Autoimmune T cell responses in the central nervous system (original) (raw)

• McFarland, H. F. & Martin, R. Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunol. 8, 913–919 (2007).
  CAS Google Scholar
• Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).
  CAS PubMed Google Scholar
• Raine, C. in Multiple Sclerosis: Clinical and Pathogenetic Basis (eds Raine, C. S., McFarland, H. F. & Tourtellotte, W. W.) 243–286 (Chapman and Hall, London, 1997).
  Google Scholar
• Ransohoff, R. M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nature Rev. Immunol. 3, 569–581 (2003).
  CAS Google Scholar
• Huseby, E. S., Sather, B., Huseby, P. G. & Goverman, J. Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity 14, 471–481 (2001).
  CAS PubMed Google Scholar
• Perchellet, A., Stromnes, I., Pang, J. M. & Goverman, J. CD8+ T cells maintain tolerance to myelin basic protein by 'epitope theft'. Nature Immunol. 5, 606–614 (2004). This paper identifies a new form of tolerance that allows CD8+ T cells specific for MBP to circulate in the periphery without responding to endogenous MBP.
  CAS Google Scholar
• Pender, M. P., Tabi, Z., Nguyen, K. B. & McCombe, P. A. The proximal peripheral nervous system is a major site of demyelination in experimental autoimmune encephalomyelitis induced in the Lewis rat by a myelin basic protein-specific T cell clone. Acta Neuropathol. 89, 527–531 (1995).
  CAS PubMed Google Scholar
• Furtado, G. C. et al. Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J. Immunol. 181, 4648–4655 (2008).
  CAS PubMed Google Scholar
• Zhang, H., Podojil, J. R., Luo, X. & Miller, S. D. Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis. J. Immunol. 181, 4638–4647 (2008).
  CAS PubMed Google Scholar
• Piccio, L. et al. Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric Gi-linked receptors. J. Immunol. 168, 1940–1949 (2002).
  CAS PubMed Google Scholar
• Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514–523 (2009).
  CAS Google Scholar
• Lassmann, H. & Wisniewski, H. M. Chronic relapsing EAE. Time course of neurological symptoms and pathology. Acta Neuropathol. 43, 35–42 (1978).
  CAS PubMed Google Scholar
• Kivisakk, P. et al. Localizing central nervous system immune surveillance: Meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann. Neurol. 21 May 2008 (doi:10.1002/ana.21379).
  PubMed PubMed Central Google Scholar
• Brown, D. A. & Sawchenko, P. E. Time course and distribution of inflammatory and neurodegenerative events suggest structural bases for the pathogenesis of experimental autoimmune encephalomyelitis. J. Comp. Neurol. 502, 236–260 (2007). This paper describes the temporal and spatial pattern of inflammatory and degenerative events that occur during the induction of EAE.
  PubMed Google Scholar
• Gimenez, M. A., Sim, J., Archambault, A. S., Klein, R. S. & Russell, J. H. A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. Am. J. Pathol. 168, 1200–1209 (2006).
  CAS PubMed PubMed Central Google Scholar
• Kawakami, N. et al. The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis. J. Exp. Med. 199, 185–197 (2004).
  CAS PubMed PubMed Central Google Scholar
• Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
  CAS PubMed PubMed Central Google Scholar
• Kim, J. V., Kang, S. S., Dustin, M. L. & McGavern, D. B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–197 (2009).
  CAS PubMed Google Scholar
• Carson, M. J., Reilly, C. R., Sutcliffe, J. G. & Lo, D. Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. Am. J. Pathol. 154, 481–494 (1999).
  CAS PubMed PubMed Central Google Scholar
• Brabb, T. et al. In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J. Exp. Med. 192, 871–880 (2000).
  CAS PubMed PubMed Central Google Scholar
• Battistini, L. et al. CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1. Blood 101, 4775–4782 (2003).
  CAS PubMed Google Scholar
• Eikelenboom, M. J. et al. Chemokine receptor expression on T cells is related to new lesion development in multiple sclerosis. J. Neuroimmunol. 133, 225–232 (2002).
  CAS PubMed Google Scholar
• Hafler, D. A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).
  CAS PubMed Google Scholar
• Harrington, C. J. et al. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 8, 571–580 (1998). This paper shows that the dependence of central tolerance on T cell functional avidity for antigen allows some, but not all, MBP-specific immune tolerance to escape immune tolerance.
  CAS PubMed Google Scholar
• Anderson, A. C. et al. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191, 761–770 (2000).
  CAS PubMed PubMed Central Google Scholar
• Klein, L., Klugmann, M., Nave, K. A., Tuohy, V. K. & Kyewski, B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nature Med. 6, 56–61 (2000).
  CAS PubMed Google Scholar
• Seamons, A., Perchellet, A. & Goverman, J. Immune tolerance to myelin proteins. Immunol. Res. 28, 201–221 (2003).
  CAS PubMed Google Scholar
• Cabbage, S. E. et al. Regulatory T cells maintain long-term tolerance to myelin basic protein by inducing a novel, dynamic state of T cell tolerance. J. Immunol. 178, 887–896 (2007).
  CAS PubMed Google Scholar
• Bielekova, B. et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J. Immunol. 172, 3893–3904 (2004).
  CAS PubMed Google Scholar
• Burns, J., Bartholomew, B. & Lobo, S. Isolation of myelin basic protein-specific T cells predominantly from the memory T-cell compartment in multiple sclerosis. Ann. Neurol. 45, 33–39 (1999).
  CAS PubMed Google Scholar
• Scholz, C., Patton, K. T., Anderson, D. E., Freeman, G. J. & Hafler, D. A. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. J. Immunol. 160, 1532–1538 (1998).
  CAS PubMed Google Scholar
• Lovett-Racke, A. E. et al. Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells. J. Clin. Invest. 101, 725–730 (1998).
  CAS PubMed PubMed Central Google Scholar
• Ponsford, M. et al. Differential responses of CD45+ve T-cell subsets to MBP in multiple sclerosis. Clin. Exp. Immunol. 124, 315–322 (2001).
  CAS PubMed PubMed Central Google Scholar
• Zhang, X. et al. Degenerate TCR recognition and dual DR2 restriction of autoreactive T cells: implications for the initiation of the autoimmune response in multiple sclerosis. Eur. J. Immunol. 38, 1297–1309 (2008).
  CAS PubMed Google Scholar
• Fujinami, R. S. & Oldstone, M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230, 1043–1045 (1985).
  CAS PubMed Google Scholar
• Münz, C., Lünemann, J. D., Getts, M. T. & Miller, S. D. Antiviral immune responses: triggers of or triggered by autoimmunity? Nature Rev. Immunol. 9, 246–258 (2009).
  Google Scholar
• Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995). This paper shows that a search using a molecular mimicry motif based on structural rather than sequence similarity identifies distinct, multiple peptides from microorganisms that can activate human T cells specific for MBP.
  CAS PubMed PubMed Central Google Scholar
• Lang, H. L. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nature Immunol. 3, 940–943 (2002).
  CAS Google Scholar
• Tejada-Simon, M. V., Zang, Y. C., Hong, J., Rivera, V. M. & Zhang, J. Z. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann. Neurol. 53, 189–197 (2003).
  CAS PubMed Google Scholar
• Holmoy, T., Kvale, E. O. & Vartdal, F. Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein–Barr virus and myelin basic protein. J. Neurovirol. 10, 278–283 (2004).
  CAS PubMed Google Scholar
• Markovic-Plese, S. et al. High level of cross-reactivity in influenza virus hemagglutinin-specific CD4+ T-cell response: implications for the initiation of autoimmune response in multiple sclerosis. J. Neuroimmunol. 169, 31–38 (2005).
  CAS PubMed Google Scholar
• Goverman, J. et al. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72, 551–560 (1993). This paper is the first to show that T cells specific for some epitopes of MBP are not subject to deletion by central tolerance in vivo and that the incidence of spontaneous autoimmunity mediated by these T cells is influenced by environmental factors.
  CAS PubMed Google Scholar
• Goverman, J. Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein. Immunol. Rev. 169, 147–159 (1999).
  CAS PubMed PubMed Central Google Scholar
• Krishnamoorthy, G. Cumulative autoimmunity: Myelin oligodendrocyte glycoprotein-specific T cells co-recognize neurofilament-M in a spontaneous experimental autoimmune encephalomyelitis of the C57BL/6 mouse. Nature Med. (in the press).
• Gutcher, I. & Becher, B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest. 117, 1119–1127 (2007).
  CAS PubMed PubMed Central Google Scholar
• Panitch, H. S., Hirsch, R. L., Haley, A. S. & Johnson, K. P. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1, 893–895 (1987).
  CAS PubMed Google Scholar
• Baron, J. L., Madri, J. A., Ruddle, N. H., Hashim, G. & Janeway, C. A. Jr. Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J. Exp. Med. 177, 57–68 (1993).
  CAS PubMed Google Scholar
• Segal, B. M. & Shevach, E. M. IL-12 unmasks latent autoimmune disease in resistant mice. J. Exp. Med. 184, 771–775 (1996).
  CAS PubMed Google Scholar
• Steinman, L. A brief history of TH17, the first major revision in the T H 1/T H 2 hypothesis of T cell-mediated tissue damage. Nature Med. 13, 139–145 (2007).
  CAS PubMed Google Scholar
• Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).
  CAS PubMed Google Scholar
• McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nature Immunol. 10, 314–324 (2009).
  CAS Google Scholar
• Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009).
  CAS PubMed Google Scholar
• Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002).
  CAS PubMed Google Scholar
• Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005). This paper is the first to show that myelin-specific T H 17 cells are more pathogenic following adoptive transfer into naive mice than T H 1 cells.
  CAS PubMed PubMed Central Google Scholar
• Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005).
  CAS Google Scholar
• Hofstetter, H. H. et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell. Immunol. 237, 123–130 (2005).
  CAS PubMed Google Scholar
• Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).
  CAS PubMed Google Scholar
• Axtell, R. C., Xu, L., Barnum, S. R. & Raman, C. CD5–CK2 binding/activation-deficient mice are resistant to experimental autoimmune encephalomyelitis: protection is associated with diminished populations of IL-17-expressing T cells in the central nervous system. J. Immunol. 177, 8542–8549 (2006).
  CAS PubMed Google Scholar
• Ivanov, II. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
  CAS PubMed Google Scholar
• Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009). This paper questions the role of IL-17A and IL-17F by showing that the lack of these cytokines in vivo does not significantly affect the manifestation of EAE mediated by MOG 35–55 -specific T cells in C57BL/6 mice.
  CAS PubMed Google Scholar
• Rohn, T. A. et al. Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis. Eur. J. Immunol. 36, 2857–2867 (2006).
  CAS PubMed Google Scholar
• Luger, D. et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205, 799–810 (2008).
  CAS PubMed PubMed Central Google Scholar
• Stromnes, I. M., Cerretti, L. M., Liggitt, D., Harris, R. A. & Goverman, J. M. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nature Med. 14, 337–342 (2008). This paper shows that inflammation is regulated differently in the brain compared with the spinal cord and provides evidence that the relative abundance of T H 17 and T H 1 cells in the infiltrating T cell population is a crucial factor in determining where inflammation localizes within the CNS.
  CAS PubMed Google Scholar
• Kroenke, M. A., Carlson, T. J., Andjelkovic, A. V. & Segal, B. M. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J. Exp. Med. 205, 1535–1541 (2008).
  CAS PubMed PubMed Central Google Scholar
• O'Connor, R. A. et al. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol. 181, 3750–3754 (2008).
  CAS PubMed Google Scholar
• Storch, M. K. et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol. 8, 681–694 (1998).
  CAS PubMed Google Scholar
• Muller, D. M., Pender, M. P. & Greer, J. M. A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction. Acta Neuropathol. (Berl.) 100, 174–182 (2000).
  CAS Google Scholar
• Wensky, A. K. et al. IFN-γ determines distinct clinical outcomes in autoimmune encephalomyelitis. J. Immunol. 174, 1416–1423 (2005).
  CAS PubMed Google Scholar
• Lees, J. R., Golumbek, P. T., Sim, J., Dorsey, D. & Russell, J. H. Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis. J. Exp. Med. 205, 2633–2642 (2008). This paper shows that IFNγ signalling in CNS resident cells is required for inflammation in the spinal cord but inhibits inflammation in the brain.
  CAS PubMed PubMed Central Google Scholar
• Tran, E. H., Hoekstra, K., van Rooijen, N., Dijkstra, C. D. & Owens, T. Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J. Immunol. 161, 3767–3775 (1998).
  CAS PubMed Google Scholar
• Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Med. 11, 328–334 (2005). This paper shows that DCs, which were previously considered to be scarce or absent from the non-inflamed CNS, are present in the CNS and are sufficient to reactivate primed T cells in the CNS and induce EAE.
  CAS PubMed Google Scholar
• Bailey, S. L., Schreiner, B., McMahon, E. J. & Miller, S. D. CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ T H-17 cells in relapsing EAE. Nature Immunol. 8, 172–180 (2007).
  CAS Google Scholar
• Deshpande, P., King, I. L. & Segal, B. M. Cutting edge: CNS CD11c+ cells from mice with encephalomyelitis polarize Th17 cells and support CD25+CD4+ T cell-mediated immunosuppression, suggesting dual roles in the disease process. J. Immunol. 178, 6695–6699 (2007).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Aloisi, F. Immune function of microglia. Glia 36, 165–179 (2001).
  CAS PubMed Google Scholar
• Becher, B., Blain, M. & Antel, J. P. CD40 engagement stimulates IL-12 p70 production by human microglial cells: basis for Th1 polarization in the CNS. J. Neuroimmunol. 102, 44–50 (2000).
  CAS PubMed Google Scholar
• Ford, A. L., Foulcher, E., Lemckert, F. A. & Sedgwick, J. D. Microglia induce CD4 T lymphocyte final effector function and death. J. Exp. Med. 184, 1737–1745 (1996).
  CAS PubMed Google Scholar
• Juedes, A. E. & Ruddle, N. H. Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis. J. Immunol. 166, 5168–5175 (2001).
  CAS PubMed Google Scholar
• Becher, B., Durell, B. G., Miga, A. V., Hickey, W. F. & Noelle, R. J. The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J. Exp. Med. 193, 967–974 (2001).
  CAS PubMed PubMed Central Google Scholar
• Heppner, F. L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nature Med. 11, 146–152 (2005).
  CAS PubMed Google Scholar
• Nikcevich, K. M. et al. IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J. Immunol. 158, 614–621 (1997).
  CAS PubMed Google Scholar
• Anderson, A. C. et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318, 1141–1143 (2007).
  CAS PubMed Google Scholar
• Goverman, J., Perchellet, A. & Huseby, E. S. The role of CD8+ T cells in multiple sclerosis and its animal models. Curr. Drug Targets Inflamm. Allergy 4, 239–245 (2005).
  CAS PubMed Google Scholar
• Friese, M. A. & Fugger, L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 128, 1747–1763 (2005).
  PubMed Google Scholar
• Coles, A. J. et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J. Neurol. 253, 98–108 (2006).
  PubMed Google Scholar
• Junker, A. et al. Multiple sclerosis: T-cell receptor expression in distinct brain regions. Brain 130, 2789–2799 (2007).
  PubMed Google Scholar
• Crawford, M. P. et al. High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood 103, 4222–4231 (2004).
  CAS PubMed Google Scholar
• Brynedal, B. et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS ONE 2, e664 (2007).
  PubMed PubMed Central Google Scholar
• Burfoot, R. K. et al. SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians. Tissue Antigens 71, 42–50 (2008).
  CAS PubMed Google Scholar
• Koh, D. R. et al. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8−/− mice. Science 256, 1210–1213 (1992).
  CAS PubMed Google Scholar
• Jiang, H., Zhang, S.-l. & Pernis, B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256, 1213–1215 (1992).
  CAS PubMed Google Scholar
• Huseby, E. S. et al. A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis. J. Exp. Med. 194, 669–676 (2001). This paper shows that CD8+ T cells specific for MBP can induce a distinct form of EAE that recapitulates some aspects of multiple sclerosis not seen in CD4+ T cell-mediated EAE.
  CAS PubMed PubMed Central Google Scholar
• Sun, D. et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J. Immunol. 166, 7579–7587 (2001). This paper shows that CD8+ T cells specific for MOG can induce EAE pathology.
  CAS PubMed Google Scholar
• Friese, M. A. et al. Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nature Med. 14, 1227–1235 (2008). This paper uses humanized mice to show that one HLA allele promotes induction of EAE mediated by CD8+ PLP-specific T cells and a different HLA allele protects from disease, thereby identifying mechanisms by which MHC class I alleles can determine susceptibility to multiple sclerosis.
  CAS PubMed Google Scholar
• Calzascia, T. et al. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 22, 175–184 (2005).
  CAS PubMed Google Scholar
• Perchellet, A., Brabb, T. & Goverman, J. M. Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein. Proc. Natl Acad. Sci. USA 105, 14040–14045 (2008).
  CAS PubMed PubMed Central Google Scholar
• Galea, I. et al. An antigen-specific pathway for CD8 T cells across the blood–brain barrier. J. Exp. Med. 204, 2023–2030 (2007).
  CAS PubMed PubMed Central Google Scholar
• Na, S. Y. et al. Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system. Brain 131, 2353–2365 (2008).
  PubMed Google Scholar
• Saxena, A. et al. Cutting edge: Multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J. Immunol. 181, 1617–1621 (2008).
  CAS PubMed Google Scholar
• Serafini, B. et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).
  CAS PubMed PubMed Central Google Scholar
• Zang, Y. C. et al. Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis. J. Immunol. 172, 5120–5127 (2004).
  CAS PubMed Google Scholar
• Tzartos, J. S. 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. 172, 146–155 (2008).
  CAS PubMed PubMed Central Google Scholar
• Lafaille, J. J., Nagashima, K., Katsuki, M. & Tonegawa, S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78, 399–408 (1994).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Korn, T. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nature Med. 13, 423–431 (2007).
  CAS PubMed Google Scholar
• Pender, M. P. Treating autoimmune demyelination by augmenting lymphocyte apoptosis in the central nervous system. J. Neuroimmunol. 191, 26–38 (2007).
  CAS PubMed Google Scholar
• O'Connor, R. A. & Anderton, S. M. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J. Neuroimmunol. 193, 1–11 (2008).
  CAS PubMed Google Scholar
• Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
  CAS PubMed Google Scholar
• Zozulya, A. L. & Wiendl, H. The role of CD8 suppressors versus destructors in autoimmune central nervous system inflammation. Hum. Immunol. 69, 797–804 (2008).
  CAS PubMed Google Scholar
• Rifa'i, M. et al. CD8+CD122+ regulatory T cells recognize activated T cells via conventional MHC class I–αβTCR interaction and become IL-10-producing active regulatory cells. Int. Immunol. 20, 937–947 (2008).
  CAS PubMed Google Scholar
• Feger, U. et al. HLA-G. expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation. Blood 110, 568–577 (2007).
  CAS PubMed Google Scholar
• Najafian, N. et al. Regulatory functions of CD8+CD28− T cells in an autoimmune disease model. J. Clin. Invest. 112, 1037–1048 (2003).
  CAS PubMed PubMed Central Google Scholar
• Vlad, G., Cortesini, R. & Suciu-Foca, N. License to heal: bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC. J. Immunol. 174, 5907–5914 (2005).
  CAS PubMed Google Scholar
• Jiang, H. et al. Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor Vβ repertoire during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 100, 8378–8383 (2003).
  CAS PubMed PubMed Central Google Scholar
• Lu, L., Kim, H. J., Werneck, M. B. & Cantor, H. Regulation of CD8+ regulatory T cells: interruption of the NKG2A–Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc. Natl Acad. Sci. USA 105, 19420–19425 (2008).
  CAS PubMed PubMed Central Google Scholar
• Zhang, J., Medaer, R., Stinissen, P., Hafler, D. & Raus, J. MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination. Science 261, 1451–1454 (1993).
  CAS PubMed Google Scholar
• Correale, J. et al. T cell vaccination in secondary progressive multiple sclerosis. J. Neuroimmunol. 107, 130–139 (2000).
  CAS PubMed Google Scholar
• Tennakoon, D. K. et al. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J. Immunol. 176, 7119–7129 (2006).
  CAS PubMed Google Scholar
• Wyss-Coray, T., Borrow, P., Brooker, M. J. & Mucke, L. Astroglial overproduction of TGF-β1 enhances inflammatory central nervous system disease in transgenic mice. J. Neuroimmunol. 77, 45–50 (1997).
  CAS PubMed Google Scholar
• Luo, J. et al. Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis. J. Clin. Invest. 117, 3306–3315 (2007).
  CAS PubMed PubMed Central Google Scholar
• Bettelli, E. et al. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J. Immunol. 161, 3299–3306 (1998).
  CAS PubMed Google Scholar
• Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immunol. 7, 937–945 (2006).
  CAS Google Scholar
• Fitzgerald, D. C. et al. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179, 3268–3275 (2007).
  CAS PubMed Google Scholar
• Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002).
  CAS PubMed Google Scholar
• Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nature Immunol. 7, 929–936 (2006).
  CAS Google Scholar
• Kleinschek, M. A. et al. IL-25 regulates Th17 function in autoimmune inflammation. J. Exp. Med. 204, 161–170 (2007).
  CAS PubMed PubMed Central Google Scholar
• Ousman, S. S. et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 448, 474–479 (2007).
  CAS PubMed Google Scholar
• Beriou, G. et al. IL-17 producing human peripheral regulatory T cells retain suppressive function. Blood 26 Jan 2009 (doi:10.1182/blood-2008-10-183251).
  CAS PubMed PubMed Central Google Scholar
• Voo, K. S. et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc. Natl Acad. Sci. USA 106, 4793–4798 (2009).
  CAS PubMed PubMed Central Google Scholar
• Blink, S. E. & Miller, S. D. The contribution of γδ T cells to the pathogenesis of EAE and MS. Curr. Mol. Med. 9, 15–22 (2009).
  CAS PubMed PubMed Central Google Scholar
• Ponomarev, E. D. & Dittel, B. N. γδ T cells regulate the extent and duration of inflammation in the central nervous system by a Fas ligand-dependent mechanism. J. Immunol. 174, 4678–4687 (2005).
  CAS PubMed Google Scholar
• Lees, J. R., Iwakura, Y. & Russell, J. H. Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis induced by adoptive transfer of Th1 cell lines. J. Immunol. 180, 8066–8072 (2008).
  CAS PubMed Google Scholar
• Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008). This paper reports the findings of a Phase II clinical trial that indicate depletion of B cells mediated by rituximab is beneficial in patients with multiple sclerosis.
  CAS PubMed Google Scholar
• McLaughlin, K. A. & Wucherpfennig, K. W. B cells and autoantibodies in the pathogenesis of multiple sclerosis and related inflammatory demyelinating diseases. Adv. Immunol. 98, 121–149 (2008).
  CAS PubMed PubMed Central Google Scholar
• Colombo, M. et al. Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J. Immunol. 164, 2782–2789 (2000).
  CAS PubMed Google Scholar
• Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).
  PubMed Google Scholar
• Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).
  PubMed Google Scholar
• Iglesias, A., Bauer, J., Litzenburger, T., Schubart, A. & Linington, C. T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 36, 220–234 (2001).
  CAS PubMed Google Scholar
• Mathey, E. K. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 204, 2363–2372 (2007).
  CAS PubMed PubMed Central Google Scholar
• Bettelli, E., Baeten, D., Jager, A., Sobel, R. A. & Kuchroo, V. K. Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J. Clin. Invest. 116, 2393–2402 (2006).
  CAS PubMed PubMed Central Google Scholar
• Krishnamoorthy, G., Lassmann, H., Wekerle, H. & Holz, A. Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J. Clin. Invest. 116, 2385–2392 (2006).
  CAS PubMed PubMed Central Google Scholar
• Mann, M. K., Maresz, K., Shriver, L. P., Tan, Y. & Dittel, B. N. B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J. Immunol. 178, 3447–3456 (2007).
  CAS PubMed Google Scholar
• Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nature Immunol. 3, 944–950 (2002).
  CAS Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Duddy, M. et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J. Immunol. 178, 6092–6099 (2007).
  CAS PubMed Google Scholar
• Chung, Y. et al. Critical regulation of early TH17 cell differentiation by interleukin-1 signalling. Immunity 30, 576–587 (2009).
  CAS PubMed PubMed Central Google Scholar