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

Abstract

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...

Apoptosis of Hippocampal Pyramidal Neurons Is Virus Independent in a Mouse Model of Acute Neurovirulent Picornavirus Infection

“…18 These authors proposed that apoptosis of hippocampal neurons is a protective mechanism that serves to initiate viral clearance before the generation of an adaptive immune response. 24 In support of this hypothesis, we found that hippocampal pyramidal neurons in C57BL/6J mice had already progressed to the end stage of the apoptotic cascade by 4 dpi, a time point that precedes both the appearance of virus-specific cytotoxic T cells in the CNS 62,63 and the generation of virus-specific antibody titer. 64 Moreover, the 4-day time point represents a stage in the infection when viral load has already started to wane in the brain, 65,66 suggesting that a mechanism for limiting the spread of infection has already been engaged.…”

Role of Dendritic Cells in Differential Susceptibility to Viral Demyelinating Disease

“…It has recently been shown that generation of the anti-TMEV CD8 + T cell response in the CNS requires a BM-derived APC population [29]. Similarly, induction of the T cell response is impaired by DCs infected with foot-and-mouth disease virus, a member of the Picornaviridae [30].…”

What is immune privilege (not)?

“…Indeed, the uninflamed brain cannot prime naive T cells in situ [17]. Once inflammation is established, DCs appear within the brain parenchyma [16], and a recent study has correlated the appearance of DCs with xenograft rejection [18].…”