Cuprizone-induced demyelination triggers a CD8-pronounced T cell recruitment

Hannes Kaddatz, Sarah Joost, Julia Nedelcu, Uta Chrzanowski, Christoph Schmitz, Stefan Gingele, Viktoria Gudi, Martin Stangel, Jiangshan Zhan, Emily Santrau, Theresa Greiner, Julia Frenz, Brigitte Müller-Hilke, Michael Müller, Sandra Amor, Paul van der Valk, Markus Kipp

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)


The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone-intoxicated mice and post-mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro-inflammatory milieu in the CNS of cuprizone-intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone-intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone-induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.

Original languageEnglish
Pages (from-to)925-942
Number of pages18
Issue number4
Publication statusPublished - Apr 2021


  • cuprizone
  • multiple sclerosis
  • neuroinflammation
  • oligodendrocyte injury
  • peripheral immune cell recruitment

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