Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity
Catriona A. Wagner, Pamela J. Roqué, Trevor R. Mileur, Denny Liggitt, Joan M. Goverman
Catriona A. Wagner, Pamela J. Roqué, Trevor R. Mileur, Denny Liggitt, Joan M. Goverman
View: Text | PDF
Research Article Autoimmunity

Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4+ T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8+ T cells in disease pathogenesis. We previously showed that an MHC class I–restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4+ T cell–initiated EAE. Here, we investigated whether naive MBP-specific CD8+ T cells recruited to the CNS during CD4+ T cell–initiated EAE engaged in determinant spreading and influenced disease. We found that the MBP-specific CD8+ T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I–restricted MBP ligand in the brain compared with the spinal cord. Infiltration of MBP-specific CD8+ T cells enhanced ROS production in the brain only in these cell types and only when the MBP-specific CD8+ T cells expressed Fas ligand (FasL). These results suggest that myelin-specific CD8+ T cells may contribute to disease pathogenesis via a FasL-dependent mechanism that preferentially promotes lesion formation in the brain.

Authors

Catriona A. Wagner, Pamela J. Roqué, Trevor R. Mileur, Denny Liggitt, Joan M. Goverman

×

Figure 3

Recruitment of 8.8 CD8+ T cells enhances chemokine and cytokine gene expression as well as the numbers of donor CD4+ T cells, MdCs, and monocytes in the brain.

Options: View larger image (or click on image) Download as PowerPoint
Recruitment of 8.8 CD8+ T cells enhances chemokine and cytokine gene exp...
EAE was induced by transfer of Thy1.1+ MOG-specific CD4+ T cells into Thy1.2+ WT mice that had received Thy1.2+ WT or 8.8 CD8+ T cells. (A and B) Brain and spinal cord (SC) tissues were harvested 6 days after CD4+ T cell transfer (WT, n = 9; 8.8, n = 10). Chemokine (A) and cytokine (B) gene expression were analyzed directly ex vivo by quantitative PCR. All data were normalized to GAPDH. The fold change was calculated relative to gene expression values in irradiated healthy control mice (n = 2). (C) The numbers of CD45hiCD11b+Ly6ChiMHCII– monocytes and CD45hiCD11b+Ly6C+/–MHCII+ MdCs were determined on days 5 (WT, n = 9; 8.8, n = 10) and 7 (WT, n = 12; 8.8, n = 13) after CD4+ T cell transfer for the brain and spinal cord by flow cytometry. (D) The number of Thy1.1+ donor CD4+ T cells was determined on days 5 (n = 8 per group) and 7 (WT, n = 19; 8.8, n = 23) after CD4+ T cell transfer for the brain and spinal cord by flow cytometry. (E) Brain and spinal cord mononuclear cells isolated from WT (n = 10) and 8.8 (n = 9) recipients on day 7 after CD4+ T cell transfer were stimulated with MOG97–114 before intracellular cytokine staining. Percentages of Thy1.1+ donor CD4+ T cells producing the indicated cytokines are shown. Gating strategies for C–E are shown in Supplemental Figure 4. Graphs show mean + SEM (1 mouse per symbol) and are compiled from at least 2 independent experiments. Statistical significance was determined using a Mann-Whitney U test. *P < 0.05, **P < 0.01.