Reply: Tissue-resident CD8+ memory T cells in multiple sclerosis

We thank Hohlfield et al. (2020) for their appreciation and discussion of our work. Our data provide an extension of the data earlier reported by Machado-Santos et al. (2018). We showed that white matter perivascular CD8+ T cells of multiple sclerosis donors co-expressed CD69 with variable levels of CD103 and CD49a, PD-1, and CXCR6 (Fransen et al., 2020), characterizing them as tissue-resident memory T (TRM) cells (Kumar et al., 2017). Studying multiple sclerosis lesional T cells in brain autopsy tissue, we focused our work on the latest stages of multiple sclerosis. However, we fully agree that brain TRM cells may also be relevant in the first stages of multiple sclerosis (Smolders et al., 2020). Since all patterns of white matter lesions in early multiple sclerosis are associated with profound infiltration of T cells (Lucchinetti et al., 2000), an important question is how perivascular TRM cells relate numerically to T cells infiltrating from the circulation through inflamed post-venular endothelium. Of note, Machado-Santos et al. and we observed in early multiple sclerosis lesions derived from diagnostic biopsies CD103-positive lymphocytes in both perivascular cuffs and brain parenchyma (Machado-Santos et al., 2018; Fransen et al., 2020). The sequence of events in which these resident and infiltrating populations are recruited to the perivascular space and multiple sclerosis lesions, and how their origins and clonality relate to each other is not understood. Within and beyond this context, the observation of Beltrán et al. (2019) concerning CD8+ TRM cells in CSF of twins discordant for multiple sclerosis is intriguing. It suggests that specific multiple sclerosis-related CD8+ TRM-like cells are recruited into the CSF as one of the earliest events in the disease. Potentially, viral infections account for the establishment of multiple sclerosis-associated brain CD8+ TRM populations as suggested by Steinbach et al. (2019). Of note, where normal-appearing white matter and multiple sclerosis white matter lesions are dominated by CD8+ TRM cells, CD4+ central memory T (TCM)-like cells dominate the CSF (Kivisäkk et al., 2003). Although less prevalent numerically, CD4+ T cells also accumulate in association with active and mixed active/inactive white matter lesions (Fransen et al., 2020). Additionally to white matter and CSF T-cell pools, meningeal infiltrates containing T cells characterize the disease process of multiple sclerosis and associate with cortical demyelination already prevalent early in disease (Lucchinetti et al., 2011). A detailed phenotypic profiling of these different T-cell fractions in the context of multiple sclerosis pathology is still is to be performed. We fully agree with Hohlfeld and colleagues in their interpretation that further studies on the interplay between different CNS resident and infiltrating T cell subsets, and their temporal evolution during the onset and course of multiple sclerosis, may provide valuable insights to the nature and pathophysiology of multiple sclerosis. That is, both in early and advanced multiple sclerosis. Data sharing is not applicable to this article as no new data were created or analysed in this study. This research is funded by MS Research (grant MS 14-888), the Vriendenloterij, the Thyssen Foundation (2015-00387), the German Research Foundation (FOR 2149), and the Nationaal MS Fonds (OZ2018-003). The authors report no competing interests. I.H. received lecture and/or consultancy fee from Biogen and Novartis. J.S. received lecture and/or consultancy fee from Biogen, Merck, Novartis, and Sanofi-Genzyme.