Theiler's Virus Infection Induces a Predominant Pathogenic CD4⁺T Cell Response to RNA Polymerase in Susceptible SJL/J Mice

Abstract

Theiler's murine encephalomyelitis virus (TMEV)-induced immune-mediated demyelinating disease in susceptible mouse strains has been extensively investigated as a relevant model for human multiple sclerosis. Previous investigations of antiviral T-cell responses focus on immune responses to viral capsid proteins, while virtually nothing is reported on immune responses to nonstructural proteins. In this study, we have identified noncapsid regions recognized by CD4؉ T cells from TMEV-infected mice using an overlapping peptide library. Interestingly, a greater number of CD4 ؉ T cells recognizing an epitope (3D 21-36 ) of the 3D viral RNA polymerase, in contrast to capsid epitopes, were detected in the CNS of TMEV-infected SJL mice, whereas only a minor population of CD4 ؉ T cells from infected C57BL/6 mice recognized this region. The effects of preimmunization and tolerization with these epitopes on the development of demyelinating disease indicated that capsid-specific CD4 ؉ T cells are protective during the early stages of viral infection, whereas 3D 21-36 -specific CD4؉ T cells exacerbate disease development. Therefore, protective versus pathogenic CD4 ؉ T-cell responses directed to TMEV appear to be epitope dependent, and the differences in CD4؉ T-cell responses to these epitopes between susceptible and resistant mice may play an important role in the resistance or susceptibility to virally induced demyelinating disease.Although the cause of human multiple sclerosis (MS) is unknown, one or multiple infectious agents may be involved in the initial infliction of tissue damage leading to autoimmunity. A possible viral association with MS is suggested by epidemiological studies (1,8,44), as well as the detection of viral antigens and virus-specific antibodies in the majority of MS patients (44). Intracerebral infection of the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains induces a progressive demyelinating disease that is similar to a form of MS (25). In addition, various immunological and genetic factors that affect the disease outcome in TMEV-infected mice closely parallel those associated with the development of MS (22). Furthermore, recent studies suggest that TMEV is an emerging human viral group (6, 24). Therefore, TMEV-induced demyelinating disease (TMEV-IDD) is an attractive and relevant infectious model for studying the underlying mechanisms of MS.Previous immunological studies with susceptible SJL mice suggested that a Th1 response to viral capsid proteins is involved in the pathogenesis of demyelination (19,36,49,50). The major population of Th cells specific for TMEV during the course of disease essentially recognizes three predominant viral epitopes (VP1 233-250 , VP2 [74][75][76][77][78][79][80][81][82][83][84][85][86] , and VP3 24-37 ), one each on the external capsid proteins (11,48,49). However, a recent study indicated that Ͻ4% of the CD4 ϩ T cells in the central nervous systems (CNS) of TMEV-infected susceptible SJL/J (SJL) mice are reactive to viral ...

Epitope-Specific CD8+T Cells Play a Differential Pathogenic Role in the Development of a Viral Disease Model for Multiple Sclerosis

“…However, epitope-specific CD4 ϩ T cells can be protective, depending on the time of availability in conjunction with viral infection (36). In addition, the pathogenicity of CD4 ϩ T cells may also be dependent on the recognizing viral epitopes (21,54). Therefore, epitope-specific cytotoxic CD8 ϩ T cells may similarly play a protective or pathogenic role depending on the type and/or reactivity of epitopes.…”

The Role of Interleukin-6 in the Expression of PD-1 and PDL-1 on Central Nervous System Cells following Infection with Theiler's Murine Encephalomyelitis Virus

“…Th17 cells, in contrast to Th1 cells, promote viral persistence by enhancing the survival of TMEVinfected cells (12). Moreover, the immunization of SJL mice with UV-inactivated TMEV prior to viral infection, which promotes the Th1 response, confers protection, whereas immunization after viral infection, which promotes the Th17 response, exacerbates the development of TMEV-IDD (11,13). These data suggest that distinct immune responses against TMEV involve the protection and/or pathogenesis of TMEV-IDD.…”

“…ϩ T cell responses are pathogenic in susceptible SJL mice (9,11). In addition, the level of virusspecific Th1 cells in the CNS of infected mice is significantly higher in resistant B6 mice than susceptible SJL mice, suggesting a protective role for Th1 cells (9).…”

Therapeutic effects of anti-Delta1 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease

“…Thus, it seems that anti-Delta1 mAb reduced the development of TMEV-IDD without interfering viral persistence. Consistently, viral levels may not be necessarily associated with the development of demyelinating disease in this model (Myoung et al, 2008;Jin et al, 2009).…”