title: CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology.
abstract: Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) induces a chronic, progressive demyelinating disease in susceptible mouse strains characterized by inflammatory mononuclear infiltrates and spastic hind limb paralysis. Our lab has previously demonstrated a critical role for TMEV- and myelin-specific CD4(+) T cells in initiating and perpetuating this pathology. It has however, also been shown that the MHC class I loci are associated with susceptibility/resistance to TMEV infection and persistence. For this reason, we investigated the contribution of CD8(+) T cells to the TMEV-induced demyelinating pathology in the highly susceptible SJL/J mouse strain. Here we show that beta2M-deficient SJL mice have similar disease incidence rates to wild-type controls, however beta2M-deficient mice demonstrated earlier onset of clinical disease, elevated in vitro responses to TMEV and myelin proteolipid (PLP) epitopes, and significantly higher levels of CNS demyelination and macrophage infiltration at 50 days post-infection. beta2M-deficient mice also displayed a significant elevation in persisting viral titers, as well as an increase in macrophage-derived pro-inflammatory cytokine mRNA expression in the spinal cord at this same time point. Taken together, these results indicate that CD8(+) T cells are not required for clinical or histologic disease initiation or progression in TMEV-infected SJL mice. Rather, these data stress the critical role of CD4(+) T cells in this capacity and further emphasize the potential for CD8(+) T cells to contribute to protection from TMEV-induced demyelination.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Begolka
authors.forename: L M
authors.initials: LM
authors.lastname: Haynes
authors.forename: J K
authors.initials: JK
authors.lastname: Olson
authors.forename: J
authors.initials: J
authors.lastname: Padilla
authors.forename: K L
authors.initials: KL
authors.lastname: Neville
authors.forename: M
authors.initials: M
authors.lastname: Dal Canto
authors.forename: J
authors.initials: J
authors.lastname: Palma
authors.forename: B S
authors.initials: BS
authors.lastname: Kim
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001921:Brain / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003711:Demyelinating Diseases; D000939:Epitopes / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006968:Hypersensitivity, Delayed / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013116:Spinal Cord / Q000473:pathology / Q000821:virology; D017945:Theilovirus / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics
chemical_list: D000956:Antigens, Viral; D016827:CD8 Antigens; D036022:Capsid Proteins; D016207:Cytokines; D000939:Epitopes; D018836:Inflammation Mediators; D018991:Myelin Proteolipid Protein; C111390:OVA 323-339; D010446:Peptide Fragments; D012333:RNA, Messenger; C442556:VP2 protein, Theilovirus; D001613:beta 2-Microglobulin; C435023:myelin proteolipid protein (139-151); D010047:Ovalbumin