Skip to main content

Advertisement

SpringerLink
Log in

T Cells and Cerebral Ischemic Stroke

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Stroke results in cerebral inflammation that causes brain injury and triggers immunodepression, resulting in an increased incidence of morbidity and mortality secondary to remote infection. It is well known that T cells modulate brain inflammation after ischemic stroke, and targeting T cells may be an innovative therapeutic strategy for stroke treatment. T cell deficiency is neuro-protective, but the observed protective effects differ between ischemic models. Recent studies suggest different T cell subsets may have distinct effects on the injured brain. In addition to their role in cerebral inflammation, T cells also play a role in stroke-induced immunodepression. Therefore, T cell-targeted therapies designed to provide protection against brain inflammation might paradoxically contribute to remote organ infection and mortality. Further investigations are required to determine the role of specific T cell subsets in cerebral inflammation and stroke-induced immunodepression, the optimal therapeutic window for treatment, and the appropriate dose of anti-T cell therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Chamorro A, Hallenbeck J (2006) The harms and benefits of inflammatory and immune responses in vascular disease. Stroke 37(2):291–293

    Article  PubMed Central  PubMed  Google Scholar 

  2. Samson Y, Lapergue B, Hosseini H (2005) Inflammation and ischaemic stroke: current status and future perspectives. Rev Neurol (Paris) 161(12 Pt 1):1177–1182

    Article  CAS  Google Scholar 

  3. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184(1–2):53–68

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, Austinat M, Nieswandt B, Wiendl H, Stoll G (2010) Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115(18):3835–3842

    Article  CAS  PubMed  Google Scholar 

  5. Yilmaz G, Arumugam TV, Stokes KY, Granger DN (2006) Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 113(17):2105–2112

    Article  PubMed  Google Scholar 

  6. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15(2):192–199

    Article  CAS  PubMed  Google Scholar 

  7. Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, Offner H (2007) T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab 27(11):1798–1805

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Hedrick SM (2002) T cell development: bottoms-up. Immunity 16(5):619–622

    Article  CAS  PubMed  Google Scholar 

  9. Stockinger B, Bourgeois C, Kassiotis G (2006) CD4 + memory T cells: functional differentiation and homeostasis. Immunol Rev 211:39–48

    Article  CAS  PubMed  Google Scholar 

  10. King C, Tangye SG, Mackay CR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26:741–766

    Article  CAS  PubMed  Google Scholar 

  11. Inatsu A, Kogiso M, Jeschke MG, Asai A, Kobayashi M, Herndon DN, Suzuki F (2011) Lack of Th17 cell generation in patients with severe burn injuries. J Immunol 187(5):2155–2161

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Heizmann O, Koeller M, Muhr G, Oertli D, Schinkel C (2008) Th1- and Th2-type cytokines in plasma after major trauma. J Trauma 65(6):1374–1378

    Article  CAS  PubMed  Google Scholar 

  13. Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607–656

    Article  CAS  PubMed  Google Scholar 

  14. Kono DH, Balomenos D, Pearson DL, Park MS, Hildebrandt B, Hultman P, Pollard KM (1998) The prototypic Th2 autoimmunity induced by mercury is dependent on IFN-gamma and not Th1/Th2 imbalance. J Immunol 161(1):234–240

    CAS  PubMed  Google Scholar 

  15. Steinke JW, Borish L (2001) Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res 2(2):66–70

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Lee MKT, Moore DJ, Chiaccio M, Lian MM, Deng S, Mohiuddin M, Huang X, Koeberlein B, Zakheim A, Porrett PM, Barker CF, Caton AJ, Markmann JF (2006) T-reg mediated suppression of the allograft response in the draining lymph node. Transplantation 81(7):1063–1066

    Article  PubMed  Google Scholar 

  17. van Santen HM, Benoist C, Mathis D (2004) Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J Exp Med 200(10):1221–1230

    Article  PubMed Central  PubMed  Google Scholar 

  18. Webster KE, Walters S, Kohler RE, Mrkvan T, Boyman O, Surh CD, Grey ST, Sprent J (2009) In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 206(4):751–760

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2(6):401–409

    CAS  PubMed  Google Scholar 

  20. Russell JH, Ley TJ (2002) Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20:323–370

    Article  CAS  PubMed  Google Scholar 

  21. Deng H, Han HS, Cheng D, Sun GH, Yenari MA (2003) Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke 34(10):2495–2501

    Article  PubMed  Google Scholar 

  22. Harris AK, Ergul A, Kozak A, Machado LS, Johnson MH, Fagan SC (2005) Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke. BMC Neurosci 6:49

    Article  PubMed Central  PubMed  Google Scholar 

  23. Huisse MG, Pease S, Hurtado-Nedelec M, Arnaud B, Malaquin C, Wolff M, Gougerot-Pocidalo MA, Kermarrec N, Bezeaud A, Guillin MC, Paoletti X, Chollet-Martin S (2008) Leukocyte activation: the link between inflammation and coagulation during heatstroke. A study of patients during the 2003 heat wave in Paris. Crit Care Med 36(8):2288–2295

    Article  CAS  PubMed  Google Scholar 

  24. Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40(5):1849–1857

    Article  PubMed  Google Scholar 

  25. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Denker SP, Ji S, Dingman A, Lee SY, Derugin N, Wendland MF, Vexler ZS (2007) Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem 100(4):893–904

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G (1995) Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 15(1):42–51

    Article  CAS  PubMed  Google Scholar 

  28. Campanella M, Sciorati C, Tarozzo G, Beltramo M (2002) Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 33(2):586–592

    Article  PubMed  Google Scholar 

  29. Stevens SL, Bao J, Hollis J, Lessov NS, Clark WM, Stenzel-Poore MP (2002) The use of flow cytometry to evaluate temporal changes in inflammatory cells following focal cerebral ischemia in mice. Brain Res 932(1–2):110–119

    Article  CAS  PubMed  Google Scholar 

  30. Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE, Guida E, Broughton BR, Drummond GR, Sobey CG (2010) Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 30(7):1306–1317

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Deng G, Carter J, Traystman RJ, Wagner DH, Herson PS (2014) Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation. J Neuroimmunol 274(1–2):132–140

    Article  CAS  PubMed  Google Scholar 

  32. Gu L, Xiong X, Wei D, Gao X, Krams S, Zhao H (2013) T cells contribute to stroke-induced lymphopenia in rats. PLoS One 8(3):e59602

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Gu LJ, Xiong XX, Ito T, Lee J, Xu BH, Krams S, Steinberg GK, Zhao H (2014) Moderate hypothermia inhibits brain inflammation and attenuates stroke-induced immunodepression in rats. CNS Neurosci Ther 20(1):67–75

    Article  CAS  PubMed  Google Scholar 

  34. Brecht S, Schwarze K, Waetzig V, Christner C, Heiland S, Fischer G, Sartor K, Herdegen T (2003) Changes in peptidyl-prolyl cis/trans isomerase activity and FK506 binding protein expression following neuroprotection by FK506 in the ischemic rat brain. Neuroscience 120(4):1037–1048

    Article  CAS  PubMed  Google Scholar 

  35. Xiong X, Gu L, Zhang H, Xu B, Zhu S, Zhao H (2013) The protective effects of T cell deficiency against brain injury are ischemic model-dependent in rats. Neurochem Int 62(3):265–270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Xiong X, Barreto GE, Xu L, Ouyang YB, Xie X, Giffard RG (2011) Increased brain injury and worsened neurological outcome in interleukin-4 knockout mice after transient focal cerebral ischemia. Stroke 42(7):2026–2032

    Article  PubMed Central  PubMed  Google Scholar 

  37. Gu L, Xiong X, Zhang H, Xu B, Steinberg GK, Zhao H (2012) Distinctive effects of T cell subsets in neuronal injury induced by cocultured splenocytes in vitro and by in vivo stroke in mice. Stroke 43(7):1941–1946

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Vogelgesang A, Dressel A (2011) Immunological consequences of ischemic stroke: immunosuppression and autoimmunity. J Neuroimmunol 231(1–2):105–110

    Article  CAS  PubMed  Google Scholar 

  39. Czlonkowska A, Cyrta B, Korlak J (1979) Immunological observations on patients with acute cerebral vascular disease. J Neurol Sci 43(3):455–464

    Article  CAS  PubMed  Google Scholar 

  40. Offner H, Subramanian S, Parker SM, Wang C, Afentoulis ME, Lewis A, Vandenbark AA, Hurn PD (2006) Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol 176(11):6523–6531

    Article  CAS  PubMed  Google Scholar 

  41. Offner H, Vandenbark AA, Hurn PD (2009) Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience 158(3):1098–1111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Haeusler KG, Schmidt WU, Fohring F, Meisel C, Helms T, Jungehulsing GJ, Nolte CH, Schmolke K, Wegner B, Meisel A, Dirnagl U, Villringer A, Volk HD (2008) Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis 25(1–2):50–58

    Article  CAS  PubMed  Google Scholar 

  43. Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, Halle E, Volk HD, Dirnagl U, Meisel A (2004) Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke 35(1):2–6

    Article  CAS  PubMed  Google Scholar 

  44. Sarrafzadeh A, Schlenk F, Meisel A, Dreier J, Vajkoczy P, Meisel C (2011) Immunodepression after aneurysmal subarachnoid hemorrhage. Stroke 42(1):53–58

    Article  PubMed  Google Scholar 

  45. Gendron A, Teitelbaum J, Cossette C, Nuara S, Dumont M, Geadah D, du Souich P, Kouassi E (2002) Temporal effects of left versus right middle cerebral artery occlusion on spleen lymphocyte subsets and mitogenic response in Wistar rats. Brain Res 955(1–2):85–97

    Article  CAS  PubMed  Google Scholar 

  46. Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A (2003) Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med 198(5):725–736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Liesz A, Hagmann S, Zschoche C, Adamek J, Zhou W, Sun L, Hug A, Zorn M, Dalpke A, Nawroth P, Veltkamp R (2009) The spectrum of systemic immune alterations after murine focal ischemia: immunodepression versus immunomodulation. Stroke 40(8):2849–2858

    Article  CAS  PubMed  Google Scholar 

  48. Vogelgesang A, Grunwald U, Langner S, Jack R, Broker BM, Kessler C, Dressel A (2008) Analysis of lymphocyte subsets in patients with stroke and their influence on infection after stroke. Stroke 39(1):237–241

    Article  PubMed  Google Scholar 

  49. Urra X, Cervera A, Villamor N, Planas AM, Chamorro A (2009) Harms and benefits of lymphocyte subpopulations in patients with acute stroke. Neuroscience 158(3):1174–1183

    Article  CAS  PubMed  Google Scholar 

  50. Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagl U, Meisel A, Meisel C (2009) Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience 158(3):1184–1193

    Article  CAS  PubMed  Google Scholar 

  51. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U (2005) Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 6(10):775–786

    Article  CAS  PubMed  Google Scholar 

  52. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P (2011) Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334(6052):101–105

    Article  CAS  PubMed  Google Scholar 

  53. Prass K, Braun JS, Dirnagl U, Meisel C, Meisel A (2006) Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia. Stroke 37(10):2607–2612

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81301019) and an American Heart Association award 14FTF19970029 to CMS.

Author information

Author notes

    Authors and Affiliations

    1. Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

      Lijuan Gu & Xiaoxing Xiong

    2. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

      Zhihong Jian & Xiaoxing Xiong

    3. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA

      Creed Stary

    Authors
    1. Lijuan Gu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zhihong Jian
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Creed Stary
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiaoxing Xiong
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Xiaoxing Xiong.

    Ethics declarations

    Conflict of interest

    The authors have no conflict of interest.

    Additional information

    Lijuan Gu and Zhihong Jian have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Gu, L., Jian, Z., Stary, C. et al. T Cells and Cerebral Ischemic Stroke. Neurochem Res 40, 1786–1791 (2015). https://doi.org/10.1007/s11064-015-1676-0

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11064-015-1676-0

    Keywords

    Search

    Navigation