Perspective | Published:


Promises and limitations of immune cell-based therapies in neurological disorders

Nature Reviews Neurology (2018) | Download Citation


The healthy immune system has natural checkpoints that temper pernicious inflammation. Cells mediating these checkpoints include regulatory T cells, regulatory B cells, regulatory dendritic cells, microglia, macrophages and monocytes. Here, we highlight discoveries on the beneficial functions of regulatory immune cells and their mechanisms of action and evaluate their potential use as novel cell-based therapies for brain disorders. Regulatory immune cell therapies have the potential not only to mitigate the exacerbation of brain injury by inflammation but also to promote an active post-injury brain repair programme. By harnessing the reparative properties of these cells, we can reduce over-reliance on medications that mask clinical symptoms but fail to impede or reverse the progression of brain disorders. Although these discoveries encourage further testing and genetic engineering of regulatory immune cells for the clinical management of neurological disorders, a number of challenges must be surmounted to improve their safety and efficacy in humans.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Hu, X. et al. Microglial and macrophage polarization-new prospects for brain repair. Nat. Rev. Neurol. 11, 56–64 (2015).

  2. 2.

    Fu, Y., Liu, Q., Anrather, J. & Shi, F. D. Immune interventions in stroke. Nat. Rev. Neurol. 11, 524–535 (2015).

  3. 3.

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

  4. 4.

    Li, P. et al. Adoptive regulatory T cell therapy protects against cerebral ischemia. Ann. Neurol. 74, 458–471 (2013).

  5. 5.

    Ren, X. et al. Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J. Neurosci. 31, 8556–8563 (2011).

  6. 6.

    Mohammad, M. G. et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J. Clin. Invest. 124, 1228–1241 (2014).

  7. 7.

    Hu, X. et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43, 3063–3070 (2012).

  8. 8.

    Wang, J. 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. 9, 361 (2015).

  9. 9.

    Dombrowski, Y. et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat. Neurosci. 20, 674–680 (2017).

  10. 10.

    Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).

  11. 11.

    Koutrolos, M., Berer, K., Kawakami, N., Wekerle, H. & Krishnamoorthy, G. Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS. Acta Neuropathol. Commun. 2, 163 (2014).

  12. 12.

    McGeachy, M. J., Stephens, L. A. & Anderton, S. M. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J. Immunol. 175, 3025–3032 (2005).

  13. 13.

    Chi, Y. et al. Novel role of aquaporin-4 in CD4+ CD25+ T regulatory cell development and severity of Parkinson’s disease. Aging Cell 10, 368–382 (2011).

  14. 14.

    Dansokho, C. et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139, 1237–1251 (2016).

  15. 15.

    Zhao, W., Beers, D. R., Liao, B., Henkel, J. S. & Appel, S. H. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol. Dis. 48, 418–428 (2012).

  16. 16.

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

  17. 17.

    Kleinschnitz, C. et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood 121, 679–691 (2013).

  18. 18.

    Tullius, S. G. et al. NAD+ protects against EAE by regulating CD4+ T cell differentiation. Nat. Commun. 5, 5101 (2014).

  19. 19.

    Kleinschnitz, C. et al. Early detrimental T cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115, 3835–3842 (2010).

  20. 20.

    Shichita, T. et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat. Med. 15, 946–950 (2009).

  21. 21.

    Gelderblom, M. et al. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood 120, 3793–3802 (2012).

  22. 22.

    Shevach, E. M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

  23. 23.

    Gondek, D. C. et al. Transplantation survival is maintained by granzyme B+ regulatory cells and adaptive regulatory T cells. J. Immunol. 181, 4752–4760 (2008).

  24. 24.

    Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

  25. 25.

    Garin, M. I. et al. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109, 2058–2065 (2007).

  26. 26.

    Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

  27. 27.

    Read, S. et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177, 4376–4383 (2006).

  28. 28.

    Sauer, A. V. et al. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood 119, 1428–1439 (2012).

  29. 29.

    Andre, S., Tough, D. F., Lacroix-Desmazes, S., Kaveri, S. V. & Bayry, J. Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications. Am. J. Pathol. 174, 1575–1587 (2009).

  30. 30.

    Ghiringhelli, F. et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J. Exp. Med. 202, 1075–1085 (2005).

  31. 31.

    Zhou, K. et al. Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3beta/PTEN axis. J. Cereb. Blood Flow Metab. 37, 967–979 (2017).

  32. 32.

    Mao, L. et al. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain 140, 1914–1931 (2017).

  33. 33.

    Saino, O. et al. Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J. Neurosci. Res. 88, 2385–2397 (2010).

  34. 34.

    Pang, X. & Qian, W. Changes in regulatory T-cell levels in acute cerebral ischemia. J. Neurol. Surg. A Cent. Eur. Neurosurg. 78, 374–379 (2017).

  35. 35.

    Golshayan, D. et al. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood 109, 827–835 (2007).

  36. 36.

    Zhang, H. et al. Sequential monitoring and stability of ex vivo-expanded autologous and nonautologous regulatory T cells following infusion in nonhuman primates. Am. J. Transplant. 15, 1253–1266 (2015).

  37. 37.

    Hippen, K. L. et al. Umbilical cord blood regulatory T cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells. Blood 112, 2847–2857 (2008).

  38. 38.

    Dijke, I. E. et al. Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells. Am. J. Transplant 16, 58–71 (2016).

  39. 39.

    Shevach, E. M. Application of IL-2 therapy to target T regulatory cell function. Trends Immunol. 33, 626–632 (2012).

  40. 40.

    Kim, B. S. et al. Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. Blood 126, 546–557 (2015).

  41. 41.

    Biswas, M. et al. Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4+CD25+FoxP3+ Treg. Blood 125, 2937–2947 (2015).

  42. 42.

    Clemente-Casares, X. et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434–440 (2016).

  43. 43.

    Kasagi, S. et al. In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response. Sci. Transl Med. 6, 241ra78 (2014).

  44. 44.

    MacDonald, K. G. et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J. Clin. Invest. 126, 1413–1424 (2016).

  45. 45.

    Yoon, J. et al. FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T and B cell responses to FVIII. Blood 129, 238–245 (2017).

  46. 46.

    Fransson, M. et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J. Neuroinflammation 9, 112 (2012).

  47. 47.

    Matsushita, T., Yanaba, K., Bouaziz, J. D., Fujimoto, M. & Tedder, T. F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 118, 3420–3430 (2008).

  48. 48.

    Matsushita, T., Horikawa, M., Iwata, Y. & Tedder, T. F. Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis. J. Immunol. 185, 2240–2252 (2010).

  49. 49.

    Lundy, S. K. et al. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B cell subsets. Neurol. Neuroimmunol. Neuroinflamm. 3, e211 (2016).

  50. 50.

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

  51. 51.

    Ray, A., Basu, S., Williams, C. B., Salzman, N. H. & Dittel, B. N. A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J. Immunol. 188, 3188–3198 (2012).

  52. 52.

    Lee, K. M. et al. TGF-beta-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. Eur. J. Immunol. 44, 1728–1736 (2014).

  53. 53.

    Korniotis, S. et al. Treatment of ongoing autoimmune encephalomyelitis with activated B cell progenitors maturing into regulatory B cells. Nat. Commun. 7, 12134 (2016).

  54. 54.

    Hori, S., Haury, M., Coutinho, A. & Demengeot, J. Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc. Natl Acad. Sci. USA 99, 8213–8218 (2002).

  55. 55.

    Matsumoto, M. et al. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34, 703–714 (2011).

  56. 56.

    Yu, P. et al. Specific T regulatory cells display broad suppressive functions against experimental allergic encephalomyelitis upon activation with cognate antigen. J. Immunol. 174, 6772–6780 (2005).

  57. 57.

    Miyao, T. et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262–275 (2012).

  58. 58.

    Chen, W. J. et al. Human umbilical vein endothelial cells promote the inhibitory activation of CD4(+)CD25(+)Foxp3(+) regulatory T cells via PD-L1. Atherosclerosis 244, 108–112 (2016).

  59. 59.

    Bedke, T., Pretsch, L., Karakhanova, S., Enk, A. H. & Mahnke, K. Endothelial cells augment the suppressive function of CD4+ CD25+ Foxp3+ regulatory T cells: involvement of programmed death-1 and IL-10. J. Immunol. 184, 5562–5570 (2010).

  60. 60.

    Taflin, C. et al. Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions. Proc. Natl Acad. Sci. USA 108, 2891–2896 (2011).

  61. 61.

    Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 10, 1178–1184 (2009).

  62. 62.

    Gabrysova, L. et al. Integrated T cell receptor and costimulatory signals determine TGF-beta-dependent differentiation and maintenance of Foxp3+ regulatory T cells. Eur. J. Immunol. 41, 1242–1248 (2011).

  63. 63.

    Korn, T. et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc. Natl Acad. Sci. USA 105, 18460–18465 (2008).

  64. 64.

    Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014).

  65. 65.

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

  66. 66.

    Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).

  67. 67.

    Bailey-Bucktrout, S. L. et al. Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. J. Immunol. 180, 6457–6461 (2008).

  68. 68.

    Irla, M. et al. MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity. J. Exp. Med. 207, 1891–1905 (2010).

  69. 69.

    Obregon, C., Kumar, R., Pascual, M. A., Vassalli, G. & Golshayan, D. Update on dendritic cell-induced immunological and clinical tolerance. Front. Immunol. 8, 1514 (2017).

  70. 70.

    Raich-Regue, D., Glancy, M. & Thomson, A. W. Regulatory dendritic cell therapy: from rodents to clinical application. Immunol. Lett. 161, 216–221 (2014).

  71. 71.

    Getts, D. R. et al. Microparticles bearing encephalitogenic peptides induce T cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nat. Biotechnol. 30, 1217–1224 (2012).

  72. 72.

    Maldonado, R. A. et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc. Natl Acad. Sci. USA 112, E156–E165 (2015).

  73. 73.

    Terness, P. et al. Mitomycin C-treated dendritic cells inactivate autoreactive T cells: toward the development of a tolerogenic vaccine in autoimmune diseases. Proc. Natl Acad. Sci. USA 105, 18442–18447 (2008).

  74. 74.

    Hirata, S. et al. Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand. J. Immunol. 174, 1888–1897 (2005).

  75. 75.

    Maus, M. V. et al. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 32, 189–225 (2014).

  76. 76.

    Lin, Y. & Okada, H. Cellular immunotherapy for malignant gliomas. Expert Opin. Biol. Ther. 16, 1265–1275 (2016).

  77. 77.

    Kumar, A. A., Kumar, S. R., Narayanan, R., Arul, K. & Baskaran, M. Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: a phase I/II clinical safety and primary efficacy data. Exp. Clin. Transplant. 7, 241–248 (2009).

  78. 78.

    Martinez, H. R. et al. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy 11, 26–34 (2009).

  79. 79.

    Rosado-de-Castro, P. H., de Carvalho, F. G., de Freitas, G. R., Mendez-Otero, R. & Pimentel-Coelho, P. M. Review of preclinical and clinical studies of bone marrow-derived cell therapies for intracerebral hemorrhage. Stem Cells Int. 2016, 4617983 (2016).

  80. 80.

    Sharma, A. et al. A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier. Stem Cells Int. 2015, 905874 (2015).

  81. 81.

    Bhasin, A. et al. Autologous intravenous mononuclear stem cell therapy in chronic ischemic stroke. J. Stem Cells Regen. Med. 8, 181–189 (2012).

  82. 82.

    Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

  83. 83.

    Li, P. et al. Essential role of program death 1-ligand 1 in regulatory T cell-afforded protection against blood-brain barrier damage after stroke. Stroke 45, 857–864 (2014).

  84. 84.

    Singh, V. et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J. Neurosci. 36, 7428–7440 (2016).

  85. 85.

    Trzonkowski, P. et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin. Immunol. 133, 22–26 (2009).

  86. 86.

    Riley, J. L., June, C. H. & Blazar, B. R. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30, 656–665 (2009).

  87. 87.

    Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl Med. 7, 315ra189 (2015).

  88. 88.

    Brunstein, C. G. et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117, 1061–1070 (2011).

  89. 89.

    Theil, A. et al. Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Cytotherapy 17, 473–486 (2015).

  90. 90.

    Alsuliman, A. et al. A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. Cytotherapy 18, 1312–1324 (2016).

  91. 91.

    Eliseeva, D. D. et al. [The treatment by expanded ex vivo autologous regulatory T cells CD4+CD25+FoxP3+CD127low restores the balance of immune system in patients with remitting-relapsing multiple sclerosis]. Zh. Nevrol. Psikhiatr Im S. S. Korsakova 116, 54–62 (2016).

  92. 92.

    Romano, M., Tung, S. L., Smyth, L. A. & Lombardi, G. Treg therapy in transplantation: a general overview. Transpl. Int. 30, 745–753 (2016).

  93. 93.

    Lindner, S. et al. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res. 73, 2468–2479 (2013).

  94. 94.

    Dhodapkar, M. V., Steinman, R. M., Krasovsky, J., Munz, C. & Bhardwaj, N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238 (2001).

  95. 95.

    Benham, H. et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci. Transl Med. 7, 290ra87 (2015).

  96. 96.

    Raiotach-Regue, D. et al. Stable antigen-specific T cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. Eur. J. Immunol. 42, 771–782 (2012).

  97. 97.

    Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

  98. 98.

    Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).

  99. 99.

    Tey, S. K. Adoptive T cell therapy: adverse events and safety switches. Clin. Transl Immunology 3, e17 (2014).

  100. 100.

    Seifert, H. A. et al. Sex differences in regulatory cells in experimental stroke. Cell. Immunol. 318, 49–54 (2017).

  101. 101.

    Garg, S. K. et al. Aging is associated with increased regulatory T cell function. Aging Cell 13, 441–448 (2014).

  102. 102.

    Walsh, J. T. & Kipnis, J. Regulatory T cells in CNS injury: the simple, the complex and the confused. Trends Mol. Med. 17, 541–547 (2011).

  103. 103.

    Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl Acad. Sci. USA 106, 1903–1908 (2009).

  104. 104.

    Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

  105. 105.

    Gol-Ara, M., Jadidi-Niaragh, F., Sadria, R., Azizi, G. & Mirshafiey, A. The role of different subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis. Arthritis 2012, 805875 (2012).

  106. 106.

    Zohar, Y. et al. CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis. J. Clin. Invest. 124, 2009–2022 (2014).

  107. 107.

    Akane, K., Kojima, S., Mak, T. W., Shiku, H. & Suzuki, H. CD8+CD122+CD49dlow regulatory T cells maintain T cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity. Proc. Natl Acad. Sci. USA 113, 2460–2465 (2016).

  108. 108.

    Dai, H. et al. Cutting edge: programmed death-1 defines CD8+CD122+ T cells as regulatory versus memory T cells. J. Immunol. 185, 803–807 (2010).

  109. 109.

    Iwata, Y. et al. Characterization of a rare IL-10-competent B cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530–541 (2011).

  110. 110.

    Blair, P. A. et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 32, 129–140 (2010).

  111. 111.

    Yan, J. et al. Frequency and function of regulatory T cells after ischaemic stroke in humans. J. Neuroimmunol. 243, 89–94 (2012).

  112. 112.

    Chan, A., Yan, J., Csurhes, P., Greer, J. & McCombe, P. Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: effect on outcome. J. Neuroimmunol. 286, 42–47 (2015).

  113. 113.

    Yan, J. et al. Immune activation in the peripheral blood of patients with acute ischemic stroke. J. Neuroimmunol. 206, 112–117 (2009).

  114. 114.

    Huan, J. et al. Decreased FOXP3 levels in multiple sclerosis patients. J. Neurosci. Res. 81, 45–52 (2005).

  115. 115.

    Pellicano, M. et al. Immune profiling of Alzheimer patients. J. Neuroimmunol. 242, 52–59 (2012).

  116. 116.

    Saunders, J. A. et al. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharmacol. 7, 927–938 (2012).

  117. 117.

    Rosenkranz, D. et al. Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J. Neuroimmunol. 188, 117–127 (2007).

  118. 118.

    Mikulkova, Z., Praksova, P., Stourac, P., Bednarik, J. & Michalek, J. Imbalance in T cell and cytokine profiles in patients with relapsing-remitting multiple sclerosis. J. Neurol. Sci. 300, 135–141 (2011).

  119. 119.

    Beers, D. R. et al. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2, e89530 (2017).

  120. 120.

    Henkel, J. S. et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol. Med. 5, 64–79 (2013).

  121. 121.

    Pelidou, S. H. et al. High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. Eur. J. Neurol. 6, 437–442 (1999).

  122. 122.

    Huang, W. et al. Identification of distinct monocyte phenotypes and correlation with circulating cytokine profiles in acute response to spinal cord injury: a pilot study. PM R. 6, 332–341 (2014).

  123. 123.

    Cho, K. Y. et al. The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J. Stroke Cerebrovasc. Dis. 22, 910–918 (2013).

  124. 124.

    Li, P. et al. C-C chemokine receptor type 5 (CCR5)-mediated docking of transferred Tregs protects against early blood-brain barrier disruption after stroke. J. Am. Heart Assoc. 6, e006387 (2017).

  125. 125.

    Li, P. et al. Adoptive regulatory T cell therapy preserves systemic immune homeostasis after cerebral ischemia. Stroke 44, 3509–3515 (2013).

  126. 126.

    Brea, D. et al. Regulatory T cells modulate inflammation and reduce infarct volume in experimental brain ischaemia. J. Cell. Mol. Med. 18, 1571–1579 (2014).

  127. 127.

    Kohm, A. P., Carpentier, P. A., Anger, H. A. & Miller, S. D. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169, 4712–4716 (2002).

  128. 128.

    Zhang, X. et al. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int. Immunol. 16, 249–256 (2004).

  129. 129.

    Mao, L. L. et al. Adoptive regulatory T cell therapy attenuates perihematomal inflammation in a mouse model of experimental intracerebral hemorrhage. Cell. Mol. Neurobiol. 37, 919–929 (2017).

  130. 130.

    Wang, Y. et al. Adoptive regulatory T cell therapy attenuates subarachnoid hemor-rhage-induced cerebral inflammation by suppressing TLR4/NF-B signaling pathway. Curr. Neurovasc. Res. 13, 121–126 (2016).

  131. 131.

    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).

  132. 132.

    Reynolds, A. D. et al. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J. Immunol. 184, 2261–2271 (2010).

  133. 133.

    Bodhankar, S., Chen, Y., Vandenbark, A. A., Murphy, S. J. & Offner, H. IL-10-producing B cells limit CNS inflammation and infarct volume in experimental stroke. Metab. Brain Dis. 28, 375–386 (2013).

  134. 134.

    Bodhankar, S. et al. Regulatory CD8(+)CD122 (+) T cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B cells. Metab. Brain Dis. 30, 911–924 (2015).

  135. 135.

    Bodhankar, S., Chen, Y., Vandenbark, A. A., Murphy, S. J. & Offner, H. Treatment of experimental stroke with IL-10-producing B cells reduces infarct size and peripheral and CNS inflammation in wild-type B cell-sufficient mice. Metab. Brain Dis. 29, 59–73 (2014).

  136. 136.

    Chen, Y. et al. Intrastriatal B cell administration limits infarct size after stroke in B cell deficient mice. Metab. Brain Dis. 27, 487–493 (2012).

  137. 137.

    Pennati, A. et al. Regulatory B cells induce formation of IL-10-expressing T cells in mice with autoimmune neuroinflammation. J. Neurosci. 36, 12598–12610 (2016).

Download references


X.H. is supported by grants from the US National Institutes of Health (NIH) (NS094573 and NS092618). R.K.L. is supported by the NIH (1R15NS093539). A.W.T. is supported by the NIH (1R01AI118777 and U19AI131453). J.C. is supported by grants from the NIH (NS105430, NS095671, NS095029 and NS089534), the US Veterans Affairs (VA) Merit Review awards (I01BX003377 and I01BX002495) and the VA Senior Research Career Scientist Award.

Author information


  1. Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    • Xiaoming Hu
    • , Fang Yu
    • , Yuguo Xia
    • , Lawrence R. Wechsler
    •  & Jun Chen
  2. Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA

    • Rehana K. Leak
  3. Starzl Transplantation Institute, Department of Surgery and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    • Angus W. Thomson


  1. Search for Xiaoming Hu in:

  2. Search for Rehana K. Leak in:

  3. Search for Angus W. Thomson in:

  4. Search for Fang Yu in:

  5. Search for Yuguo Xia in:

  6. Search for Lawrence R. Wechsler in:

  7. Search for Jun Chen in:


All authors contributed to the review and editing of the manuscript before submission. X.H., R.K.L., A.W.T., F.Y., Y.X. and J.C. researched and wrote the article. X.H., R.K.L., A.W.T. and J.C. contributed substantially to the discussion of content.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jun Chen.

About this article

Publication history