Background and objectives: Since CD8+ T cells may be important in the pathogenesis of multiple sclerosis (MS), we examined their role in the DA rat experimental autoimmune encephalomyelitis (EAE) model induced by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG).
Methods: The inflammatory infiltrate in the spinal cord of affected animals was assessed by histology, electrophysiology and flow cytometry during the course of the disease (the first peak, remission and the second peak). The proportions of activated/memory effector (CD8+CD44+) and putative suppressor (CD8+CD28-, CD8+CD25high) CD8+ T cells in the draining lymph nodes were determined. To explore the role of CD8+ T cells, similar experiments were performed in CD8+ T cell depleted rats, before, during and after the first peak of the disease.
Results: Throughout the disease, both CD4+ T cells and macrophages/activated microglia outnumbered CD8+ T cells within the spinal cord. The number of putative suppressor CD8+ T cells increased significantly both during and after the first peak suggesting the induction of a regulatory CD8+ T-cell response. However, antibody-mediated depletion of CD8+ T cells before induction of the disease, or after the first peak, did not significantly alter the incidence, severity or course of rMOG-induced EAE.
Conclusions: The findings suggest that CD8+ T cells do not play a significant role in the pathogenesis or regulation of EAE induced by rMOG in DA rats. In this respect, rMOG-induced EAE is not an appropriate model for studying the role of CD8+ T cells in MS.
TraugottUReinherzELRaineCS. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science1983; 219: 308–310.
2.
BoossJEsiriMMTourtellotteWWMasonDY. Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J Neurol Sci1983; 62: 219–232.
3.
HauserSLBhanAKGillesFKempMKerrCWeinerHL. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol1986; 19: 578–587.
4.
WoodroofeMNBellamyASFeldmannMDavisonANCuznerML. Immunocytochemical characterisation of the immune reaction in the central nervous system in multiple sclerosis. Possible role for microglia in lesion growth. J Neurol Sci1986; 74: 135–152.
5.
HayashiTMorimotoCBurksJSKerrCHauserSL. Dual-label immunocytochemistry of the active multiple sclerosis lesion: major histocompatibility complex and activation antigens. Ann Neurol1988; 24: 523–531.
6.
GayFWDryeTJDickGWEsiriMM. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain1997; 120: 1461–1483.
7.
BitschASchuchardtJBunkowskiSKuhlmannTBruckW. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain2000; 123: 1174–1183.
8.
BabbeHRoersAWaismanALassmannHGoebelsNHohlfeldR. 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 Med2000; 192: 393–404.
9.
JacobsenMCepokSQuakEHappelMGaberRZieglerA. Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain2002; 125: 538–550.
10.
SkulinaCSchmidtSDornmairKBabbeHRoersARajewskyK. Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci U S A2004; 101: 2428–2433.
11.
NaSYCaoYTobenCNitschkeLStadelmannCGoldR. Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system. Brain2008; 131: 2353–2365.
12.
SaxenaABauerJScheiklTZappullaJAudebertMDesboisS. Cutting edge: Multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol2008; 181: 1617–1621.
13.
HusebyESLiggittDBrabbTSchnabelBOhlenCGovermanJ. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med2001; 194: 669-676.
14.
SunDWhitakerJNHuangZLiuDColecloughCWekerleH. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol2001; 166: 7579–7587.
15.
FordMLEvavoldBD. Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol2005; 35: 76–85.
16.
JiangHZhangSIPernisB. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science1992; 256: 1213–1215.
17.
KohDRFung-LeungWPHoAGrayDcha-OrbeaHMakTW. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice. Science1992; 256: 1210–1213.
18.
HuDIkizawaKLuLSanchiricoMEShinoharaMLCantorH. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol2004; 5: 516–523.
19.
StorchMKStefferlABrehmUWeissertRWallstromEKerschensteinerM. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol1998; 8: 681–694.
20.
RedfordEJHallSMSmithKJ. Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor. Brain1995; 118: 869–878.
21.
RennoTKrakowskiMPiccirilloCLinJYOwensT. TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. J Immunol1995; 154: 944–953.
22.
CridlandJCBoothVAshleyFPCurtisMAWilsonRFShepherdP. Preliminary characterisation of antigens recognised by monoclonal antibodies raised to Porphyromonas gingivalis and by sera from patients with periodontitis. J Periodontal Res1994; 29: 339–347.
23.
BecanovicKWallstromEKornekBGlaserABromanKWDahlmanI. New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. J Immunol2003; 170: 1062–1069.
24.
SedgwickJDSchwenderSImrichHDorriesRButcherGWter MeulenV. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A1991; 88: 7438–7442.
25.
BisikirskaBColganJLubanJBluestoneJAHeroldKC. TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin Invest2005; 115: 2904–2913.
26.
XystrakisEDejeanASBernardIDruetPLiblauRGonzalez-DuniaD. Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation. Blood2004; 104: 3294–3301.
27.
NajafianNChitnisTSalamaADZhuBBenouCYuanX. Regulatory functions of CD8+CD28- T cells in an autoimmune disease model. J Clin Invest2003; 112: 1037–1048.
28.
SedgwickJDFordALFoulcherEAirriessR. Central nervous system microglial cell activation and proliferation follows direct interaction with tissue-infiltrating T cell blasts. J Immunol1998; 160: 5320–5330.
29.
JiangHWareRStallAFlahertyLChessLPernisB. Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing V beta 8 TCR: a role of the Qa-1 molecule. Immunity1995; 2: 185–194.
30.
JiangHBraunsteinNSYuBWinchesterRChessL. CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice. Proc Natl Acad Sci U S A2001; 98: 6301–6306.
31.
JiangHCurranSRuiz-VazquezELiangBWinchesterRChessL. Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A2003; 100: 8378–8383.
32.
ChenAMKhannaNStohlmanSABergmannCC. Virus-specific and bystander CD8 T cells recruited during virus-induced encephalomyelitis. J Virol2005; 79: 4700–4708.
33.
LucchinettiCBruckWParisiJScheithauerBRodriguezMLassmannH. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol2000; 47: 707–717.
34.
KornekBStorchMKWeissertRWallstroemEStefferlAOlssonT. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol2000; 157: 267–276.
35.
GoldRLiningtonCLassmannH. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain2006; 129: 1953–1971.
36.
WeissertRWallstromEStorchMKStefferlALorentzenJLassmannH. MHC haplotype-dependent regulation of MOG-induced EAE in rats. J Clin Invest1998; 102: 1265–1273.
37.
SeifertTBauerJWeissertRFazekasFStorchMK. Differential expression of sonic hedgehog immunoreactivity during lesion evolution in autoimmune encephalomyelitis. J Neuropathol Exp Neurol2005; 64: 404–411.
KuhlmannTLingfeldGBitschASchuchardtJBruckW. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain2002; 125: 2202–2212.
40.
EikelenboomMJKillesteinJIzeboudTKalkersNFvan LierRABarkhofF. Chemokine receptor expression on T cells is related to new lesion development in multiple sclerosis. J Neuroimmunol2002; 133: 225–232.
41.
ArbourNLapointeRSaikaliPMcCreaERegenTAntelJP. A new clinically relevant approach to expand myelin specific T cells. J Immunol Methods2006; 310: 53–61.
