Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity
Catriona A. Wagner, … , Denny Liggitt, Joan M. Goverman
Catriona A. Wagner, … , Denny Liggitt, Joan M. Goverman
Published October 1, 2019
Citation Information: J Clin Invest. 2020;130(1):203-213. https://doi.org/10.1172/JCI132531.
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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

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Figure 1

8.8 CD8+ T cells exacerbate atypical but not classic CD4-initiated EAE.

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8.8 CD8+ T cells exacerbate atypical but not classic CD4-initiated EAE. ...
EAE was induced by transfer of MOG-specific CD4+ T cells into WT mice that received either WT or 8.8 CD8+ T cells 1 day earlier. Control mice that received 8.8 CD8+ T cells and no CD4+ T cells are designated “8.8 only.” (A) Incidence of classic EAE among all mice is shown for each indicated group. (B) Classic EAE scores (mean ± SEM) are shown for mice that developed EAE. (C) Incidence of atypical EAE among all mice is shown for each indicated group. (D) Atypical EAE scores (mean ± SEM) are shown for mice that developed EAE. (E) Histology scores (assigned as described in Methods, mean + SEM) are shown for brain and spinal cord (SC) tissues harvested 7 days after CD4+ T cell transfer. Tissues that contained at least 1 lesion in the corresponding region were included in the analyses. (F) The percentage of mice evaluated in E that exhibited parenchymal blood vessel–associated lesions is shown. Representative brain sections for E and F are shown in Supplemental Figure 1. (A–D) Data are compiled from 8 independent experiments; n = 40 for EAE-induced recipients of WT CD8+ T cells; n = 38 for EAE-induced recipients of 8.8 T cells; n = 5 for mice that received only 8.8 T cells. (E and F) Data are from 2 independent experiments; n = 12 mice per group. Statistical significance was determined using Fisher’s exact test (A, C, and F) or Mann-Whitney U test (B, D, and E). *P < 0.05, **P < 0.01, ***P < 0.001.