T cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Clinical and Experimental Immunology - Tập 162 Số 1 - Trang 1-11 - 2010
Jean M. Fletcher1, Stephen J. Lalor2, Cheryl Sweeney2, Niall Tubridy3, Kingston H. G. Mills2
1Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, St Vincent's University Hospital, Dublin, Ireland.
2Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, and
3Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland

Tóm tắt

SummaryMultiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4+ T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8+ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

Từ khóa


Tài liệu tham khảo

Frohman, 2006, Multiple sclerosis – the plaque and its pathogenesis, N Engl J Med, 354, 942, 10.1056/NEJMra052130

Compston, 2008, Multiple sclerosis, Lancet, 372, 1502, 10.1016/S0140-6736(08)61620-7

McDonald, 1970, The effects of experimental demyelination on conduction in the central nervous system, Brain, 93, 583, 10.1093/brain/93.3.583

Polman, 2006, A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis, N Engl J Med, 354, 899, 10.1056/NEJMoa044397

Stromnes, 2006, Active induction of experimental allergic encephalomyelitis, Nat Protoc, 1, 1810, 10.1038/nprot.2006.285

Furtado, 2008, Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis, J Immunol, 181, 4648, 10.4049/jimmunol.181.7.4648

O'Connor, 2008, Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis, J Immunol, 181, 3750, 10.4049/jimmunol.181.6.3750

Steinman, 1999, Assessment of animal models for MS and demyelinating disease in the design of rational therapy, Neuron, 24, 511, 10.1016/S0896-6273(00)81107-1

Stromnes, 2006, Passive induction of experimental allergic encephalomyelitis, Nat Protoc, 1, 1952, 10.1038/nprot.2006.284

Teitelbaum, 1971, Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide, Eur J Immunol, 1, 242, 10.1002/eji.1830010406

Yednock, 1992, Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin, Nature, 356, 63, 10.1038/356063a0

Panitch, 1987, Exacerbations of multiple sclerosis in patients treated with gamma interferon, Lancet, 1, 893, 10.1016/S0140-6736(87)92863-7

Ferber, 1996, Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE), J Immunol, 156, 5, 10.4049/jimmunol.156.1.5

Bettelli, 2004, Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis, J Exp Med, 200, 79, 10.1084/jem.20031819

Cua, 2003, Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain, Nature, 421, 744, 10.1038/nature01355

Langrish, 2005, IL-23 drives a pathogenic T cell population that induces autoimmune inflammation, J Exp Med, 201, 233, 10.1084/jem.20041257

Harrington, 2005, Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages, Nat Immunol, 6, 1123, 10.1038/ni1254

Mangan, 2006, Transforming growth factor-beta induces development of the T(H)17 lineage, Nature, 441, 231, 10.1038/nature04754

Das, 2009, Transforming growth factor {beta} is dispensable for the molecular orchestration of Th17 cell differentiation, J Exp Med, 206, 2407, 10.1084/jem.20082286

Sutton, 2006, A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis, J Exp Med, 203, 1685, 10.1084/jem.20060285

Yang, 2008, IL-21 and TGF-beta are required for differentiation of human T(H)17 cells, Nature, 454, 350, 10.1038/nature07021

Manel, 2008, The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat, Nat Immunol, 9, 641, 10.1038/ni.1610

Wilson, 2007, Development, cytokine profile and function of human interleukin 17-producing helper T cells, Nat Immunol, 8, 950, 10.1038/ni1497

Santarlasci, 2009, TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells, Eur J Immunol, 39, 207, 10.1002/eji.200838748

Hofstetter, 2005, Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis, Cell Immunol, 237, 123, 10.1016/j.cellimm.2005.11.002

Komiyama, 2006, IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis, J Immunol, 177, 566, 10.4049/jimmunol.177.1.566

Haak, 2009, IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice, J Clin Invest, 119, 61

Coquet, 2008, Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis, J Immunol, 180, 7097, 10.4049/jimmunol.180.11.7097

Kreymborg, 2007, IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis, J Immunol, 179, 8098, 10.4049/jimmunol.179.12.8098

Nowak, 2009, IL-9 as a mediator of Th17-driven inflammatory disease, J Exp Med, 206, 1653, 10.1084/jem.20090246

Lees, 2008, 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, 10.4049/jimmunol.180.12.8066

Kroenke, 2008, 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, 10.1084/jem.20080159

Stromnes, 2008, Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells, Nat Med, 14, 337, 10.1038/nm1715

Abromson-Leeman, 2009, Encephalitogenic T cells that stably express both T-bet and RORgammat consistently produce IFNgamma but have a spectrum of IL-17 profiles, J Neuroimmunol, 215, 10, 10.1016/j.jneuroim.2009.07.007

Shi, 2008, Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells, J Immunol, 181, 7205, 10.4049/jimmunol.181.10.7205

Yang, 2009, T-bet is essential for encephalitogenicity of both Th1 and Th17 cells, J Exp Med, 206, 1549, 10.1084/jem.20082584

Gocke, 2007, T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity, J Immunol, 178, 1341, 10.4049/jimmunol.178.3.1341

Thakker, 2007, IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis, J Immunol, 178, 2589, 10.4049/jimmunol.178.4.2589

Gyulveszi, 2009, IL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivo, Eur J Immunol, 39, 1864, 10.1002/eji.200939305

Reboldi, 2009, 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, Nat Immunol, 10, 514, 10.1038/ni.1716

Sallusto, 2009, Human Th17 cells in infection and autoimmunity, Microbes Infect, 11, 620, 10.1016/j.micinf.2009.04.004

Lock, 2002, Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis, Nat Med, 8, 500, 10.1038/nm0502-500

Montes, 2009, Oligoclonal myelin-reactive T-cell infiltrates derived from multiple sclerosis lesions are enriched in Th17 cells, Clin Immunol, 130, 133, 10.1016/j.clim.2008.08.030

Tzartos, 2008, 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, 10.2353/ajpath.2008.070690

Matusevicius, 1999, Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis, Mult Scler, 5, 101, 10.1177/135245859900500206

Durelli, 2009, T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta, Ann Neurol, 65, 499, 10.1002/ana.21652

Frisullo, 2008, IL17 and IFNgamma production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis, Cytokine, 44, 22, 10.1016/j.cyto.2008.08.007

Kebir, 2007, Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation, Nat Med, 13, 1173, 10.1038/nm1651

Kebir, 2009, Preferential recruitment of interferon-gamma-expressing T(H)17 cells in multiple sclerosis, Ann Neurol, 66, 390, 10.1002/ana.21748

Sawcer, 2005, A high-density screen for linkage in multiple sclerosis, Am J Hum Genet, 77, 454, 10.1086/444547

Friese, 2009, Pathogenic CD8(+) T cells in multiple sclerosis, Ann Neurol, 66, 132, 10.1002/ana.21744

Weiss, 2007, CD8+ T cells in inflammatory demyelinating disease, J Neuroimmunol, 191, 79, 10.1016/j.jneuroim.2007.09.011

Chen, 2009, Novel CD8(+) regulatory T cells suppress experimental autoimmune encephalomyelitis by TGF-beta- and IFN-gamma-dependent mechanisms, Eur J Immunol, 39, 3423, 10.1002/eji.200939441

Wucherpfennig, 1992, Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions, Proc Natl Acad Sci USA, 89, 4588, 10.1073/pnas.89.10.4588

Shimonkevitz, 1993, Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis, Proc Natl Acad Sci USA, 90, 923, 10.1073/pnas.90.3.923

Kobayashi, 1997, Aggravation of murine experimental allergic encephalomyelitis by administration of T-cell receptor gammadelta-specific antibody, J Neuroimmunol, 73, 169, 10.1016/S0165-5728(96)00187-7

Ponomarev, 2005, Gamma delta T cells regulate the extent and duration of inflammation in the central nervous system by a Fas ligand-dependent mechanism, J Immunol, 174, 4678, 10.4049/jimmunol.174.8.4678

Ponomarev, 2004, Gamma delta T cell regulation of IFN-gamma production by central nervous system-infiltrating encephalitogenic T cells: correlation with recovery from experimental autoimmune encephalomyelitis, J Immunol, 173, 1587, 10.4049/jimmunol.173.3.1587

Rajan, 1996, A pathogenic role for gamma delta T cells in relapsing-remitting experimental allergic encephalomyelitis in the SJL mouse, J Immunol, 157, 941, 10.4049/jimmunol.157.2.941

Rajan, 1998, The effect of gammadelta T cell depletion on cytokine gene expression in experimental allergic encephalomyelitis, J Immunol, 160, 5955, 10.4049/jimmunol.160.12.5955

Spahn, 1999, Decreased severity of myelin oligodendrocyte glycoprotein peptide 33-35-induced experimental autoimmune encephalomyelitis in mice with a disrupted TCR delta chain gene, Eur J Immunol, 29, 4060, 10.1002/(SICI)1521-4141(199912)29:12<4060::AID-IMMU4060>3.0.CO;2-S

Odyniec, 2004, Gammadelta T cells enhance the expression of experimental autoimmune encephalomyelitis by promoting antigen presentation and IL-12 production, J Immunol, 173, 682, 10.4049/jimmunol.173.1.682

Cardona, 2002, Gamma/delta T cell-deficient mice exhibit reduced disease severity and decreased inflammatory response in the brain in murine neurocysticercosis, J Immunol, 169, 3163, 10.4049/jimmunol.169.6.3163

Koenecke, 2009, In vivo application of mAb directed against the gammadelta TCR does not deplete but generates ‘invisible’ gammadelta T cells, Eur J Immunol, 39, 372, 10.1002/eji.200838741

Lockhart, 2006, IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection, J Immunol, 177, 4662, 10.4049/jimmunol.177.7.4662

Shibata, 2007, Resident Vdelta1+ gammadelta T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production, J Immunol, 178, 4466, 10.4049/jimmunol.178.7.4466

Sutton, 2009, Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity, Immunity, 31, 331, 10.1016/j.immuni.2009.08.001

Hori, 2004, Foxp3: a critical regulator of the development and function of regulatory T cells, Microbes Infect, 6, 745, 10.1016/j.micinf.2004.02.020

Fontenot, 2003, Foxp3 programs the development and function of CD4+CD25+ regulatory T cells, Nat Immunol, 4, 330, 10.1038/ni904

Sakaguchi, 1995, Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases, J Immunol, 155, 1151, 10.4049/jimmunol.155.3.1151

Roncarolo, 2006, Interleukin-10-secreting type 1 regulatory T cells in rodents and humans, Immunol Rev, 212, 28, 10.1111/j.0105-2896.2006.00420.x

Liston, 2007, Thymic development and peripheral homeostasis of regulatory T cells, Curr Opin Immunol, 19, 176, 10.1016/j.coi.2007.02.005

Curotto de Lafaille, 2009, Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?, Immunity, 30, 626, 10.1016/j.immuni.2009.05.002

Liu, 2006, CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells, J Exp Med, 203, 1701, 10.1084/jem.20060772

Martinez-Forero, 2008, IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis, Eur J Immunol, 38, 576, 10.1002/eji.200737271

Astier, 2006, Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis, J Clin Invest, 116, 3252, 10.1172/JCI29251

Venken, 2008, Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level, Immunology, 123, 79, 10.1111/j.1365-2567.2007.02690.x

Feger, 2007, Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients, Clin Exp Immunol, 147, 412, 10.1111/j.1365-2249.2006.03271.x

Haas, 2005, Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis, Eur J Immunol, 35, 3343, 10.1002/eji.200526065

Venken, 2006, Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression, J Neurosci Res, 83, 1432, 10.1002/jnr.20852

Viglietta, 2004, Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis, J Exp Med, 199, 971, 10.1084/jem.20031579

Tsaknaridis, 2003, Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity, J Neurosci Res, 74, 296, 10.1002/jnr.10766

Huan, 2005, Decreased FOXP3 levels in multiple sclerosis patients, J Neurosci Res, 81, 45, 10.1002/jnr.20522

Frisullo, 2008, Regulatory T cells fail to suppress CD4(+)T-bet(+) T cells in relapsing multiple sclerosis patients, Immunology, 127, 418, 10.1111/j.1365-2567.2008.02963.x

Venken, 2007, A CFSE based assay for measuring CD4+CD25+ regulatory T cell mediated suppression of auto-antigen specific and polyclonal T cell responses, J Immunol Methods, 322, 1, 10.1016/j.jim.2007.01.025

De Andres, 2007, Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis, J Neuroimmunol, 182, 204, 10.1016/j.jneuroim.2006.09.012

Kumar, 2006, CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis, J Neuroimmunol, 180, 178, 10.1016/j.jneuroim.2006.08.003

Korporal, 2008, Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells, Arch Neurol, 65, 1434, 10.1001/archneur.65.11.1434

Hong, 2005, Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3, Proc Natl Acad Sci USA, 102, 6449, 10.1073/pnas.0502187102

Xu, 2009, Glucocorticoid treatment restores the impaired suppressive function of regulatory T cells in patients with relapsing-remitting multiple sclerosis, Clin Exp Immunol, 158, 26, 10.1111/j.1365-2249.2009.03987.x

Michel, 2008, Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis, J Clin Invest, 118, 3411

Fletcher, 2009, CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis, J Immunol, 183, 7602, 10.4049/jimmunol.0901881

Lafaille, 1994, High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice, Cell, 78, 399, 10.1016/0092-8674(94)90419-7

Olivares-Villagomez, 1998, Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis, J Exp Med, 188, 1883, 10.1084/jem.188.10.1883

Kohm, 2002, 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, 10.4049/jimmunol.169.9.4712

Zhang, 2004, IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells, Int Immunol, 16, 249, 10.1093/intimm/dxh029

Walsh, 2009, Infection with a helminth parasite attenuates autoimmunity through TGF-beta-mediated suppression of Th17 and Th1 responses, J Immunol, 183, 1577, 10.4049/jimmunol.0803803

Reddy, 2004, Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis, Proc Natl Acad Sci USA, 101, 15434, 10.1073/pnas.0404444101

Stephens, 2005, CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity, Proc Natl Acad Sci USA, 102, 17418, 10.1073/pnas.0507454102

Korn, 2007, Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation, Nat Med, 13, 423, 10.1038/nm1564

Liu, 2006, Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE, Nat Med, 12, 518, 10.1038/nm1402

McGeachy, 2005, Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system, J Immunol, 175, 3025, 10.4049/jimmunol.175.5.3025

Zhang, 2006, Recovery from experimental allergic encephalomyelitis is TGF-beta dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells, Int Immunol, 18, 495, 10.1093/intimm/dxh390

O'Connor, 2007, The inflamed central nervous system drives the activation and rapid proliferation of Foxp3+ regulatory T cells, J Immunol, 179, 958, 10.4049/jimmunol.179.2.958

Cox, 2005, Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis, Eur J Immunol, 35, 3332, 10.1002/eji.200535075

Coles, 2008, Alemtuzumab vs. interferon beta-1a in early multiple sclerosis, N Engl J Med, 359, 1786, 10.1056/NEJMoa0802670

Stephens, 2009, Curing CNS autoimmune disease with myelin-reactive Foxp3+ Treg, Eur J Immunol, 39, 1108, 10.1002/eji.200839073

Lima, 2009, Briakinumab, Exp Opin Biol Ther, 9, 1107, 10.1517/14712590903092188

Melnikova, 2009, Psoriasis market, Nat Rev Drug Discov, 8, 767, 10.1038/nrd2996

Van Den Berg, 2009, IL-17 as a future therapeutic target for rheumatoid arthritis, Nat Rev Rheumatol, 5, 549, 10.1038/nrrheum.2009.179

Segal, 2008, Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study, Lancet Neurol, 7, 796, 10.1016/S1474-4422(08)70173-X

Longbrake, 2009, Why did IL-12/IL-23 antibody therapy fail in multiple sclerosis?, Expert Rev Neurother, 9, 319, 10.1586/14737175.9.3.319

Mills, 2008, Induction, function and regulation of IL-17-producing T cells, Eur J Immunol, 38, 2636, 10.1002/eji.200838535

Chen, 2006, Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis, J Clin Invest, 116, 1317, 10.1172/JCI25308

Eugster, 1998, IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis, Eur J Immunol, 28, 2178, 10.1002/(SICI)1521-4141(199807)28:07<2178::AID-IMMU2178>3.0.CO;2-D

Korn, 2008, 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, 10.1073/pnas.0809850105

Kleinschek, 2007, IL-25 regulates Th17 function in autoimmune inflammation, J Exp Med, 204, 161, 10.1084/jem.20061738