Immunologic Research

, Volume 59, Issue 1–3, pp 254–265 | Cite as

Immune regulation of multiple sclerosis by CD8+ T cells

  • Sushmita Sinha
  • Farah R. Itani
  • Nitin J. Karandikar


The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with underlying T cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology. It is still unclear whether these cells represent pathogenic immune responses or disease-regulating elements. Through studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), we have discovered two novel CD8+ T cell populations that play an essential immunoregulatory role in disease: (1) MHC class Ia-restricted neuroantigen-specific “autoregulatory” CD8+ T cells and (2) glatiramer acetate (GA/Copaxone®) therapy-induced Qa-1/HLA-E-restricted GA-specific CD8+ T cells. These CD8+ Tregs suppress proliferation of pathogenic CD4+ CD25− T cells when stimulated by their cognate antigens. Similarly, CD8+ Tregs significantly suppress EAE when transferred either pre-disease induction or during peak disease. The mechanism of disease inhibition depends, at least in part, on an antigen-specific, contact-dependent process and works through modulation of CD4+ T cell responses as well as antigen-presenting cells through a combination of cytotoxicity and cytokine-mediated modulation. This review provides an overview of our understanding of CD8+ T cells in immune-mediated disease, focusing particularly on our findings regarding regulatory CD8+ T cells both in MS and in EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.


Multiple sclerosis (MS) CD8+ T cells Experimental autoimmune encephalomyelitis (EAE) Immunoregulatory Glatiramer acetate (GA) 



This work was supported, in part, by Grant awards (to NJK) from the NIH and National MS Society. We thank Drs. Elliot Frohman, Benjamin Greenberg and E. Torage Shivapour as well as the staff and patients of the UT Southwestern Medical Center and University of Iowa MS Clinics for their support of our studies. We also acknowledge Drs. Vladimir Badovinac and Michael Crawford for their review of this manuscript.


  1. 1.
    Anderson DW, Ellenberg JH, Leventhal CM, Reingold SC, Rodriguez M, Silberberg DH. Revised estimate of the prevalence of multiple sclerosis in the United States. Ann Neurol. 1992;31(3):333–6. doi: 10.1002/ana.410310317.CrossRefPubMedGoogle Scholar
  2. 2.
    Arnason BG. Relevance of experimental allergic encephalomyelitis to multiple sclerosis. Neurol Clin. 1983;1(3):765–82.PubMedGoogle Scholar
  3. 3.
    Martin R, McFarland HF, McFarlin DE. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–87. doi: 10.1146/annurev.iy.10.040192.001101.CrossRefPubMedGoogle Scholar
  4. 4.
    McFarlin DE, McFarland HF. Multiple sclerosis (first of two parts). N Engl J Med. 1982;307(19):1183–8. doi: 10.1056/NEJM198211043071905.CrossRefPubMedGoogle Scholar
  5. 5.
    Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med. 2000;192(3):393–404.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Crawford MP, Yan SX, Ortega SB, Mehta RS, Hewitt RE, Price DA, et al. High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood. 2004;103(11):4222–31. doi: 10.1182/blood-2003-11-4025.CrossRefPubMedGoogle Scholar
  7. 7.
    Antel J, Bania M, Noronha A, Neely S. Defective suppressor cell function mediated by T8+ cell lines from patients with progressive multiple sclerosis. J Immunol. 1986;137(11):3436–9.PubMedGoogle Scholar
  8. 8.
    Balashov KE, Khoury SJ, Hafler DA, Weiner HL. Inhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis. J Clin Investig. 1995;95(6):2711–9. doi: 10.1172/JCI117973.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Baughman EJ, Mendoza JP, Ortega SB, Ayers CL, Greenberg BM, Frohman EM, et al. Neuroantigen-specific CD8+ regulatory T-cell function is deficient during acute exacerbation of multiple sclerosis. J Autoimmun. 2011;36(2):115–24. doi: 10.1016/j.jaut.2010.12.003.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Karandikar NJ, Crawford MP, Yan X, Ratts RB, Brenchley JM, Ambrozak DR, et al. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Investig. 2002;109(5):641–9. doi: 10.1172/JCI14380.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Tennakoon DK, Mehta RS, Ortega SB, Bhoj V, Racke MK, Karandikar NJ. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J Immunol. 2006;176(11):7119–29.CrossRefPubMedGoogle Scholar
  12. 12.
    Tyler AF, Mendoza JP, Firan M, Karandikar NJ. CD8 T cells are required for glatiramer acetate therapy in autoimmune demyelinating disease. PLoS One. 2013;8(6):e66772. doi: 10.1371/journal.pone.0066772.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    York NR, Mendoza JP, Ortega SB, Benagh A, Tyler AF, Firan M, et al. Immune regulatory CNS-reactive CD8+ T cells in experimental autoimmune encephalomyelitis. J Autoimmun. 2010;35(1):33–44. doi: 10.1016/j.jaut.2010.01.003.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Tsai S, Shameli A, Yamanouchi J, Clemente-Casares X, Wang J, Serra P, et al. Reversal of autoimmunity by boosting memory-like autoregulatory T cells. Immunity. 2010;32(4):568–80. doi: 10.1016/j.immuni.2010.03.015.CrossRefPubMedGoogle Scholar
  15. 15.
    Brimnes J, Allez M, Dotan I, Shao L, Nakazawa A, Mayer L. Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease. J Immunol. 2005;174(9):5814–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Cho BA, Sim JH, Park JA, Kim HW, Yoo WH, Lee SH, et al. Characterization of effector memory CD8+ T cells in the synovial fluid of rheumatoid arthritis. J Clin Immunol. 2012;32(4):709–20. doi: 10.1007/s10875-012-9674-3.CrossRefPubMedGoogle Scholar
  17. 17.
    Ayers CL, Mendoza JP, Sinha S, Cunnusamy K, Greenberg BM, Frohman EM, et al. Modulation of immune function occurs within hours of therapy initiation for multiple sclerosis. Clin Immunol. 2013;147(2):105–19. doi: 10.1016/j.clim.2013.02.015.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Ortega SB, Kashi VP, Tyler AF, Cunnusamy K, Mendoza JP, Karandikar NJ. The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis. J Immunol. 2013;191(1):117–26. doi: 10.4049/jimmunol.1300452.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Cunnusamy KBE, Franco J, Ortega SB, Sinha S, Chaudhary P, Greenberg BM, Frohman EM, Karandikar NJ. Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells. Clin Immunol. 2014;152(1–2):115–26. doi: 10.1016/j.clim.2014.03.005.
  20. 20.
    Biegler BW, Yan SX, Ortega SB, Tennakoon DK, Racke MK, Karandikar NJ. Glatiramer acetate (GA) therapy induces a focused, oligoclonal CD8+ T-cell repertoire in multiple sclerosis. J Neuroimmunol. 2006;180(1–2):159–71. doi: 10.1016/j.jneuroim.2006.07.015.CrossRefPubMedGoogle Scholar
  21. 21.
    Biegler BW, Yan SX, Ortega SB, Tennakoon DK, Racke MK, Karandikar NJ. Clonal composition of neuroantigen-specific CD8+ and CD4+ T-cells in multiple sclerosis. J Neuroimmunol. 2011;234(1–2):131–40. doi: 10.1016/j.jneuroim.2011.02.001.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(Suppl 1):S25–30. doi: 10.1212/WNL.0b013e3181c97e39.CrossRefPubMedGoogle Scholar
  23. 23.
    Ratts RB, Karandikar NJ, Hussain RZ, Choy J, Northrop SC, Lovett-Racke AE, et al. Phenotypic characterization of autoreactive T cells in multiple sclerosis. J Neuroimmunol. 2006;178(1–2):100–10. doi: 10.1016/j.jneuroim.2006.06.010.CrossRefPubMedGoogle Scholar
  24. 24.
    Ratts RB, Lovett-Racke AE, Choy J, Northrop SC, Hussain RZ, Karandikar NJ, et al. CD28-CD57+ T cells predominate in CD8 responses to glatiramer acetate. J Neuroimmunol. 2006;178(1–2):117–29. doi: 10.1016/j.jneuroim.2006.06.001.CrossRefPubMedGoogle Scholar
  25. 25.
    Jiang H, Canfield SM, Gallagher MP, Jiang HH, Jiang Y, Zheng Z, et al. HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. J Clin Investig. 2010;120(10):3641–50. doi: 10.1172/JCI43522.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Carvalheiro H, da Silva JA, Souto-Carneiro MM. Potential roles for CD8(+) T cells in rheumatoid arthritis. Autoimmun Rev. 2013;12(3):401–9. doi: 10.1016/j.autrev.2012.07.011.CrossRefPubMedGoogle Scholar
  27. 27.
    Correale J, Villa A. Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis. Ann Neurol. 2010;67(5):625–38. doi: 10.1002/ana.21944.PubMedGoogle Scholar
  28. 28.
    Davila E, Kang YM, Park YW, Sawai H, He X, Pryshchep S, et al. Cell-based immunotherapy with suppressor CD8+ T cells in rheumatoid arthritis. J Immunol. 2005;174(11):7292–301.CrossRefPubMedGoogle Scholar
  29. 29.
    Tada Y, Ho A, Koh DR, Mak TW. Collagen-induced arthritis in CD4− or CD8− deficient mice: cd8+ T cells play a role in initiation and regulate recovery phase of collagen-induced arthritis. J Immunol. 1996;156(11):4520–6.PubMedGoogle Scholar
  30. 30.
    Penninger JM, Neu N, Timms E, Wallace VA, Koh DR, Kishihara K, et al. The induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules [corrected]. J Exp Med. 1993;178(5):1837–42.CrossRefPubMedGoogle Scholar
  31. 31.
    Stuart PM, Summers B, Morris JE, Morrison LA, Leib DA. CD8(+) T cells control corneal disease following ocular infection with herpes simplex virus type 1. J Gen Virol. 2004;85(Pt 7):2055–63. doi: 10.1099/vir.0.80049-0.CrossRefPubMedGoogle Scholar
  32. 32.
    Jiang H, Zhang SI, Pernis B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science. 1992;256(5060):1213–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Lee YH, Ishida Y, Rifa’i M, Shi Z, Isobe K, Suzuki H. Essential role of CD8+ CD122+ regulatory T cells in the recovery from experimental autoimmune encephalomyelitis. J Immunol. 2008;180(2):825–32.CrossRefPubMedGoogle Scholar
  34. 34.
    Rifa’i M, Kawamoto Y, Nakashima I, Suzuki H. Essential roles of CD8+ CD122+ regulatory T cells in the maintenance of T cell homeostasis. J Exp Med. 2004;200(9):1123–34. doi: 10.1084/jem.20040395.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Crucian B, Dunne P, Friedman H, Ragsdale R, Pross S, Widen R. Alterations in levels of CD28−/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients. Clin Diagn Lab Immunol. 1995;2(2):249–52.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Najafian N, Chitnis T, Salama AD, Zhu B, Benou C, Yuan X, et al. Regulatory functions of CD8+ CD28− T cells in an autoimmune disease model. J Clin Investig. 2003;112(7):1037–48. doi: 10.1172/JCI17935.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol. 2004;5(5):516–23. doi: 10.1038/ni1063.CrossRefPubMedGoogle Scholar
  38. 38.
    Jiang H, Braunstein NS, Yu B, Winchester R, Chess L. CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice. Proc Natl Acad Sci USA. 2001;98(11):6301–6. doi: 10.1073/pnas.101123098.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Correale J, Villa A. Isolation and characterization of CD8+ regulatory T cells in multiple sclerosis. J Neuroimmunol. 2008;195(1–2):121–34. doi: 10.1016/j.jneuroim.2007.12.004.CrossRefPubMedGoogle Scholar
  40. 40.
    Pannemans K, Broux B, Goris A, Dubois B, Broekmans T, Van Wijmeersch B, et al. HLA-E restricted CD8+ T cell subsets are phenotypically altered in multiple sclerosis patients. Multiple sclerosis. 2013;. doi: 10.1177/1352458513509703.PubMedGoogle Scholar
  41. 41.
    Shi Z, Okuno Y, Rifa’i M, Endharti AT, Akane K, Isobe K, et al. Human CD8+ CXCR3+ T cells have the same function as murine CD8+ CD122+ Treg. Eur J Immunol. 2009;39(8):2106–19. doi: 10.1002/eji.200939314.CrossRefPubMedGoogle Scholar
  42. 42.
    Lu L, Cantor H. Generation and regulation of CD8(+) regulatory T cells. Cell Mol Immunol. 2008;5(6):401–6. doi: 10.1038/cmi.2008.50.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Jurgens B, Hainz U, Fuchs D, Felzmann T, Heitger A. Interferon-gamma-triggered indoleamine 2,3-dioxygenase competence in human monocyte-derived dendritic cells induces regulatory activity in allogeneic T cells. Blood. 2009;114(15):3235–43. doi: 10.1182/blood-2008-12-195073.CrossRefPubMedGoogle Scholar
  44. 44.
    Martini M, Testi MG, Pasetto M, Picchio MC, Innamorati G, Mazzocco M, et al. IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer. Vaccine. 2010;28(20):3548–57. doi: 10.1016/j.vaccine.2010.03.007.CrossRefPubMedGoogle Scholar
  45. 45.
    Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, et al. Role of IFN-gamma in induction of Foxp3 and conversion of CD4+ CD25− T cells to CD4+ Tregs. J Clin Investig. 2006;116(9):2434–41. doi: 10.1172/JCI25826.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Beeston T, Smith TR, Maricic I, Tang X, Kumar V. Involvement of IFN-gamma and perforin, but not Fas/FasL interactions in regulatory T cell-mediated suppression of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010;229(1–2):91–7. doi: 10.1016/j.jneuroim.2010.07.007.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Tang X, Maricic I, Purohit N, Bakamjian B, Reed-Loisel LM, Beeston T, et al. Regulation of immunity by a novel population of Qa-1-restricted CD8alphaalpha + TCRalphabeta + T cells. J Immunol. 2006;177(11):7645–55.CrossRefPubMedGoogle Scholar
  48. 48.
    Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467(7313):328–32. doi: 10.1038/nature09370.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Cone RE, Chattopadhyay S, Sharafieh R, Lemire Y, O’Rourke J, Flavell RA, et al. T cell sensitivity to TGF-beta is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber. Int Immunol. 2009;21(5):567–74. doi: 10.1093/intimm/dxp023.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Ozenci V, Kouwenhoven M, Huang YM, Kivisakk P, Link H. Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-beta) treatment. Clin Exp Immunol. 2000;120(1):147–53.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Huang WX, Huang P, Link H, Hillert J. Cytokine analysis in multiple sclerosis by competitive RT - PCR: a decreased expression of IL-10 and an increased expression of TNF-alpha in chronic progression. Multiple sclerosis. 1999;5(5):342–8.PubMedGoogle Scholar
  52. 52.
    Calabresi PA, Martin R, Jacobson S. Chemokines in chronic progressive neurological diseases: HTLV-1 associated myelopathy and multiple sclerosis. J Neurovirol. 1999;5(1):102–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Frisullo G, Nociti V, Iorio R, Patanella AK, Caggiula M, Marti A, et al. Regulatory T cells fail to suppress CD4T+ -bet + T cells in relapsing multiple sclerosis patients. Immunology. 2009;127(3):418–28. doi: 10.1111/j.1365-2567.2008.02963.x.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Sellner J, Koczi W, Harrer A, Oppermann K, Obregon-Castrillo E, Pilz G, et al. Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis. Clin Exp Immunol. 2013;173(3):381–9. doi: 10.1111/cei.12125.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Keith AB, Arnon R, Teitelbaum D, Caspary EA, Wisniewski HM. The effect of Cop 1, a synthetic polypeptide, on chronic relapsing experimental allergic encephalomyelitis in guinea pigs. J Neurol Sci. 1979;42(2):267–74.CrossRefPubMedGoogle Scholar
  56. 56.
    Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol. 1971;1(4):242–8. doi: 10.1002/eji.1830010406.CrossRefPubMedGoogle Scholar
  57. 57.
    Teitelbaum D, Webb C, Bree M, Meshorer A, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis in Rhesus monkeys by a synthetic basic copolymer. Clin Immunol Immunopathol. 1974;3(2):256–62.CrossRefPubMedGoogle Scholar
  58. 58.
    Teitelbaum D, Webb C, Meshorer A, Arnon R, Sela M. Suppression by several synthetic polypeptides of experimental allergic encephalomyelitis induced in guinea pigs and rabbits with bovine and human basic encephalitogen. Eur J Immunol. 1973;3(5):273–9. doi: 10.1002/eji.1830030505.CrossRefPubMedGoogle Scholar
  59. 59.
    Abramsky O, Teitelbaum D, Arnon R. Effect of a synthetic polypeptide (COP 1) on patients with multiple sclerosis and with acute disseminated encephalomeylitis. Preliminary report. J Neurol Sci. 1977;31(3):433–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Bornstein MB, Miller AI, Teitelbaum D, Arnon R, Sela M. Multiple sclerosis: trial of a synthetic polypeptide. Ann Neurol. 1982;11(3):317–9. doi: 10.1002/ana.410110314.CrossRefPubMedGoogle Scholar
  61. 61.
    Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The copolymer 1 multiple sclerosis study group. Neurology. 1995;45(7):1268–76.CrossRefPubMedGoogle Scholar
  62. 62.
    Johnson KP, Brooks BR, Ford CC, Goodman A, Guarnaccia J, Lisak RP, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. copolymer 1 multiple sclerosis study group. Multiple Sclerosis. 2000;6(4):255–66.CrossRefPubMedGoogle Scholar
  63. 63.
    Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, Riven-Kreitman R, et al. Humoral and cellular immune responses to copolymer 1 in multiple sclerosis patients treated with copaxone. J Neuroimmunol. 2001;115(1–2):152–60.CrossRefPubMedGoogle Scholar
  64. 64.
    Duda PW, Krieger JI, Schmied MC, Balentine C, Hafler DA. Human and murine CD4 T cell reactivity to a complex antigen: recognition of the synthetic random polypeptide glatiramer acetate. J Immunol. 2000;165(12):7300–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Investig. 2000;105(7):967–76. doi: 10.1172/JCI8970.PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Farina C, Then Bergh F, Albrecht H, Meinl E, Yassouridis A, Neuhaus O et al. Treatment of multiple sclerosis with copaxone (COP): elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells. Brain J Neurol. 2001; 124(Pt 4):705–719.Google Scholar
  67. 67.
    Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T et al. Multiple sclerosis: comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97(13):7452–7457.Google Scholar
  68. 68.
    Qin Y, Zhang DQ, Prat A, Pouly S, Antel J. Characterization of T cell lines derived from glatiramer-acetate-treated multiple sclerosis patients. J Neuroimmunol. 2000;108(1–2):201–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Hong J, Li N, Zhang X, Zheng B, Zhang JZ. Induction of CD4+ CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci USA. 2005;102(18):6449–54. doi: 10.1073/pnas.0502187102.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Weber MS, Prod’homme T, Youssef S, Dunn SE, Rundle CD, Lee L, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007;13(8):935–43. doi: 10.1038/nm1620.CrossRefPubMedGoogle Scholar
  71. 71.
    Begum-Haque S, Sharma A, Christy M, Lentini T, Ochoa-Reparaz J, Fayed IF, et al. Increased expression of B cell-associated regulatory cytokines by glatiramer acetate in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010;219(1–2):47–53. doi: 10.1016/j.jneuroim.2009.11.016.CrossRefPubMedGoogle Scholar
  72. 72.
    Kala M, Rhodes SN, Piao WH, Shi FD, Campagnolo DI, Vollmer TL. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp Neurol. 2010;221(1):136–45. doi: 10.1016/j.expneurol.2009.10.015.CrossRefPubMedGoogle Scholar
  73. 73.
    Jurewicz A, Biddison WE, Antel JP. MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes. J Immunol. 1998;160(6):3056–9.PubMedGoogle Scholar
  74. 74.
    Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008;172(1):146–55. doi: 10.2353/ajpath.2008.070690.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Annibali V, Ristori G, Angelini DF, Serafini B, Mechelli R, Cannoni S, et al. CD161 (high) CD8+ T cells bear pathogenetic potential in multiple sclerosis. Brain J Neurol. 2011;134(Pt 2):542–54. doi: 10.1093/brain/awq354.CrossRefGoogle Scholar
  76. 76.
    Jilek S, Schluep M, Rossetti AO, Guignard L, Le Goff G, Pantaleo G, et al. CSF enrichment of highly differentiated CD8+ T cells in early multiple sclerosis. Clin Immunol. 2007;123(1):105–13. doi: 10.1016/j.clim.2006.11.004.CrossRefPubMedGoogle Scholar
  77. 77.
    Bania MB, Antel JP, Reder AT, Nicholas MK, Arnason BG. Suppressor and cytolytic cell function in multiple sclerosis: effects of cyclosporine A and interleukin 2. J Clin Investig. 1986;78(2):582–6. doi: 10.1172/JCI112612.PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med. 2001;194(5):669–76.PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Ford ML, Evavold BD. Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol. 2005;35(1):76–85. doi: 10.1002/eji.200425660.CrossRefPubMedGoogle Scholar
  80. 80.
    Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, Wekerle H, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol. 2001;166(12):7579–87.CrossRefPubMedGoogle Scholar
  81. 81.
    Mars LT, Bauer J, Gross DA, Bucciarelli F, Firat H, Hudrisier D, et al. CD8 T cell responses to myelin oligodendrocyte glycoprotein-derived peptides in humanized HLA-A*0201-transgenic mice. J Immunol. 2007;179(8):5090–8.CrossRefPubMedGoogle Scholar
  82. 82.
    Saxena A, Bauer J, Scheikl T, Zappulla J, Audebert M, Desbois S, et al. Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol. 2008;181(3):1617–21.CrossRefPubMedGoogle Scholar
  83. 83.
    Saitoh O, Abiru N, Nakahara M, Nagayama Y. CD8+ CD122+ T cells, a newly identified regulatory T subset, negatively regulate Graves’ hyperthyroidism in a murine model. Endocrinology. 2007;148(12):6040–6. doi: 10.1210/en.2007-0300.CrossRefPubMedGoogle Scholar
  84. 84.
    Endharti AT, Okuno Y, Shi Z, Misawa N, Toyokuni S, Ito M, et al. CD8+ CD122+ regulatory T cells (Tregs) and CD4+ Tregs cooperatively prevent and cure CD4+ cell-induced colitis. J Immunol. 2011;186(1):41–52. doi: 10.4049/jimmunol.1000800.CrossRefPubMedGoogle Scholar
  85. 85.
    Wang R, Han G, Song L, Wang J, Chen G, Xu R, et al. CD8+ regulatory T cells are responsible for GAD-IgG gene-transferred tolerance induction in NOD mice. Immunology. 2009;126(1):123–31. doi: 10.1111/j.1365-2567.2008.02884.x.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sushmita Sinha
    • 1
  • Farah R. Itani
    • 1
  • Nitin J. Karandikar
    • 1
  1. 1.The Interdisciplinary Graduate Program in Immunology, Department of PathologyUniversity of IowaIowa CityUSA

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