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Immune cell compartmentalization for brain surveillance and protection

Abstract

For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.

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Fig. 1: Immune cell subsets in the CP, the meninges and the CSF.
Fig. 2: Professional immune cell types in the brain.
Fig. 3: Communication between the CNS and the peripheral immune system.

References

  1. 1.

    Shirai, Y. On the transplantation of the rat sarcoma in adult heterogenous animals. Jpn. Med. World 1, 14–15 (1921).

    Google Scholar 

  2. 2.

    Grinker, R. R. & Bassoe, P. Disseminated encephalomyelitis. Arch. Neur. Psych. 25, 723 (1931).

    Google Scholar 

  3. 3.

    Levy, R. L. Facial paralysis following pasteur antirabic treatment. JAMA LXIX, 1873–1875 (1917).

    Google Scholar 

  4. 4.

    Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).

    CAS  PubMed  Google Scholar 

  5. 5.

    Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275 (2006).

    CAS  PubMed  Google Scholar 

  6. 6.

    Rapalino, O. et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med. 4, 814–821 (1998).

    CAS  PubMed  Google Scholar 

  7. 7.

    Peferoen, L., Kipp, M., van der Valk, P., van Noort, J. M. & Amor, S. Oligodendrocyte–microglia cross-talk in the central nervous system. Immunology 141, 302–313 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Linnerbauer, M., Wheeler, M. A. & Quintana, F. J. Astrocyte crosstalk in CNS inflammation. Neuron 108, 608–622 (2020).

    CAS  PubMed  Google Scholar 

  9. 9.

    Chavan, S. S., Pavlov, V. A. & Tracey, K. J. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46, 927–942 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Filiano, A. J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Alves de Lima, K. et al. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat. Immunol. 21, 1421–1429 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Sharma, D. & Farrar, J. D. Adrenergic regulation of immune cell function and inflammation. Semin Immunopathol. 42, 709–717 (2020).

    CAS  PubMed  Google Scholar 

  14. 14.

    Kipnis, J., Cohen, H., Cardon, M., Ziv, Y. & Schwartz, M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl Acad. Sci. USA 101, 8180–8185 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Lewitus, G. M., Cohen, H. & Schwartz, M. Reducing post-traumatic anxiety by immunization. Brain Behav. Immun. 22, 1108–1114 (2008).

    CAS  PubMed  Google Scholar 

  16. 16.

    Baruch, K. & Schwartz, M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34, 11–16 (2013).

    CAS  PubMed  Google Scholar 

  17. 17.

    Shechter, R. et al. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38, 555–569 (2013). This paper highlights the role of the CP as a physiological gateway for leucocyte entry to the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kertser, A. et al. Corticosteroid signaling at the brain-immune interface impedes coping with severe psychological stress. Sci. Adv. 5, eaav4111 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kunis, G. et al. IFN-γ-dependent activation of the brain’s choroid plexus for CNS immune surveillance and repair. Brain 136, 3427–3440 (2013).

    PubMed  Google Scholar 

  20. 20.

    Butchi, N. B., Woods, T., Du, M., Morgan, T. W. & Peterson, K. E. TLR7 and TLR9 trigger distinct neuroinflammatory responses in the CNS. Am. J. Pathol. 179, 783–794 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Dani, N. et al. A cellular and spatial map of the choroid plexus across brain ventricles and ages. Cell 184, 3056–3074.E21 (2021). This study provided an exhaustive description of the immune landscape of the different CPs throughout development.

    CAS  PubMed  Google Scholar 

  22. 22.

    Baruch, K. et al. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc. Natl Acad. Sci. USA 110, 2264–2269 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Silva-Vargas, V., Maldonado-Soto, A. R., Mizrak, D., Codega, P. & Doetsch, F. Age-dependent niche signals from the choroid plexus regulate adult neural stem. Cell Stem Cell 19, 643–652 (2016).

    CAS  PubMed  Google Scholar 

  24. 24.

    Carlén, M. et al. Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat. Neurosci. 12, 259–267 (2009).

    PubMed  Google Scholar 

  25. 25.

    Mirzadeh, Z., Merkle, F. T., Soriano-Navarro, M., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3, 265–278 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).

    CAS  PubMed  Google Scholar 

  27. 27.

    Altman, J. Are new neurons formed in the brains of adult mammals? Science 135, 1127–1128 (1962).

    CAS  PubMed  Google Scholar 

  28. 28.

    Herisson, F. et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat. Neurosci. 21, 1209–1217 (2018). This is the first study showing a direct local connection between the brain and the skull bone marrow.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Cugurra, A. et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science https://doi.org/10.1126/science.abf7844 (2021).

  30. 30.

    Brioschi, S. et al. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science https://doi.org/10.1126/science.abf9277(2021).

  31. 31.

    Rustenhoven, J. et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184, 1000–1016 (2021). This paper revealed the existence of an immunological interface at the level of the dural sinuses, where APCs efficiently present CNS antigens.

    CAS  PubMed  Google Scholar 

  32. 32.

    Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015). This study revealed a lymphatic vasculature responsible for the drainage of the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Alves de Lima, K., Rustenhoven, J. & Kipnis, J. Meningeal immunity and its function in maintenance of the central nervous system in health and disease. Annu. Rev. Immunol. 38, 597–620 (2020).

    CAS  PubMed  Google Scholar 

  34. 34.

    Ousman, S. S. & Kubes, P. Immune surveillance in the central nervous system. Nat. Neurosci. 15, 1096–1101 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    de Graaf, M. T. et al. Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry B Clin. Cytom. 80, 43–50 (2011).

    PubMed  Google Scholar 

  36. 36.

    Han, S. et al. Comprehensive immunophenotyping of cerebrospinal fluid cells in patients with neuroimmunological diseases. J. Immunol. 192, 2551–2563 (2014).

    CAS  PubMed  Google Scholar 

  37. 37.

    Raper, D., Louveau, A. & Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 39, 581–586 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Wardlaw, J. M. et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat. Rev. Neurol. 16, 137–153 (2020).

    PubMed  Google Scholar 

  39. 39.

    Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Jessen, N. A., Munk, A. S. F., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Ding, Y. et al. Astrogliosis inhibition attenuates hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix hemorrhage. Exp. Neurol. 320, 113003 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Granberg, T. et al. Enlarged perivascular spaces in multiple sclerosis on magnetic resonance imaging: a systematic review and meta-analysis. J. Neurol. 267, 3199–3212 (2020).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Kierdorf, K. & Prinz, M. Microglia in steady state. J. Clin. Invest. 127, 3201–3209 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Masuda, T., Sankowski, R., Staszewski, O. & Prinz, M. Microglia heterogeneity in the single-cell era. Cell Rep. 30, 1271–1281 (2020).

    CAS  PubMed  Google Scholar 

  46. 46.

    Kierdorf, K., Masuda, T., Jordão, M. J. C. & Prinz, M. Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat. Rev. Neurosci. 20, 547–562 (2019).

    CAS  PubMed  Google Scholar 

  47. 47.

    Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395.e6 (2018). Use of single-cell mass cytometry to characterize diverse immune cells in the steady-state CNS, with a special focus on macrophages and DCs.

    CAS  PubMed  Google Scholar 

  48. 48.

    Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016). Using several approaches, this paper reported the origin and individual transcriptomic profiles of CNS-resident macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Chinnery, H. R., Ruitenberg, M. J. & McMenamin, P. G. Novel characterization of monocyte-derived cell populations in the meninges and choroid plexus and their rates of replenishment in bone marrow chimeric mice. J. Neuropathol. Exp. Neurol. 69, 896–909 (2010).

    PubMed  Google Scholar 

  51. 51.

    Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Jordão, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019). This study unraveled the complexity of the CNS myeloid landscape, and the dynamics of several myeloid populations by single-cell RNA sequencing.

    PubMed  Google Scholar 

  53. 53.

    Rajan, W. D. et al. Defining molecular identity and fates of CNS-border associated macrophages after ischemic stroke in rodents and humans. Neurobiol. Dis. 137, 104722 (2020).

    CAS  PubMed  Google Scholar 

  54. 54.

    Mato, M. et al. Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex. Proc. Natl Acad. Sci. USA 93, 3269–3274 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Song, E. et al. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 577, 689–694 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Varvel, N. H. et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc. Natl Acad. Sci. USA 113, E5665–74 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Vasilache, A. M., Qian, H. & Blomqvist, A. Immune challenge by intraperitoneal administration of lipopolysaccharide directs gene expression in distinct blood-brain barrier cells toward enhanced prostaglandin E2 signaling. Brain Behav. Immun. 48, 31–41 (2015).

    CAS  PubMed  Google Scholar 

  58. 58.

    Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Thanopoulou, K., Fragkouli, A., Stylianopoulou, F. & Georgopoulos, S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc. Natl Acad. Sci. USA 107, 20816–20821 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Hawkes, C. A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 106, 1261–1266 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ajami, B. et al. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 21, 541–551 (2018).

    CAS  PubMed  Google Scholar 

  62. 62.

    Korin, B., Dubovik, T. & Rolls, A. Mass cytometry analysis of immune cells in the brain. Nat. Protoc. 13, 377–391 (2018).

    CAS  PubMed  Google Scholar 

  63. 63.

    Menezes, S. et al. The heterogeneity of Ly6Chi monocytes controls their differentiation into iNOS+ macrophages or monocyte-derived dendritic cells. Immunity 45, 1205–1218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Rojo, R. et al. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat. Commun. 10, 3215 (2019).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Yin, Y. et al. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat. Neurosci. 9, 843–852 (2006).

    CAS  PubMed  Google Scholar 

  67. 67.

    Rolls, A. et al. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 5, e171 (2008).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Raposo, C. et al. CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles. J. Neurosci. 34, 10141–10155 (2014).

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Shichita, T. et al. MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1. Nat. Med. 23, 723–732 (2017).

    CAS  PubMed  Google Scholar 

  70. 70.

    Anandasabapathy, N. et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208, 1695–1705 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Quintana, E. et al. DNGR-1+ dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia 63, 2231–2248 (2015).

    PubMed  Google Scholar 

  72. 72.

    Reizis, B. Plasmacytoid dendritic cells: development, regulation, and function. Immunity 50, 37–50 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).

    CAS  PubMed  Google Scholar 

  74. 74.

    Miller, S. D., McMahon, E. J., Schreiner, B. & Bailey, S. L. Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann. N Y Acad. Sci. 1103, 179–191 (2007).

    CAS  PubMed  Google Scholar 

  75. 75.

    Gelderblom, M. et al. IL-23 (interleukin-23)-producing conventional dendritic cells control the detrimental IL-17 (interleukin-17) response in stroke. Stroke 49, 155–164 (2018).

    CAS  PubMed  Google Scholar 

  76. 76.

    Ludewig, P. et al. Dendritic cells in brain diseases. Biochim. Biophys. Acta 1862, 352–367 (2016).

    CAS  PubMed  Google Scholar 

  77. 77.

    Gallizioli, M. et al. Dendritic cells and microglia have non-redundant functions in the inflamed brain with protective effects of type 1 cDCs. Cell Rep. 33, 108291 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Krienke, C. et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021).

    CAS  PubMed  Google Scholar 

  79. 79.

    Kaunzner, U. W. et al. Accumulation of resident and peripheral dendritic cells in the aging CNS. Neurobiol. Aging 33, 681–693.e1 (2012).

    PubMed  Google Scholar 

  80. 80.

    Karman, J., Ling, C., Sandor, M. & Fabry, Z. Initiation of immune responses in brain is promoted by local dendritic cells. J. Immunol. 173, 2353–2361 (2004).

    CAS  PubMed  Google Scholar 

  81. 81.

    Bartholomäus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

    PubMed  Google Scholar 

  82. 82.

    Schetters, S. T. T., Gomez-Nicola, D., Garcia-Vallejo, J. J. & Van Kooyk, Y. Neuroinflammation: microglia and T cells get ready to tango. Front. Immunol. 8, 1905 (2017).

    PubMed  Google Scholar 

  83. 83.

    Pappalardo, J. L. et al. Transcriptomic and clonal characterization of T cells in the human central nervous system. Sci. Immunol. 5, eabb8786 (2020). This study provides insight into the T cell landscape in the CNS compartments.

    CAS  PubMed  Google Scholar 

  84. 84.

    Klein, R. S. & Hunter, C. A. Protective and pathological immunity during central nervous system infections. Immunity 46, 891–909 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Medana, I., Martinic, M. A., Wekerle, H. & Neumann, H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159, 809–815 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Brochard, V. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009).

    CAS  PubMed  Google Scholar 

  88. 88.

    Marsh, S. E. et al. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl Acad. Sci. USA 113, E1316–25 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Beers, D. R., Henkel, J. S., Zhao, W., Wang, J. & Appel, S. H. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl Acad. Sci. USA 105, 15558–15563 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Baruch, K. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 22, 135–137 (2016).

    CAS  PubMed  Google Scholar 

  91. 91.

    Zuo, Z. et al. Bacille Calmette-Guérin attenuates vascular amyloid pathology and maximizes synaptic preservation in APP/PS1 mice following active amyloid-β immunotherapy. Neurobiol. Aging 101, 94–108 (2021).

    CAS  PubMed  Google Scholar 

  92. 92.

    Rosenzweig, N. et al. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat. Commun. 10, 465 (2019). This study demonstrates the pivotal part that MDMs, via MSR1, play in protecting the brain in a model of tauopathy.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Baruch, K. et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Ito, M. et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246–250 (2019). This study describes novel mechasnisms for Treg cell involvment in tissue repair after brain injury.

    CAS  PubMed  Google Scholar 

  95. 95.

    Iellem, A. et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+CD25+ regulatory T cells. J. Exp. Med. 194, 847–853 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Liesz, A. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009).

    CAS  PubMed  Google Scholar 

  97. 97.

    Beers, D. R. et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134, 1293–1314 (2011).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Reynolds, A. D., Banerjee, R., Liu, J., Gendelman, H. E. & Mosley, R. L. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J. Leukoc. Biol. 82, 1083–1094 (2007).

    CAS  PubMed  Google Scholar 

  99. 99.

    Ito, M., Komai, K., Nakamura, T., Srirat, T. & Yoshimura, A. Tissue regulatory T cells and neural repair. Int. Immunol. 31, 361–369 (2019).

    CAS  PubMed  Google Scholar 

  100. 100.

    Baruch, K. et al. Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology. Nat. Commun. 6, 7967 (2015).

    CAS  PubMed  Google Scholar 

  101. 101.

    Alpert, A. et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25, 487–495 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Anthony, I. C., Crawford, D. H. & Bell, J. E. B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas. Brain 126, 1058–1067 (2003).

    CAS  PubMed  Google Scholar 

  103. 103.

    Sabatino, J. J., Pröbstel, A.-K. & Zamvil, S. S. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat. Rev. Neurosci. 20, 728–745 (2019).

    CAS  PubMed  Google Scholar 

  104. 104.

    Fitzpatrick, Z. et al. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature 587, 472–476 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Lisak, R. P. et al. Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J. Neuroimmunol. 246, 85–95 (2012).

    CAS  PubMed  Google Scholar 

  106. 106.

    Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).

    PubMed  Google Scholar 

  107. 107.

    Lucchinetti, C. F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188–2197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Duddy, M. et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J. Immunol. 178, 6092–6099 (2007).

    CAS  PubMed  Google Scholar 

  109. 109.

    Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Edling, A. E., Nanavati, T., Johnson, J. M. & Tuohy, V. K. Human and murine lymphocyte neurotrophin expression is confined to B cells. J. Neurosci. Res. 77, 709–717 (2004).

    CAS  PubMed  Google Scholar 

  111. 111.

    Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    CAS  PubMed  Google Scholar 

  112. 112.

    Pellkofer, H. L. et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 76, 1310–1315 (2011).

    CAS  PubMed  Google Scholar 

  113. 113.

    Kim, K. et al. Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nat. Commun. 12, 2185 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Ortega, S. B. et al. B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice. Proc. Natl Acad. Sci. USA 117, 4983–4993 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Kim, Y. R. et al. Neutrophils return to bloodstream through the brain blood vessel after crosstalk with microglia during LPS-induced neuroinflammation. Front. Cell Dev. Biol. 8, 613733 (2020).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Fehr, J. & Bütler, S. Importance of prostaglandins for the in vitro adhesiveness and in vivo margination of neutrophilic granulocytes. Klin. Wochenschr. 63, 152–157 (1985).

    CAS  PubMed  Google Scholar 

  117. 117.

    Ley, K. et al. Neutrophils: new insights and open questions. Sci. Immunol. 3, eaat4579 (2018).

    PubMed  Google Scholar 

  118. 118.

    Kang, L. et al. Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke. Nat. Commun. 11, 2488 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Zenaro, E. et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).

    CAS  PubMed  Google Scholar 

  120. 120.

    Otxoa-de-Amezaga, A. et al. Location of neutrophils in different compartments of the damaged mouse brain after severe ischemia/reperfusion. Stroke 50, 1548–1557 (2019).

    CAS  PubMed  Google Scholar 

  121. 121.

    Zhang, R. L. et al. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44, 1747–1751 (1994).

    CAS  PubMed  Google Scholar 

  122. 122.

    Cuartero, M. I. et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARγ agonist rosiglitazone. Stroke 44, 3498–3508 (2013).

    CAS  PubMed  Google Scholar 

  123. 123.

    Sas, A. R. et al. A new neutrophil subset promotes CNS neuron survival and axon regeneration. Nat. Immunol. 21, 1496–1505 (2020).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Campbell, D. J. & Kernan, J. A. Mast cells in the central nervous system. Nature 210, 756–757 (1966).

    CAS  PubMed  Google Scholar 

  125. 125.

    Hendrix, S. et al. The majority of brain mast cells in B10.PL mice is present in the hippocampal formation. Neurosci. Lett. 392, 174–177 (2006).

    CAS  PubMed  Google Scholar 

  126. 126.

    Hendriksen, E., van Bergeijk, D., Oosting, R. S. & Redegeld, F. A. Mast cells in neuroinflammation and brain disorders. Neurosci. Biobehav. Rev. 79, 119–133 (2017).

    CAS  PubMed  Google Scholar 

  127. 127.

    Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

    CAS  PubMed  Google Scholar 

  128. 128.

    Russi, A. E., Walker-Caulfield, M. E., Guo, Y., Lucchinetti, C. F. & Brown, M. A. Meningeal mast cell-T cell crosstalk regulates T cell encephalitogenicity. J. Autoimmun. 73, 100–110 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Costanza, M., Colombo, M. P. & Pedotti, R. Mast cells in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. Int. J. Mol. Sci. 13, 15107–15125 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Poli, A. et al. NK cells in central nervous system disorders. J. Immunol. 190, 5355–5362 (2013).

    CAS  PubMed  Google Scholar 

  131. 131.

    Hao, J. et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann. Neurol. 69, 721–734 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Jiang, W. et al. Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages. Proc. Natl Acad. Sci. USA 114, E6202–E6211 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Jin, W.-N. et al. Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition. Nat. Neurosci. 24, 61–73 (2021).

    CAS  PubMed  Google Scholar 

  134. 134.

    Zhang, Y. et al. Depletion of NK cells improves cognitive function in the alzheimer disease mouse model. J. Immunol. 205, 502–510 (2020).

    CAS  PubMed  Google Scholar 

  135. 135.

    Benakis, C. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat. Med. 22, 516–523 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Schirmer, L., Rothhammer, V., Hemmer, B. & Korn, T. Enriched CD161high CCR6+ γδ T cells in the cerebrospinal fluid of patients with multiple sclerosis. JAMA Neurol. 70, 345–351 (2013).

    PubMed  Google Scholar 

  137. 137.

    Ribeiro, M. et al. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci. Immunol. 4, eaay5199 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Klein, R. S., Garber, C. & Howard, N. Infectious immunity in the central nervous system and brain function. Nat. Immunol. 18, 132–141 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Schmitt, C., Strazielle, N. & Ghersi-Egea, J.-F. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain. J. Neuroinflammation 9, 187 (2012).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Greenhalgh, A. D., David, S. & Bennett, F. C. Immune cell regulation of glia during CNS injury and disease. Nat. Rev. Neurosci. 21, 139–152 (2020).

    CAS  PubMed  Google Scholar 

  142. 142.

    Bereshchenko, O., Bruscoli, S. & Riccardi, C. Glucocorticoids, sex hormones, and immunity. Front. Immunol. 9, 1332 (2018).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Palin, K. et al. Interleukin-6 activates arginine vasopressin neurons in the supraoptic nucleus during immune challenge in rats. Am. J. Physiol. Endocrinol. Metab. 296, E1289–99 (2009).

    CAS  PubMed  Google Scholar 

  144. 144.

    Schiller, M., Ben-Shaanan, T. L. & Rolls, A. Neuronal regulation of immunity: why, how and where? Nat. Rev. Immunol. 21, 20–36 (2021).

    CAS  PubMed  Google Scholar 

  145. 145.

    Kohm, A. P. & Sanders, V. M. Norepinephrine: a messenger from the brain to the immune system. Immunol. Today 21, 539–542 (2000).

    CAS  PubMed  Google Scholar 

  146. 146.

    Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    CAS  PubMed  Google Scholar 

  147. 147.

    Abe, C. et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20, 700–707 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Gao, X. et al. Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature 589, 591–596 (2021).

    CAS  PubMed  Google Scholar 

  149. 149.

    Baral, P. et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat. Med. 24, 417–426 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Huang, S. et al. Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential. Cell 184, 441–459.e25 (2021).

    CAS  PubMed  Google Scholar 

  151. 151.

    Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020).

    CAS  PubMed  Google Scholar 

  152. 152.

    Nevin, J. T., Moussa, M., Corwin, W. L., Mandoiu, I. I. & Srivastava, P. K. Sympathetic nervous tone limits the development of myeloid-derived suppressor cells. Sci. Immunol. 5, eaay9368 (2020).

    CAS  PubMed  Google Scholar 

  153. 153.

    ThyagaRajan, S. et al. Age-associated alterations in sympathetic noradrenergic innervation of primary and secondary lymphoid organs in female Fischer 344 rats. J. Neuroimmunol. 233, 54–64 (2011).

    CAS  PubMed  Google Scholar 

  154. 154.

    O’Donnell, M. P., Fox, B. W., Chao, P.-H., Schroeder, F. C. & Sengupta, P. A neurotransmitter produced by gut bacteria modulates host sensory behaviour. Nature 583, 415–420 (2020).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–381 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Thaiss, C. A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016).

    CAS  PubMed  Google Scholar 

  158. 158.

    Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Heneka, M. T., McManus, R. M. & Latz, E. Inflammasome signalling in brain function and neurodegenerative disease. Nat. Rev. Neurosci. 19, 610–621 (2018).

    CAS  PubMed  Google Scholar 

  160. 160.

    Elyahu, Y. et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci. Adv. 5, eaaw8330 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Minhas, P. S. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590, 122–128 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Ma, Q., Ineichen, B. V., Detmar, M. & Proulx, S. T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat. Commun. 8, 1434 (2017).

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Mesquita, S. D. et al. The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer’s disease. Brain Behav. Immun. 49, 280–292 (2015).

    CAS  PubMed  Google Scholar 

  166. 166.

    Deczkowska, A. et al. Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner. Nat. Commun. 8, 717 (2017).

    PubMed  PubMed Central  Google Scholar 

  167. 167.

    Xue, F., Tian, J., Yu, C., Du, H. & Guo, L. Type I interferon response-related microglial Mef2c deregulation at the onset of Alzheimer’s pathology in 5×FAD mice. Neurobiol. Dis. 152, 105272 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Serot, J.-M., Béné, M.-C. & Faure, G. C. Choroid plexus, aging of the brain, and Alzheimer’s disease. Front. Biosci. 8, s515–21 (2003).

    PubMed  Google Scholar 

  169. 169.

    Griciuc, A. et al. TREM2 acts downstream of CD33 in modulating microglial pathology in alzheimer’s disease. Neuron 103, 820–835.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Baek, H. et al. Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer’s disease model. Oncotarget 7, 69347–69357 (2016).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The Schwartz research group is supported by an Advanced European Research Council grant (no. 7417), an Israel Science Foundation (ISF) research grant (no. 991/16) and an ISF Legacy Heritage Bio-Medical Science Partnership research grant (no. 1354/15). We thank the Thompson Foundation for generous support of Alzheimer’s disease research, and S. Schwarzbaum for editing the manuscript.

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T.C., G.C. and M.S. contributed equally to the writing of the manuscript.

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Correspondence to Michal Schwartz.

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M.S. is a consultant for ImmunoBrain Checkpoint. All other authors have no competing interests.

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Peer review information Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. Ioana Visan was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Croese, T., Castellani, G. & Schwartz, M. Immune cell compartmentalization for brain surveillance and protection. Nat Immunol 22, 1083–1092 (2021). https://doi.org/10.1038/s41590-021-00994-2

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