An early, abundant cytotoxic T-lymphocyte response against Theiler's virus is critical for preventing viral persistence

Dethlefs, Sven; Brahic, Michel; Larsson-Sciard, Eva-Lotta

doi:10.1128/jvi.71.11.8875-8878.1997

Cited by 67 publications

(29 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Generation of a strong virus-specific CD8 + cytotoxic T lymphocyte (CTL) response early in infection may confer resistance to subsequent development of demyelinating disease. Splenocytes from resistant C57BL/6 mice mount a faster and stronger anti-TMEV CTL response than splenocytes from susceptible SJL/J mice (Dethlefs et al, 1997). However, a recent study demonstrated within the CNS of TMEV-infected SJL/J mice CD8 + T cells against a dominant VP3 virus capsid epitope (Kang et al, 2002).…”

Section: Theiler's Murine Encephalomyelitis Virus (Tmev)mentioning

confidence: 95%

Virus Demyelination

Fazakerley

Walker

2003

J Neurovirol

View full text Add to dashboard Cite

A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.

show abstract

Section: Theiler's Murine Encephalomyelitis Virus (Tmev)mentioning

confidence: 95%

Virus Demyelination

Fazakerley

Walker

2003

J Neurovirol

View full text Add to dashboard Cite

show abstract

“…Resistant B6 mice are capable of generating a strong CTL response specific for the VP2 protein of TMEV as early as 3 days p.i. (96,242,244). A predominant H-2D b -restricted VP2 [121][122][123][124][125][126][127][128][129][130] viral peptide in BeAn-or DA-infected mice recognized by CTL has been identified (322,354).…”

Section: Cytotoxic T Lymphocytesmentioning

confidence: 99%

“…Two other H-2D brestricted TMEV epitopes (VP [165][166][167][168][169][170][171][172][173] and VP 110-120 ) recognized by CTL have been also described (270). In contrast, only a weak TMEV-specific CTL response is generated in the CNS of TMEV-infected SJL mice (96,242,244). Although the appearance of CD8 ϩ T cells infiltrating the CNS of TMEVinfected SJL mice at 11 days p.i.…”

Section: Cytotoxic T Lymphocytesmentioning

confidence: 99%

Theiler's Virus Infection: a Model for Multiple Sclerosis

Chang²,

et al. 2004

View full text Add to dashboard Cite

Both genetic background and environmental factors, very probably viruses, appear to play a role in the etiology of multiple sclerosis (MS). Lessons from viral experimental models suggest that many different viruses may trigger inflammatory demyelinating diseases resembling MS. Theiler's virus, a picornavirus, induces in susceptible strains of mice early acute disease resembling encephalomyelitis followed by late chronic demyelinating disease, which is one of the best, if not the best, animal model for MS. During early acute disease the virus replicates in gray matter of the central nervous system but is eliminated to very low titers 2 weeks postinfection. Late chronic demyelinating disease becomes clinically apparent approximately 2 weeks later and is characterized by extensive demyelinating lesions and mononuclear cell infiltrates, progressive spinal cord atrophy, and axonal loss. Myelin damage is immunologically mediated, but it is not clear whether it is due to molecular mimicry or epitope spreading. Cytokines, nitric oxide/reactive nitrogen species, and costimulatory molecules are involved in the pathogenesis of both diseases. Close similarities between Theiler's virus-induced demyelinating disease in mice and MS in humans, include the following: major histocompatibility complex-dependent susceptibility; substantial similarities in neuropathology, including axonal damage and remyelination; and paucity of T-cell apoptosis in demyelinating disease. Both diseases are immunologically mediated. These common features emphasize the close similarities of Theiler's virus-induced demyelinating disease in mice and MS in humans

show abstract

“…Although data indicating the pivotal role of CD4 C T cells in the pathogenesis of TMEV-IDD have been previously reported, an equally compelling body of work also demonstrates the critical role CD8 C T cells play in the control of disease susceptibility. It has been clearly shown that : 1) susceptibility/resistance to TMEV maps to Class I H-2D (Clatch et al, 1985;Rodriguez and David, 1985;Rodriguez et al, 1986b;Kappel et al, 1991); 2) monoclonal antibody depletion of CD8 C T cells leads to earlier onset and increased disease severity ; 3) virus-speci c CTLs are found at a higher frequency in the CNS of resistant mice than susceptible mice, and in vivo IL-2 therapy can effectively boost CTL responses in susceptible strains and diminish viral persistence (Lindsley et al, 1991;Pena Rossi et al, 1991;Lin et al, 1995;Dethlefs et al, 1997); 4) perforin KO mice on the normally resistant C57BL/6 background are able to be persistently in-fected with TMEV (Pena-Rossi et al, 1998); and 5) in the BALB/c system, transfer of a CD8 C population from the spleen of TMEV-infected donors protects recipients from disease induction (Nicholson et al, 1996;Haynes et al, 2000). Taken as a whole, our data in the susceptible SJL/J mouse supplement and are consistent with these previously documented observations and further support a critical role for CD8 C T cells in regulating disease susceptibility and severity.…”

Section: Discussionmentioning

confidence: 99%

CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology

Begolka

2001

J Neurovirol

View full text Add to dashboard Cite

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.

show abstract

An early, abundant cytotoxic T-lymphocyte response against Theiler's virus is critical for preventing viral persistence

Cited by 67 publications

References 23 publications

Virus Demyelination

Virus Demyelination

Theiler's Virus Infection: a Model for Multiple Sclerosis

CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology

Contact Info

Product

Resources

About