Tissue-resident CD8+ memory T cells in multiple sclerosis

We read with interest the article by Fransen et al. (2020) in Brain. The authors studied the role of CD8+ T cells in a large cohort of chronic multiple sclerosis autopsy cases from the Netherlands Brain Bank. In all white matter samples, CD8+ T cells were conspicuous in the perivascular space (PVS; Virchow-Robin space). At the level of postcapillary venules where lymphocyte extravasation takes place, this specialized compartment is bordered by the endothelial basement membrane on the vascular side, and the glia limitans on the brain parenchymal side (Engelhardt et al., 2017). A large proportion of the CD8+ cells displayed the phenotype of tissue-resident memory cells (TRM) (CD69+, CD103+/−, S1P1−, CCR7−, CXCR6+), similar to observations previously reported by Machado-Santos et al. (2018). TRM cells have emerged as an important subset of memory T cells. Unlike central memory and effector memory T cells, TRM cells do not recirculate but are sessile residents in various tissues, including the brain, where they provide a first line of protection, especially against local viral spread (Mueller and Mackay, 2016; Smolders et al., 2018). Fransen et al. suggest that (re)activation of CD8+ TRM cells in the PVS ‘is a key mechanism in the maintenance of white matter lesion activity in advanced progressive multiple sclerosis’ (Fransen et al. 2020). Recruitment of CD8+ TRM cells might reflect an antiviral response that drives or facilitates the autoimmune process in a similar way as recently described in an animal model of multiple sclerosis (Steinbach et al., 2019). It is interesting to compare the findings by Fransen et al. in late chronic multiple sclerosis with our observations in subjects with early prodromal (sublinical) multiple sclerosis (Beltran et al., 2019). In our cohort of monozygotic twins who are clinically discordant for multiple sclerosis, we identified a subgroup of clinically healthy co-twins who show evidence of ‘subclininal neuroinflammation’ on MRI or CSF analysis. Using single-cell transcriptomics (RNA-seq) we found that activated, clonally expanded CD8+ TRM cells are conspicuous components of the CSF from subjects with subclinical neuroinflammation (prodromal multiple sclerosis) (Beltran et al., 2019). The anatomy of the PVS and especially its connection with the CSF is complicated and controversial (Wardlaw et al., 2020). Nevertheless, there are obvious links and parallels between the CD8+ TRM cells observed in the PVS of autopsy cases with late-stage chronic multiple sclerosis (Fransen et al., 2020), and the CD8+ TRM cells detected in the CSF of subjects with early prodromal multiple sclerosis (Beltran et al., 2019). We conclude that CD8+ TRM cells are not just involved in the chronic late phase of multiple sclerosis, but are key players even in the earliest detectable (prodromal) stage of the disease process. Data availability is not applicable to this article as no new data were created or analysed in this study. The authors’ studies were supported by the German Research Council through CRC128-A5, DO 420/3-1 DACH, the Munich Cluster for Systems Neurology (SyNergy EXC 2145, project 390857198), the Dr. Leopold und Carmen Ellinger foundation, the Gemeinnützige Hertie Stiftung, the national division of the German MS Society (DMSG), the Bavarian association of the German MS society (DMSG-Bayern), the BMBF organization “Krankheitsbezogenes Kompetenznetz Multiple Sklerose”, and the association “Verein zur Therapieforschung für MS Kranke e. V.”. The authors report no competing interests.