The Role of T Cells in Post-stroke Regeneration

  • Julia V. Cramer
  • Arthur LieszEmail author
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


The interaction of the immune system with the brain is necessary for development and surveillance of the healthy brain. The influence of the adaptive immune system on several brain diseases has been described in great detail. In ischemic stroke, a growing body of evidence has demonstrated a key role for T cells in the acute phase after stroke. Pro- and anti-inflammatory T cell subpopulations impact in this early phase the inflammatory milieu and directly affect secondary lesion progression and neuronal injury. Recently, a functional role for T cells has also become more evident also in delayed neuronal (dys-)function and late-phase recovery after stroke. Here, T cells may also affect various non-immunological pathways involved in tissue repair, neuronal plasticity and functional recovery. These pleiotropic effects of T cells on mechanisms such as neurogenesis and angiogenesis suggest T cells as potential therapeutic target to modulate post-stroke regeneration. This chapter will provide a comprehensive overview of the current knowledge about the role of T cells in stroke with a particular focus on regenerative processes in the chronic phase.


Stroke Brain ischemia T cell Lymphocyte Inflammation Neuroimmunology Regeneration Cytokines 



Antigen presenting cell


Blood brain barrier


Brain derived neurotrophic factor


Chemokine receptor


Central nervous system


Cluster of Differentiation


Cytotoxic T-lymphocyte-associated Protein 4


Damage-Associated Molecular Patterns


Glucocorticoid-induced TNF receptor


Interferon gamma


Immunoglobulin E


Insulin like growth factor 1




Middle Cerebral Artery Occlusion


Major Histocompatibility Complex




Neural Precursor Cell


Receptor for advanced glycosylation endproducts


Subgranular zone


Subventricular zone


Transforming growth factor beta

Th cell

T helper cell


Toll-like receptors


Tumor necrosis factor alpha


Regulatory T cell


Vascular Endothelial Growth Factor


  1. 1.
    Stenger S, Hanson DA, Teitelbaum R, Dewan P, Niazi KR, Froelich CJ, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science. 1998;282:121–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Kägi D, Odermatt B, Seiler P, Zinkernagel RM, Mak TW, Hengartner H. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med. 1997;186(7):989–97.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Rieux-Laucat F, Le Deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med. 2005;352:306–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Hsieh C, Macatonia S, Tripp C, Wolf S, O’Garra A, Murphy K. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993;260:547–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4 + T cell subsets and induces early resistance to leishmania major in mice. J Exp Med. 1993;178:567–77.PubMedCrossRefGoogle Scholar
  6. 6.
    Min B, Prout M, Hu-Li J, Zhu J, Jankovic D, Morgan ES, et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med. 2004;200(4):507–17.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Shinkai K, Mohrs M, Locksley RM. Helper T cells regulate type-2 innate immunity in vivo. Nature. 2002;420:825–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17(3):138–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;0(2):233–40.CrossRefGoogle Scholar
  10. 10.
    Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24:677–88.PubMedCrossRefGoogle Scholar
  11. 11.
    Sakaguchi S, Regulatory T. cells: minireview key controllers of immunologic self-tolerance. Cell. 2000;101:455–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.PubMedCrossRefGoogle Scholar
  13. 13.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Vantourout P, Hayday A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol. 2013;13:88–100.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Bonneville M, O’Brien RL, Born WK. γδ T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol. 2010;10:469–78.CrossRefGoogle Scholar
  16. 16.
    Vermijlen D, Ellis P, Langford C, Klein A, Engel R, Willimann K, et al. Distinct cytokine-driven responses of activated blood γδ T cells: insights into unconventional T cell pleiotropy1. J Immunol. 2007;178(7):4304–14.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268–75.PubMedCrossRefGoogle Scholar
  18. 18.
    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 U S A. 2004;101(21):8180–95.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Lewitus GM, Wilf-Yarkoni A, Ziv Y, Shabat-Simon M, Gersner R, Zangen A, et al. Vaccination as a novel approach for treating depressive behavior. Biol Psychiatry. 2009;65:283–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26(9):485–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Hickey WF. Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol. 1991 Jan;1(2):97–105.PubMedCrossRefGoogle Scholar
  22. 22.
    Engelhardt B, Carare RO, Bechmann I, Flügel A, Laman JD, Weller RO. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 2016;132:317–38.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Allt G, Lawrenson JG. Is the pial microvessel a good model for blood-brain barrier studies? Brain Res Rev. 1997;24:67–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Bechmann I, Galea I, Perry VH. What is the blood-brain barrier (not)? Trends Immunol. 2007;28(1):5–11.PubMedCrossRefGoogle Scholar
  25. 25.
    Bartholomäus I, Kawakami N, Odoardi F, Schläger C, Miljkovic D, Ellwart JW, et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009;462:94–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Kivisakk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM, et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol. 2009;65(4):457–69.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol. 2006;80(October):797–801.PubMedCrossRefGoogle Scholar
  28. 28.
    Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, et al. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013;110(6):2264–9.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kivisäkk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, et al. Human cerebrospinal fluid central memory CD4 T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A. 2003;100(14):8389–94.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Wolf SA, Steiner B, Akpinarli A, Kammertoens T, Nassenstein C, Braun A, et al. CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol. 2009;182:3979–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Brynskikh A, Warren T, Zhu J, Kipnis J. Adaptive immunity affects learning behavior in mice. Brain Behav Immun. 2008;22(6):861–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Radjavi A, Smirnov I, Kipnis J. Brain antigen-reactive CD4 + T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav Immun. 2014;35:58–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016;535:425–9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010;207(5):1067–80.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Balschun D, Wetzel W, Del Rey A, Pitossi F, Schneider H, Zuschratter W, et al. Interleukin-6: a cytokine to forget. FASEB J. 2004;18:1788–91.PubMedGoogle Scholar
  36. 36.
    Filiano AJ, Gadani SP, Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci. 2017;18(6):375–84.PubMedCrossRefGoogle Scholar
  37. 37.
    Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol. 2008;8(4):279–89.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lotze MT, Tracey KJ. High - mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005;5:331–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA, et al. Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab. 2007;27(12):1941–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796–808.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Kuric E, Ruscher K. Dynamics of major histocompatibility complex class II-positive cells in the postischemic brain - influence of levodopa treatment. J Neuroimmunol. 2014;11(145):1–12.Google Scholar
  43. 43.
    Yilmaz G, Granger DN. Cell adhesion molecules and ischemic stroke. Neurol Res. 2008;30(8):783–93.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Huang J, Upadhyay UM, Vascular TRJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol. 2006;66:323–245.CrossRefGoogle Scholar
  45. 45.
    Doll DN, Barr TL, Simpkins JW. Cytokines: their role in stroke and potential use as biomarkers and therapeutic targets. Aging Dis. 2014;5(5):294–306.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Bauer AT, Bürgers HF, Rabie T, Marti HH. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J Cereb Blood Flow Metab. 2010;30:837–48.PubMedCrossRefGoogle Scholar
  47. 47.
    Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol. 2003;183:25–33.PubMedCrossRefGoogle Scholar
  48. 48.
    Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009;40:1849–57.PubMedCrossRefGoogle Scholar
  49. 49.
    Enzmann G, Mysiorek C, Roser G, Cheng Y-J, Sharang G, Hannocks M-J, et al. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol. 2013;125:395–412.PubMedCrossRefGoogle Scholar
  50. 50.
    Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G. Lymphocytic infiltration and expression of intercellular adhesion molecule-l in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab. 1995;15:42–51.PubMedCrossRefGoogle Scholar
  51. 51.
    Stubbe T, Ebner F, Richter D, Engel OR, Klehmet J, Royl G, et al. Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO. J Cereb Blood Flow Metab. 2013;33(10):37–47.PubMedCrossRefGoogle Scholar
  52. 52.
    Chu HX, Kim HA, Lee S, Moore JP, Chan CT, Vinh A, et al. Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia. J Cereb Blood Flow Metab. 2013;34(10):450–9.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Gill D, Veltkamp R. Dynamics of T cell responses after stroke. Curr Opin Pharmacol. 2016;26:26–32.PubMedCrossRefGoogle Scholar
  54. 54.
    Chamorro Á, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R. The immunology of acute stroke. Nat Rev Neurol. 2012;8(7):401–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15(2):192–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Liesz A, Zhou W, Mracskó É, Karcher S, Bauer H, Schwarting S, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain. 2011;134:704–20.PubMedCrossRefGoogle Scholar
  57. 57.
    Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood. 2010;115:3835–42.PubMedCrossRefGoogle Scholar
  58. 58.
    Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation. 2006;113:2105–12.PubMedCrossRefGoogle Scholar
  59. 59.
    Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, et al. T-and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007;27:1798–805.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Subramanian S, Zhang B, Kosaka Y, Burrows GG, Grafe MR, Vandenbark AA, et al. Recombinant T cell receptor ligand (RTL) treats experimental stroke. Stroke. 2009;40(7):2539–45.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Mracsko E, Liesz A, Stojanovic A, Pak-Kin Lou W, Osswald M, Zhou W, et al. Antigen dependently activated cluster of differentiation 8-positive T cells cause perforin-mediated neurotoxicity in experimental stroke. J Neurosci. 2014;34:16784–95.PubMedCrossRefGoogle Scholar
  62. 62.
    Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17–producing gdT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946–50.PubMedCrossRefGoogle Scholar
  63. 63.
    Gelderblom M, Weymar A, Bernreuther C, Velden J, Arunachalam P, Steinbach K, et al. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood. 2012;120:3793–802.PubMedCrossRefGoogle Scholar
  64. 64.
    Luo Y, Zhou Y, Xiao W, Liang Z, Dai J, Weng X, et al. Interleukin-33 ameliorates ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response. Brain Res. 2015;1597:86–94.PubMedCrossRefGoogle Scholar
  65. 65.
    Neumann H, Cavalie A, Jenne DE, Wekerle H. Induction of MHC class I genes in neurons. Science. 1995;269:549–52.PubMedCrossRefGoogle Scholar
  66. 66.
    Lin Y, Zhang J-C, Yao C-Y, Wu Y, Abdelgawad A, Yao S-L, et al. Critical role of astrocytic interleukin-17 A in post-stroke survival and neuronal differentiation of neural precursor cells in adult mice. Cell Death Dis. 2016;7:1–14.CrossRefGoogle Scholar
  67. 67.
    Wang D-D, Zhao Y-F, Wang G-Y, Sun B, Kong Q-F, Zhao K, et al. IL-17 potentiates neuronal injury induced by oxygen–glucose deprivation and affects neuronal IL-17 receptor expression. J Neuroimmunol. 2009;212:17–25.PubMedCrossRefGoogle Scholar
  68. 68.
    Zepp J, Wu L, Li X. IL-17 receptor signaling and Th17-mediated autoimmune demyelinating disease Pathogenic Th17 cells and Autoimmune Diseases. Trends Immunol. 2011;32(5):232–9.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hetman M, Cavanaugh JE, Kimelman D, Xia Z. Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci. 2000;20(7):2567–74.PubMedGoogle Scholar
  70. 70.
    Pap M, Cooper GM. Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta signaling pathway. Mol Cell Biol. 2002;22(2):578–86.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Swardfager W, Winer DA, Herrmann N, Winer S, Lanctôt KL. Interleukin-17 in post-stroke neurodegeneration. Neurosci Biobehav Rev. 2013;37:436–47.PubMedCrossRefGoogle Scholar
  72. 72.
    Liesz A, Hu X, Kleinschnitz C, Offner H. Functional role of regulatory lymphocytes in stroke: facts and controversies. Stroke. 2015 May;46(5):1422–30.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Liesz A, Zhou W, Na S-Y, Hämmerling GJ, Garbi N, Karcher S, et al. Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. J Neurosci. 2013;33(44):17350–62.PubMedCrossRefGoogle Scholar
  74. 74.
    Xie L, Sun F, Wang J, Mao X, Xie L, Yang S-H, et al. mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol. 2014;192(2):6009–19.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Na SY, Mracsko E, Liesz A, Hünig T, Veltkamp R. Amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice. Stroke. 2015;46(1):212–20.PubMedCrossRefGoogle Scholar
  76. 76.
    De Bilbao F, Arsenijevic D, Moll T, Garcia-Gabay I, Vallet P, Langhans W, et al. In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. J Neurochem. 2009;110(1):12–22.PubMedCrossRefGoogle Scholar
  77. 77.
    Kipnis J, Avidan H, Caspi RR, Schwartz M. Dual effect of CD4 regulatory T cells in neurodegeneration: a dialogue with microglia. Proc Natl Acad Sci U S A. 2004;101:14663–9.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Ooboshi H, Ibayashi S, Shichita T, Kumai Y, Takada J, Ago T, et al. Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation. 2005;111(7):913–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Li P, Mao L, Liu X, Gan Y, Zheng J, Thomson AW, et al. Essential role of PD-L1 in regulatory T cell-afforded protection against blood-brain barrier damage after stroke. Stroke. 2014;45(3):857–64.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Gage FH. Mammalian neural stem cells. Science. 2000;287:1433–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Lois C, Alvarez-BuyIIa A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994;264:1145–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 2009;32:149–84.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol. 2002;52:802–13.PubMedCrossRefGoogle Scholar
  84. 84.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–70.PubMedCrossRefGoogle Scholar
  85. 85.
    Hou SW, Wang YQ, Xu M, Shen DH, Wang JJ, Huang F, et al. Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke. 2008;39(10):2837–44.PubMedCrossRefGoogle Scholar
  86. 86.
    Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A. 2006;103(35):13198–202.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Lu P, Jones LL, Snyder EY, Tuszynski MH. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol. 2003;181:115–29.PubMedCrossRefGoogle Scholar
  88. 88.
    Lindvall O, Kokaia Z. Stem cell research in stroke: how far from the clinic? Stroke. 2011;42(8):2369–75.PubMedCrossRefGoogle Scholar
  89. 89.
    Einstein O, Karussis D, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Abramsky O, et al. Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci. 2003;24:1074–82.PubMedCrossRefGoogle Scholar
  90. 90.
    Martino G, Pluchino S. The therapeutic potential of neural stem cells. Nat Rev Neurosci. 2006;7:395–406.PubMedCrossRefGoogle Scholar
  91. 91.
    Schwartz M, Shechter R. Protective autoimmunity functions by intracranial immunosurveillance to support the mind: the missing link between health and disease. Mol Psychiatry. 2010;15:342–54.PubMedCrossRefGoogle Scholar
  92. 92.
    Ron-Harel N, Cardon M, Schwartz M. Brain homeostasis is maintained by “danger” signals stimulating a supportive immune response within the brain’s borders. Brain Behav Immun. 2011;25:1036–43.PubMedCrossRefGoogle Scholar
  93. 93.
    Kokaia Z, Martino G, Schwartz M, Lindvall O. Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci. 2012;15:1078–87.PubMedCrossRefGoogle Scholar
  94. 94.
    Saino O, Taguchi A, Nakagomi T, Nakano-Doi A, Kashiwamura SI, Doe N, et al. Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J Neurosci Res. 2010;88:2385–97.PubMedGoogle Scholar
  95. 95.
    Takata M, Nakagomi T, Kashiwamura S, Nakano-Doi A, Saino O, Nakagomi N, et al. Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke. Cell Death Differ. 2011;19(10):756–67.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Wang J, Xie L, Yang C, Ren C, Zhou K, Wang B, et al. Activated regulatory T cell regulates neural stem cell proliferation in the subventricular zone of normal and ischemic mouse brain through interleukin 10. Front Cell Neurosci. 2015;9(361):1–11.Google Scholar
  97. 97.
    Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M. Activation of microglia by aggregated B-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Biol. 2005;29:381–93.Google Scholar
  98. 98.
    Gudi V, Kuljec JŠ, Yildiz Z, Frichert K, Skripuletz T, Moharregh-Khiabani D, et al. Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming. PLoS One. 2011;6(7):e22623.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149–60.PubMedCrossRefGoogle Scholar
  100. 100.
    Nielsen HH, Toft-Hansen H, Lykke Lambertsen K, Owens T, Finsen B. Stimulation of adult oligodendrogenesis by myelin-specific T cells. Am J Pathol. 2011;179:2028–41.CrossRefGoogle Scholar
  101. 101.
    Wu B, Matic D, Djogo N, Szpotowicz E, Schachner M, Jakovcevski I. Improved regeneration after spinal cord injury in mice lacking functional T- and B-lymphocytes. Exp Neurol. 2012;237:274–85.PubMedCrossRefGoogle Scholar
  102. 102.
    Pool M, Rambaldi I, Darlington PJ, Wright MC, Fournier AE, Bar-Or A. Neurite outgrowth is differentially impacted by distinct immune cell subsets. Mol Cell Neurosci. 2012;49:68–76.PubMedCrossRefGoogle Scholar
  103. 103.
    An C, Shi Y, Li P, Hu X, Gan Y, Stetler RA, et al. Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol. 2014;115:6):6–24.PubMedCrossRefGoogle Scholar
  104. 104.
    Nossent AY, Bastiaansen AJNM, Peters EAB, de Vries MR, Aref Z, Welten SMJ, et al. CCR7-CCL19/CCL21 axis is essential for effective arteriogenesis in a murine model of hindlimb ischemia. J Am Heart Assoc. 2017;6:e005281.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Stabile E, Susan Burnett M, Watkins C, Kinnaird T, Bachis A, La Sala A, et al. Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice. Circulation. 2003;108(2):205–10.PubMedCrossRefGoogle Scholar
  106. 106.
    Albini A, Marchisone C, Del GF, Benelli R, Masiello L, Tacchetti C, et al. Inhibition of angiogenesis and vascular tumor growth by interferon-producing cells. Am J Pathol. 2000;156(4):1381–93.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zhong Q, Jenkins J, Moldobaeva A, D’Alessio F, Wagner EM. Effector T cells and ischemia-induced systemic angiogenesis in the lung. Am J Respir Cell Mol Biol. 2016 Mar;54(3):394–401.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang L-P, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T reg cells. Nature. 2011;475:226–30.PubMedCrossRefGoogle Scholar
  109. 109.
    D’Alessio FR, Zhong Q, Jenkins J, Moldobaeva A, Wagner EM. Lung angiogenesis requires CD4(+) forkhead homeobox protein-3(+) regulatory T cells. Am J Respir Cell Mol Biol. 2015 May;52(5):603–10.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Larsson J, Goumans MJ, Sjöstrand LJ, Van Rooijen MA, Ward D, Levéen P, et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J. 2001;20(7):1663–73.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Wei L-H, Kuo M-L, Chen C-A, Chou C-H, Lai K-B, Lee C-N, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22:1517–27.PubMedCrossRefGoogle Scholar
  112. 112.
    Numasaki M, Fukushi J-I, Ono M, Narula SK, Zavodny PJ, Kudo T, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101(7):2620.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute for Stroke and Dementia Research (ISD)Klinikum der Universität MünchenMunichGermany

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