Journal of Molecular Medicine

, Volume 82, Issue 6, pp 364–372 | Cite as

Astrocytes protect the CNS: antigen-specific T helper cell responses are inhibited by astrocyte-induced upregulation of CTLA-4 (CD152)

  • Ulrike Gimsa
  • Anita Øren
  • Pushpa Pandiyan
  • Daniela Teichmann
  • Ingo Bechmann
  • Robert Nitsch
  • Monika C. Brunner-Weinzierl
Original Article

Abstract

Astrocytes are the first cells that are encountered by T cells invading the central nervous system (CNS) by crossing the blood-brain barrier. We show that primary astrocytes contribute to the immune privilege of the CNS by suppressing Th1 and Th2 cell activation, proliferation and effector function. Moreover, this astrocyte-mediated inhibition of Th effector cells was effective on already activated, proliferating cells. Transforming growth factor (TGF)-β secreted by astrocytes or T cells was not the major factor in the inhibition. The inhibition of T-cell proliferation induced by astrocytes was mainly mediated by upregulation of CTLA-4 on already activated T cells, which occurred both with and without cell-cell contact. Upregulation of the inhibitory molecule CTLA-4 on autoreactive Th cells, as mediated by astrocytes, thus represents a novel mechanism for securing the immune privilege of the CNS.

Keywords

Transgenic mice Lymphocyte activation Neuroimmunomodulation Immune privilege 

Notes

Acknowledgements

The authors thank David C. Wraith, University of Bristol, for providing MBP-TCR transgenic mice. We are most grateful to N. Avrion Mitchison, University College London, for critical reading of the manuscript and fruitful discussions. The authors thank Jan Gimsa, University of Rostock, and Asle Sudbø, Norwegian University of Science and Technology, for discussion of the manuscript. Arndt Rolfs, University of Rostock, and Gerd.-R. Burmester, Charité University Hospital (Berlin), are acknowledged for their generous support and helpful discussion. This work was supported by the Gemeinnützige Hertie-Stiftung (1.319.110-01-04 and 191/00/15), the Bundesministerium für Bildung und Forschung (01 ZZ 0108), and the Deutsche Forschungsgemeinschaft SFB 507/B11 and BR 1860/3.

References

  1. 1.
    Haydon PG (2001) Glia: listening and talking to the synapse. Nat Rev Neurosci 2:185–193CrossRefPubMedGoogle Scholar
  2. 2.
    Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295:2282–2285CrossRefPubMedGoogle Scholar
  3. 3.
    Villoslada P, Hauser SL, Bartke I, Unger J, Heald N, Rosenberg D, Cheung SW, Mobley WC, Fisher S, Genain CP (2000) Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 191:1799–1806CrossRefPubMedGoogle Scholar
  4. 4.
    Flügel A, Matsumuro K, Neumann H, Klinkert WE, Birnbacher R, Lassmann H, Otten U, Wekerle H (2001) Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur J Immunol 31:11–22CrossRefPubMedGoogle Scholar
  5. 5.
    Tuszynski MH (2000) Intraparenchymal NGF infusions rescue degenerating cholinergic neurons. Cell Transplant 9:629–636PubMedGoogle Scholar
  6. 6.
    Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350:230–232PubMedGoogle Scholar
  7. 7.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedGoogle Scholar
  8. 8.
    Aloisi F, Ria F, Adorini L (2000) Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol Today 21:141–147PubMedGoogle Scholar
  9. 9.
    Soos JM, Morrow J, Ashley TA, Szente BE, Bikoff EK, Zamvil SS (1998) Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigens for presentation to encephalitogenic T cells. J Immunol 161:5959–5966PubMedGoogle Scholar
  10. 10.
    Tan L, Gordon KB, Mueller JP, Matis LA, Miller SD (1998) Presentation of proteolipid protein epitopes and B7–1-dependent activation of encephalitogenic T cells by IFN-gamma-activated SJL/J astrocytes. J Immunol 160:4271–4279PubMedGoogle Scholar
  11. 11.
    Aloisi F, Ria F, Penna G, Adorini L (1998) Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation. J Immunol 160:4671–4680PubMedGoogle Scholar
  12. 12.
    Aloisi F, Penna G, Cerase J, Menendez Iglesias B, Adorini L (1997) IL-12 production by central nervous system microglia is inhibited by astrocytes. J Immunol 159:1604–1612PubMedGoogle Scholar
  13. 13.
    Aloisi F, Penna G, Polazzi E, Minghetti L, Adorini L (1999) CD40-CD154 interaction and IFN-gamma are required for IL-12 but not prostaglandin E2 secretion by microglia during antigen presentation to Th1 cells. J Immunol 162:1384–1391PubMedGoogle Scholar
  14. 14.
    O’Banion MK, Miller JC, Chang JW, Kaplan MD, Coleman PD (1996) Interleukin-1 beta induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murine astrocyte cultures. J Neurochem 66:2532–2540PubMedGoogle Scholar
  15. 15.
    Palma C, Minghetti L, Astolfi M, Ambrosini E, Silberstein FC, Manzini S, Levi G, Aloisi F (1997) Functional characterization of substance P receptors on cultured human spinal cord astrocytes: synergism of substance P with cytokines in inducing interleukin-6 and prostaglandin E2 production. Glia 21:183–193CrossRefPubMedGoogle Scholar
  16. 16.
    Meinl E, Aloisi F, Ertl B, Weber F, de Waal MR, Wekerle H, Hohlfeld R (1994) Multiple sclerosis. Immunomodulatory effects of human astrocytes on T cells. Brain 117: 1323–1332PubMedGoogle Scholar
  17. 17.
    Weber F, Meinl E, Aloisi F, Nevinny-Stickel C, Albert E, Wekerle H, Hohlfeld R (1994) Human astrocytes are only partially competent antigen presenting cells. Possible implications for lesion development in multiple sclerosis. Brain 117: 59–69PubMedGoogle Scholar
  18. 18.
    Chambers CA, Krummel MF, Boitel B, Hurwitz A, Sullivan TJ, Fournier S, Cassell D, Brunner M, Allison JP (1996) The role of CTLA-4 in the regulation and initiation of T-cell responses. Immunol Rev 153:27–46PubMedGoogle Scholar
  19. 19.
    Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3:611–618CrossRefPubMedGoogle Scholar
  20. 20.
    Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP (1999) CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 162:5813–5820PubMedGoogle Scholar
  21. 21.
    Maszyna F, Hoff H, Kunkel D, Radbruch A, Brunner-Weinzierl MC (2003) Diversity of clonal T cell proliferation is mediated by differential expression of CD152 (CTLA-4) on the cell surface of activated individual T lymphocytes. J Immunol 171:3459–3466PubMedGoogle Scholar
  22. 22.
    Martin M, Schneider H, Azouz A, Rudd CE (2001) Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function. J Exp Med 194:1675–1681CrossRefPubMedGoogle Scholar
  23. 23.
    Chen W, Jin W, Wahl SM (1998) Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. J Exp Med 188:1849–1857CrossRefPubMedGoogle Scholar
  24. 24.
    Sullivan TJ, Letterio JJ, van Elsas A, Mamura M, van Amelsfort J, Sharpe S, Metzler B, Chambers CA, Allison JP (2001) Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation. Proc Natl Acad Sci USA 98:2587–2592CrossRefPubMedGoogle Scholar
  25. 25.
    Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA (1996) CTLA-4: a negative regulator of autoimmune disease. J Exp Med 184:783–788PubMedGoogle Scholar
  26. 26.
    Hurwitz AA, Sullivan TJ, Sobel RA, Allison JP (2002) Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice. Proc Natl Acad Sci USA 99:3013–3017CrossRefPubMedGoogle Scholar
  27. 27.
    Oliveira EM, Bar-Or A, Waliszewska AI, Cai G, Anderson DE, Krieger JI, Hafler DA (2003) CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls. J Autoimmun 20:71–81CrossRefPubMedGoogle Scholar
  28. 28.
    Kantarci OH, Hebrink DD, Achenbach SJ, Atkinson EJ, Waliszewska A, Buckle G, McMurray CT, de Andrade M, Hafler DA, Weinshenker BG (2003) CTLA4 is associated with susceptibility to multiple sclerosis. J Neuroimmunol 134:133–141CrossRefPubMedGoogle Scholar
  29. 29.
    Mäurer M, Ponath A, Kruse N, Rieckmann P (2002) CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. J Neuroimmunol 131:213–215CrossRefPubMedGoogle Scholar
  30. 30.
    Masterman T, Ligers A, Zhang Z, Hellgren D, Salter H, Anvret M, Hillert J (2002) CTLA4 dimorphisms and the multiple sclerosis phenotype. J Neuroimmunol 131:208–212CrossRefPubMedGoogle Scholar
  31. 31.
    Andreevskii TV, Sudomoina MA, Gusev EI, Boiko AN, Alekseenkov AD, Favorova OO (2002) Polymorphism A/G in position +49 of CTLA4 exon 1 in multiple sclerosis in Russians. Mol Biol (Mosk) 36:643–648Google Scholar
  32. 32.
    Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J (2001) CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2:145–152PubMedGoogle Scholar
  33. 33.
    Rasmussen HB, Kelly MA, Francis DA, Clausen J (2001) CTLA4 in multiple sclerosis. Lack of genetic association in a European Caucasian population but evidence of interaction with HLA-DR2 among Shanghai Chinese. J Neurol Sci 184:143–147CrossRefPubMedGoogle Scholar
  34. 34.
    Liu GY, Fairchild PJ, Smith RM, Prowle JR, Kioussis D, Wraith DC (1995) Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3:407–415PubMedGoogle Scholar
  35. 35.
    Schiff PB, Horwitz SB (1980) Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 77:1561–1565PubMedGoogle Scholar
  36. 36.
    Lyons AB, Parish CR (1994) Determination of lymphocyte division by flow cytometry. J Immunol Methods 171:131–137PubMedGoogle Scholar
  37. 37.
    Alegre ML, Shiels H, Thompson CB, Gajewski TF (1998) Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol 161:3347–3356PubMedGoogle Scholar
  38. 38.
    Wekerle H, Linington C, Lassmann H, Meyermann R (1986) Cellular immune reactivity within the CNS. Trends Neurosci 9:271–277CrossRefGoogle Scholar
  39. 39.
    Bechmann I, Lossau S, Steiner B, Mor G, Gimsa U, Nitsch R (2000) Reactive astrocytes upregulate Fas (CD95) and Fas ligand (CD95L) expression but do not undergo programmed cell death during the course of anterograde degeneration. Glia 32:25–41CrossRefPubMedGoogle Scholar
  40. 40.
    Bechmann I, Steiner B, Gimsa U, Mor G, Wolf S, Beyer M, Nitsch R, Zipp F (2002) Astrocyte-induced T cell elimination is CD95 ligand dependent. J Neuroimmunol 132:60–65CrossRefPubMedGoogle Scholar
  41. 41.
    Aloisi F, Ria F, Columba CS, Hess H, Penna G, Adorini L (1999) Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation. Eur J Immunol 29:2705–2714CrossRefPubMedGoogle Scholar
  42. 42.
    Nikcevich KM, Gordon KB, Tan L, Hurst SD, Kroepfl JF, Gardinier M, Barrett TA, Miller SD (1997) IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J Immunol 158:614–621PubMedGoogle Scholar
  43. 43.
    Sun D, Coleclough C, Whitaker JN (1997) Nonactivated astrocytes downregulate T cell receptor expression and reduce antigen-specific proliferation and cytokine production of myelin basic protein (MBP)-reactive T cells. J Neuroimmunol 78:69–78CrossRefPubMedGoogle Scholar
  44. 44.
    Xiao BG, Diab A, Zhu J, van der Meide P, Link H (1998) Astrocytes induce hyporesponses of myelin basic protein-reactive T and B cell function. J Neuroimmunol 89:113–121CrossRefPubMedGoogle Scholar
  45. 45.
    Ohmori K, Hong Y, Fujiwara M, Matsumoto Y (1992) In situ demonstration of proliferating cells in the rat central nervous system during experimental autoimmune encephalomyelitis. Evidence suggesting that most infiltrating T cells do not proliferate in the target organ. Lab Invest 66:54–62PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ulrike Gimsa
    • 1
  • Anita Øren
    • 2
    • 3
  • Pushpa Pandiyan
    • 4
  • Daniela Teichmann
    • 1
  • Ingo Bechmann
    • 3
  • Robert Nitsch
    • 3
  • Monika C. Brunner-Weinzierl
    • 4
    • 5
  1. 1.Department of NeurologyUniversity of RostockRostockGermany
  2. 2.Institute of Cancer Research and Molecular MedicineNorwegian University of Science and TechnologyTrondheimNorway
  3. 3.Department of Cell and Neurobiology, Institute of AnatomyCharité University HospitalBerlinGermany
  4. 4.Deutsches Rheuma-Forschungszentrum BerlinBerlinGermany
  5. 5.Department of Rheumatology and Clinical ImmunologyCharité University HospitalBerlinGermany

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