Potential role of CD4+ T cell-mediated apoptosis of activated astrocytes in Theiler's virus-induced demyelination.
Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains results in a chronic, immune-mediated demyelinating disease similar to human multiple sclerosis. Here, we examined the role of astrocytes as an APC population in TMEV-induced demyelination and assessed the potential consequences of T cell activation following Ag presentation. IFN-gamma-pretreated astrocytes were able to process and present all the predominant T cell epitopes of TMEV to virus-specific T cell hybridomas, clones, as well as bulk T cells. Despite low levels of proliferation of T cells due to prostaglandins produced by astrocytes, such Ag presentation by activated astrocytes induced the production of IFN-gamma, a representative proinflammatory cytokine, in TMEV-specific Th cell clones derived from the CNS of virus-infected mice. Furthermore, these Th cell clones mediate lysis of the astrocytes in vitro in a Fas-dependent mechanism. TUNEL staining of CNS tissue demonstrates the presence of apoptotic GFAP+ cells in the white matter of TMEV-infected mice. These results strongly suggest that astrocytes could play an important role in the pathogenesis of TMEV-induced demyelination by activating T cells, subsequently leading to T cell-mediated apoptosis of astrocytes and thereby compromising the blood-brain barrier.
Palma
J P
JP
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.
Yauch
R L
RL
Lang
S
S
Kim
B S
BS
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018188:Cardiovirus Infections / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003711:Demyelinating Diseases / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D006825:Hybridomas; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D017945:Theilovirus / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007371:Interferon-gamma; D007213:Indomethacin