid cells in the central nervous system. Immunity 46:6943–56
    [Google Scholar]
  65. 65. 
    Norris GT, Kipnis J. 2019. Immune cells and CNS physiology: microglia and beyond. J. Exp. Med. 216:160–70
    [Google Scholar]
  66. 66. 
    Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR et al. 2019. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22:61021–35
    [Google Scholar]
  67. 67. 
    Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG et al. 2018. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48:2380–95.e6
    [Google Scholar]
  68. 68. 
    Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A et al. 2010. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207:51067–80
    [Google Scholar]
  69. 69. 
    Radjavi A, Smirnov I, Kipnis J 2014. Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain. Behav. Immun. 35:58–63
    [Google Scholar]
  70. 70. 
    Radjavi A, Smirnov I, Derecki N, Kipnis J 2014. Dynamics of the meningeal CD4+ T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol. Psychiatry 19:5531–32
    [Google Scholar]
  71. 71. 
    Sallusto F, Impellizzieri D, Basso C, Laroni A, Uccelli A et al. 2012. T-cell trafficking in the central nervous system: T-cell traffic in the CNS. Immunol. Rev. 248:1216–27
    [Google Scholar]
  72. 72. 
    von Andrian UH, Mackay CR 2000. T-cell function and migration—two sides of the same coin. N. Engl. J. Med. 343:141020–34
    [Google Scholar]
  73. 73. 
    Foxman EF, Campbell JJ, Butcher EC 1997. Multistep navigation and the combinatorial control of leukocyte chemotaxis. J. Cell Biol. 139:51349–60
    [Google Scholar]
  74. 74. 
    Daneman R, Zhou L, Kebede AA, Barres BA 2010. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:7323562–66
    [Google Scholar]
  75. 75. 
    Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN et al. 2019. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat. Med. 25:6988–1000
    [Google Scholar]
  76. 76. 
    Rua R, McGavern DB. 2018. Advances in meningeal immunity. Trends Mol. Med. 24:6542–59
    [Google Scholar]
  77. 77. 
    Proebstl D, Voisin M-B, Woodfin A, Whiteford J, D'Acquisto F et al. 2012. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J. Exp. Med. 209:61219–34
    [Google Scholar]
  78. 78. 
    Rustenhoven J, Jansson D, Smyth LC, Dragunow M 2017. Brain pericytes as mediators of neuroinflammation. Trends Pharmacol. Sci. 38:3291–304
    [Google Scholar]
  79. 79. 
    Duan L, Zhang X-D, Miao W-Y, Sun Y-J, Xiong G et al. 2018. PDGFRβ cells rapidly relay inflammatory signal from the circulatory system to neurons via chemokine CCL2. Neuron 100:1183–200.e8
    [Google Scholar]
  80. 80. 
    Sigmundsdottir H, Butcher EC. 2008. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat. Immunol. 9:9981–87
    [Google Scholar]
  81. 81. 
    Bajénoff M, Egen JG, Koo LY, Laugier JP, Brau F et al. 2006. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25:6989–1001
    [Google Scholar]
  82. 82. 
    Lv X, Wu Z, Li Y 2014. Innervation of the cerebral dura mater. Neuroradiol. J. 27:3293–98
    [Google Scholar]
  83. 83. 
    Messlinger K. 2018. The big CGRP flood—sources, sinks and signalling sites in the trigeminovascular system. J. Headache Pain 19:122
    [Google Scholar]
  84. 84. 
    McCulloch J, Uddman R, Kingman TA, Edvinsson L 1986. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. PNAS 83:155731–35
    [Google Scholar]
  85. 85. 
    Ding X, Wang H, Qian X, Han X, Yang L et al. 2019. Panicle-shaped sympathetic architecture in the spleen parenchyma modulates antibacterial innate immunity. Cell Rep 27:133799–807.e3
    [Google Scholar]
  86. 86. 
    Cohen JA, Edwards TN, Liu AW, Hirai T, Jones MR et al. 2019. Cutaneous TRPV1+ neurons trigger protective innate type 17 anticipatory immunity. Cell 178:4919–32.e14
    [Google Scholar]
  87. 87. 
    Rankin LC, Artis D. 2018. Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell 173:3554–67
    [Google Scholar]
  88. 88. 
    Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M 2004. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. PNAS 101:218180–85
    [Google Scholar]
  89. 89. 
    Brynskikh A, Warren T, Zhu J, Kipnis J 2008. Adaptive immunity affects learning behavior in mice. Brain. Behav. Immun. 22:6861–69
    [Google Scholar]
  90. 90. 
    Wolf SA, Steiner B, Akpinarli A, Kammertoens T, Nassenstein C et al. 2009. CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J. Immunol. 182:73979–84
    [Google Scholar]
  91. 91. 
    Rattazzi L, Piras G, Ono M, Deacon R, Pariante CM, D'Acquisto F 2013. CD4+ but not CD8+ T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice. Transl. Psychiatry 3:7e280
    [Google Scholar]
  92. 92. 
    Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W et al. 2016. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535:7612425–29
    [Google Scholar]
  93. 93. 
    Cohen H, Ziv Y, Cardon M, Kaplan Z, Matar MA et al. 2006. Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. J. Neurobiol. 66:6552–63
    [Google Scholar]
  94. 94. 
    Quinnies KM, Cox KH, Rissman EF 2015. Immune deficiency influences juvenile social behavior and maternal behavior. Behav. Neurosci. 129:3331–38
    [Google Scholar]
  95. 95. 
    Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9:146–56
    [Google Scholar]
  96. 96. 
    Choi GB, Yim YS, Wong H, Kim S, Kim H et al. 2016. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351:6276933–39
    [Google Scholar]
  97. 97. 
    Chen C, Itakura E, Nelson GM, Sheng M, Laurent P et al. 2017. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542:763943–48
    [Google Scholar]
  98. 98. 
    Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB 2014. Transcranial amelioration of inflammation and cell death after brain injury. Nature 505:7482223–28
    [Google Scholar]
  99. 99. 
    Reed MD, Yim YS, Wimmer RD, Kim H, Ryu C et al. 2020. IL-17a promotes sociability in mouse models of neurodevelopmental disorders. Nature 577:249–53 https://doi.org/10.1038/s41586-019-1843-6
    [Crossref] [Google Scholar]
  100. 100. 
    Da Mesquita S, Fu Z, Kipnis J 2018. The meningeal lymphatic system: a new player in neurophysiology. Neuron 100:2375–88
    [Google Scholar]
  101. 101. 
    Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M 1999. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5:149–55
    [Google Scholar]
  102. 102. 
    Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E et al. 2013. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. PNAS 110:62264–69
    [Google Scholar]
  103. 103. 
    Cohen IR. 1992. The cognitive paradigm and the immunological homunculus. Immunol. Today 13:12490–94
    [Google Scholar]
  104. 104. 
    Frenkel D, Huang Z, Maron R, Koldzic DN, Moskowitz MA, Weiner HL 2005. Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke. J. Neurol. Sci. 233:1–2125–32
    [Google Scholar]
  105. 105. 
    Moalem G, Yoles E, Leibowitz-Amit R, Muller-Gilor S, Mor F et al. 2000. Autoimmune T cells retard the loss of function in injured rat optic nerves. J. Neuroimmunol. 106:1–2189–97
    [Google Scholar]
  106. 106. 
    Serpe CJ, Byram SC, Sanders VM, Jones KJ 2005. Brain-derived neurotrophic factor supports facial motoneuron survival after facial nerve transection in immunodeficient mice. Brain. Behav. Immun. 19:2173–80
    [Google Scholar]
  107. 107. 
    Ziv Y, Ron N, Butovsky O, Landa G, Sudai E et al. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9:2268–75
    [Google Scholar]
  108. 108. 
    Kipnis J, Yoles E, Schori H, Hauben E, Shaked I, Schwartz M 2001. Neuronal survival after CNS insult is determined by a genetically encoded autoimmune response. J. Neurosci. 21:134564–71
    [Google Scholar]
  109. 109. 
    Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A et al. 2001. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J. Clin. Investig. 108:4591–99
    [Google Scholar]
  110. 110. 
    Moalem G, Gdalyahu A, Shani Y, Otten U, Lazarovici P et al. 2000. Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J. Autoimmun. 15:3331–45
    [Google Scholar]
  111. 111. 
    Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E et al. 2002. Neuroprotective autoimmunity: Naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. PNAS 99:2415620–25 https://doi.org/10.1073/pnas.232565399
    [Crossref] [Google Scholar]
  112. 112. 
    Walsh JT, Zheng J, Smirnov I, Lorenz U, Tung K, Kipnis J 2014. Regulatory T cells in central nervous system injury: a double-edged sword. J. Immunol. 193:105013–22 https://doi.org/10.4049/jimmunol.1302401
    [Crossref] [Google Scholar]
  113. 113. 
    Liesz A, Zhou W, Na S-Y, Hämmerling GJ, Garbi N et al. 2013. Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. J. Neurosci. 33:4417350–62 https://doi.org/10.1523/JNEUROSCI.4901-12.2013
    [Crossref] [Google Scholar]
  114. 114. 
    Mowat AM, Agace WW. 2014. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14:10667–85
    [Google Scholar]
  115. 115. 
    Kumamoto Y, Iwasaki A. 2012. Unique features of antiviral immune system of the vaginal mucosa. Curr. Opin. Immunol. 24:4411–16
    [Google Scholar]
  116. 116. 
    Belkaid Y, Tamoutounour S. 2016. The influence of skin microorganisms on cutaneous immunity. Nat. Rev. Immunol. 16:6353–66
    [Google Scholar]
  117. 117. 
    Chen K, Kolls JK. 2013. T cell-mediated host immune defenses in the lung. Annu. Rev. Immunol. 31:605–33
    [Google Scholar]
  118. 118. 
    Harrison OJ, Linehan JL, Shih H-Y, Bouladoux N, Han S-J et al. 2019. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science 363:6422eaat6280
    [Google Scholar]
  119. 119. 
    Kisielow J, Obermair F-J, Kopf M 2019. Deciphering CD4+ T cell specificity using novel MHC-TCR chimeric receptors. Nat. Immunol. 20:5652–62
    [Google Scholar]
  120. 120. 
    Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J et al. 2014. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157:51073–87
    [Google Scholar]
  121. 121. 
    Ise W, Kohyama M, Nutsch KM, Lee HM, Suri A et al. 2010. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat. Immunol. 11:2129–35
    [Google Scholar]
  122. 122. 
    Kim JV, Kang SS, Dustin ML, McGavern DB 2009. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457:7226191–95
    [Google Scholar]
  123. 123. 
    Arac A, Grimbaldeston MA, Nepomuceno ARB, Olayiwola O, Pereira MP et al. 2014. Evidence that meningeal mast cells can worsen stroke pathology in mice. Am. J. Pathol. 184:92493–504
    [Google Scholar]
  124. 124. 
    Dendrou CA, Fugger L, Friese MA 2015. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15:9545–58
    [Google Scholar]
  125. 125. 
    Schläger C, Körner H, Krueger M, Vidoli S, Haberl M et al. 2016. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530:7590349–53
    [Google Scholar]
  126. 126. 
    Russi AE, Brown MA. 2015. The meninges: new therapeutic targets for multiple sclerosis. Transl. Res. 165:2255–69
    [Google Scholar]
  127. 127. 
    Pikor NB, Astarita JL, Summers-Deluca L, Galicia G, Qu J et al. 2015. Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity 43:61160–73
    [Google Scholar]
  128. 128. 
    Bartholomäus I, Kawakami N, Odoardi F, Schläger C, Miljkovic D et al. 2009. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462:726994–98
    [Google Scholar]
  129. 129. 
    Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, Arvaniti E et al. 2019. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nat. Med. 25:81290–300
    [Google Scholar]
  130. 130. 
    Ransohoff RM, Kivisäkk P, Kidd G 2003. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3:7569–81
    [Google Scholar]
  131. 131. 
    Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N et al. 2005. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11:3328–34
    [Google Scholar]
  132. 132. 
    Lodygin D, Hermann M, Schweingruber N, Flügel-Koch C, Watanabe T et al. 2019. β-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration. Nature 566:7745503–8
    [Google Scholar]
  133. 133. 
    Flügel A, Berkowicz T, Ritter T, Labeur M, Jenne DE et al. 2001. Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14:5547–60
    [Google Scholar]
  134. 134. 
    Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schläger C et al. 2012. T cells become licensed in the lung to enter the central nervous system. Nature 488:7413675–79
    [Google Scholar]
  135. 135. 
    Furtado GC, Marcondes MCG, Latkowski J-A, Tsai J, Wensky A, Lafaille JJ 2008. Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J. Immunol. 181:74648–55
    [Google Scholar]
  136. 136. 
    van Zwam M, Huizinga R, Heijmans N, van Meurs M, Wierenga-Wolf AF et al. 2009. Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J. Pathol. 217:4543–51
    [Google Scholar]
  137. 137. 
    Phillips MJ, Needham M, Weller RO 1997. Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat. J. Pathol. 182:4457–64
    [Google Scholar]
  138. 138. 
    Oeppen J. 2002. Broken limits to life expectancy. Science 296:55701029–31
    [Google Scholar]
  139. 139. 
    Niccoli T, Partridge L. 2012. Ageing as a risk factor for disease. Curr. Biol. 22:17R741–52
    [Google Scholar]
  140. 140. 
    Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R et al. 2019. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571:7764205–10
    [Google Scholar]
  141. 141. 
    Maslov AY. 2004. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24:71726–33
    [Google Scholar]
  142. 142. 
    Ma Q, Ineichen BV, Detmar M, Proulx ST 2017. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat. Commun. 8:11434
    [Google Scholar]
  143. 143. 
    Brookmeyer R, Abdalla N, Kawas CH, Corrada MM 2018. Forecasting the prevalence of preclinical and clinical Alzheimer's disease in the United States. Alzheimers Dement 14:2121–29
    [Google Scholar]
  144. 144. 
    Benilova I, Karran E, De Strooper B 2012. The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes. Nat. Neurosci. 15:3349–57
    [Google Scholar]
  145. 145. 
    Kress BT, Iliff JJ, Xia M, Wang M, Wei HS et al. 2014. Impairment of paravascular clearance pathways in the aging brain: paravascular clearance. Ann. Neurol. 76:6845–61
    [Google Scholar]
/content/journals/10.1146/annurev-immunol-102319-103410
Loading
/content/journals/10.1146/annurev-immunol-102319-103410
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error