Abstract
In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known about the role of CD8 T cells in MS, partly due to the prevalent use of experimental autoimmune encephalomyelitis (EAE) models mediated by CD4 T cells, which have limited involvement of CD8 T cells. Importantly, MS and EAE differ in both their distribution of CNS lesions and neurologic deficits, indicating differences in CNS inflammation. MS lesions are more commonly found in the brain, whereas EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in MS rarely parallel the ascending paralysis typical for CD4 T cell–mediated EAE (CD4-EAE). In contrast, CD8-EAE models suggest that CD8 T cells preferentially cause brain inflammation; however, little is known about how brain and spinal cord inflammation may differ, or how CD8 T cells contribute to these differences. We have established an adoptive CD8-EAE mouse model characterized by brain-centered inflammation, ataxia, and weight loss. CNS inflammation in the brain and spinal cord differed in immune cell numbers, cellular composition, and inflammatory signatures. CD8-EAE could be suppressed by blocking IFN-γ, and exacerbated by blocking PD-1, with concomitant changes in the numbers of CNS-infiltrating monocytes. Most CD8 T cells in the CNS were CD11c+, suggesting that they are the pathogenic subset. We describe a robust CD8-EAE model, identify differences between brain and spinal cord inflammation, and characterize mechanisms that control CD8 T cell–mediated neuroinflammation, thereby furthering understanding of EAE and MS.
Authors
Daniel Hwang, Gholamreza Azizi, Larissa Lumi Watanabe Ishikawa, Maryam Seyedsadr, Arin Cox, Soohwa Jang, Ezgi Kasimoglu, Abdolmohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric
Figure 6
Blocking PD-1 signaling exacerbates CD8-EAE.
