H-2D b −/− Mice Are Susceptible to Persistent Infection by Theiler's Virus

Theiler's murine encephalomyelitis virus (TMEV) infection of the brain induces a virus-specific CD8؉ T-cell response in genetically resistant mice. The peak of the immune response to the virus occurs 7 days after infection, with an immunodominant CD8 ؉ T-cell response against a VP2-derived capsid peptide in the context of the D b molecule. The process of activation of antigen-specific T cells that migrate to the brain in the TMEV model has not been defined. The site of antigenic challenge in the TMEV model is directly into the brain parenchyma, a site that is considered immune privileged. We investigated the hypothesis that antiviral CD8 ؉ T-cell responses are initiated in situ upon intracranial inoculation with TMEV. To determine whether a brain parenchymal antigen-presenting cell is responsible for the activation of virus-specific CD8؉ T cells, we evaluated the CD8 ؉ T-cell response to the VP2 peptide in bone marrow chimeras and mutant mice lacking peripheral lymphoid organs. The generation of the anti-TMEV CD8؉ T-cell response in the brain requires priming by a bone marrow-derived antigen-presenting cell and the presence of peripheral lymphoid organs. Although our results show that activation of TMEV-specific CD8؉ T cells occurs in the peripheral lymphoid compartment, they do not exclude the possibility that the immune response to TMEV is initiated by a brain-resident, bone marrow-derived, antigen-presenting cell.The brain is considered an immune-privileged site, protected by physical barriers isolating the organ from circulating immune cells and soluble factors. Most cells in the central nervous system (CNS) normally do not express the major histocompatibility-encoded antigen-presenting molecules that mediate communication between cells in the body and T cells of the immune system. Little is known about how an immune response is mobilized in the brain, particularly because a welldefined lymphatic system is not present in the CNS. To delineate how T-cell-mediated immune responses develop in the brain, we have investigated how an effective antiviral T-cell response to Theiler's murine encephalitis virus (TMEV) becomes established, defining the nature of the antigen-presenting cells (APCs) initiating the response and the anatomical requirements for the T-cell response to develop.TMEV is a mouse picornavirus that causes a biphasic disease in the central nervous system of susceptible mice (39, 54). During the acute phase, the virus selectively infects the gray matter of the brain and spinal cord. By day 3, infection is associated with a massive influx of inflammatory cells into the brain, including CD4 ϩ and CD8 ϩ T cells. In susceptible mice, the ensuing immune response is ineffective and the virus infection persists in glial cells and macrophages for the life of the animal, resulting in extensive demyelination in the brain and spinal cord. In mice expressing the H-2D b class I antigenpresenting molecule, a dominant population of CD8 ϩ T cells specific for the viral peptide VP2 121-130 appears in the brain by da...

Section: Activation Of Virus-specific Cd8mentioning

confidence: 99%

Anatomical and Cellular Requirements for the Activation and Migration of Virus-Specific CD8⁺T Cells to the Brain during Theiler's Virus Infection

Mendez-Fernandez¹,

Hansen²,

Rodriguez

et al. 2005

“…Moreover, H-2D bϪ/Ϫ mice on the resistant C57BL/6 back-ground are susceptible to persistent virus infection (2), while H-2K bϪ/Ϫ mice are not. Taken together, these data suggest that an H-2D b -restricted CTL response is likely involved in virus clearance and is not required for the development of demyelination.…”

mentioning

confidence: 99%

Capsid-Specific Cytotoxic T Lymphocytes Recognize Three Distinct H-2D^b-Restricted Regions of the BeAn Strain of Theiler's Virus and Exhibit Different Cytokine Profiles

Lyman

Lee

Kang

et al. 2002

The role of virus-specific cytotoxic T lymphocytes (CTL) inBased on cytokine profiles, CTL specific for these subdominant epitopes are Tc2, in contrast to CTL for the immunodominant epitope, which are of the Tc1 type. Interestingly, CTL function towards both of these subdominant epitopes is restricted by the H-2D molecule, despite the fact that these epitopes bind both H-2K and H-2D molecules. This skewing toward an H-2D b -restricted response may confer resistance to TMEVinduced demyelinating disease, which is known to be associated with the H-2D genetic locus.

“…3 and Table 1 non-H-2 loci with a major effect on viral RNA load are expressed in the hematopoietic system, most likely in the immune system. Since the Tmevp1 locus has the characteristics of an H-2 class I gene (2,5,6), all loci identified so far with a major effect on Theiler's viral RNA load in the central nervous system of mice seem to act via the immune system. However, we cannot rule out that the non-H-2 loci modify permissiveness of monocytes/macrophages to the virus.…”

mentioning

confidence: 99%

Bone Marrow Chimeras Reveal Non-H-2Hematopoietic Control of Susceptibility to Theiler's Virus Persistent Infection

Aubagnac

Brahic

Bureau

2002

Self Cite

The DA strain of Theiler's murine encephalomyelitis virus persists in the white matter of the spinal cords of susceptible mice. Previous results showed that the difference in susceptibility to viral persistence between the susceptible SJL/J strain and the resistant B10.S strain was due to multiple non-H-2 loci. The respective roles of hematopoietic and nonhematopoietic cells in this difference have been evaluated with bone marrow chimeras. The results show that non-H-2 loci with a major effect on susceptibility are expressed in hematopoietic cells. However, the study of the SJL.B10-D10Mit180-D10Mit74 congenic line suggests that other loci expressed in nonhematopoietic cells also play a role.The primary demyelinating disease induced by Theiler's murine encephalomyelitis virus is studied as an animal model for multiple sclerosis (13,16). After intracranial inoculation, the DA strain of Theiler's virus replicates in neurons of the brain and spinal cord in all strains of mice (30). This encephalomyelitis disappears after 2 weeks regardless of the mouse genotype. However, in genetically susceptible mice the virus persists for the lifetime of the animal in the white matter of the spinal cord in oligodendrocytes, macrophages, and possibly astrocytes (3,15,18,25,26) and induces chronic inflammation and primary demyelination (1,8,17,22). A previous study accounted for the variation of viral RNA level in 17 inbred strains by the interaction of two groups of loci (11). One locus with a major effect was named Tmevp1 for Theiler's murine encephalomyelitis virus persistence locus 1. It is located on chromosome 17 in the H-2D region. Several reports strongly suggest that the same locus controls not only viral persistence but also demyelination (14,20,27,29) and that the H-2D b class I gene plays a major role in resistance to both (4,19,28). The existence of non-H-2 susceptibility loci is shown by the fact that the SJL/J strain is more susceptible to viral persistence than the B10.S strain, although both bear the same H-2 s haplotype (11). Two of these non-H-2 loci, named Tmevp2 and Tmevp3, have been located on chromosome 10 close to Ifng by studying an F 1 (SJL/J ϫ B10.S) ϫ B10.S backcross and SJL/J lines congenic for different B10.S genetic intervals of chromosome 10 (7, 10). However, the Ifng gene does not explain the effect of either Tmevp2 or Tmevp3 (7, 24). One of these studies also showed that other susceptibility loci, with minor effects, must contribute to the difference in viral RNA load between these two mouse strains (10).The non-H-2 loci responsible for the difference in susceptibility between the SJL/J and the B10.S strains could affect the efficiency of the immune response against the virus or the viral life cycle. To distinguish between these possibilities, we measured the viral RNA load in bone marrow chimeras between these two immunocompatible H-2 s strains. The SJL.B10-D10Mit180-D10Mit74 congenic line, which has a small B10.S genetic interval containing the Tmevp3 locus (7), was also studied in an attempt to ...