Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterised by demyelinating lesions within the central nervous system (CNS). In MS, peripheral immune cells gain access to the CNS and cause severe neuroinflammation, myelin damage, and subsequent neurodegeneration. In the past decades, a wealth of knowledge has been gained on the role of monocyte-derived macrophages, CD8⁺ and CD4⁺ T cells, B cells and antibody-secreting cells in MS pathogenesis (Machado-Santos et al., 2018; Vogel et al., 2013). To date, however, we still know relatively little about the presence and roles of other immune cell subsets in the MS brain, such as natural killer (NK) cells.

Brain regions around the ventricles are hotspots for MS lesions (Brownell and Hughes, 1962; Jehna et al., 2015; Palmer et al., 1999; Simon et al., 1986), but underlying mechanisms are poorly understood (Pardini et al., 2021). Since the majority of periventricular MS lesions occur around a central vessel (Adams et al., 1987; Tallantyre et al., 2011), it has been suggested that vascular topography may influence MS pathology (Martinez Sosa and Smith, 2017). Although the accumulation of immune cell infiltrates around post-capillary venules suggests their trafficking across the blood-brain barrier (Smolders et al., 2020), periventricular veins drain to the cerebrospinal fluid (CSF) (Pardini et al., 2016). Thus, MS periventricular pathology may be related to factors from both the blood and the CSF.

In MS, the CSF that flows through the ventricles is enriched in immune cells (Cepok et al., 2001; Rodríguez-Martín et al., 2015; Schafflick et al., 2020) and inflammatory factors (Khaibullin et al., 2017; Vidaurre et al., 2014). The main source of CSF is the choroid plexus, a secretory tissue located in the brain ventricles that acts as an immunological hub (Strominger et al., 2018) and forms the blood-CSF barrier. Thus, the location and functions of the choroid plexus are strategic to regulate periventricular homeostasis and thereby influence neuroinflammation (Ghersi-Egea et al., 2018; Monaco et al., 2020). For example, pro-inflammatory immune cells infiltrate the brain through the choroid plexus in the early stages in an MS animal model (Reboldi et al., 2009). On the contrary, in progressive MS patients, the choroid plexus may be a source of neuroprotective factors in response to chronic periventricular damage (Rodríguez-Lorenzo et al., 2020a). Moreover, we and others have shown that immune cells accumulate at the choroid plexus in the progressive phases of the disease (Rodríguez-Lorenzo et al., 2020b; Vercellino et al., 2008). We postulate that CSF-mediated immune processes originating in the choroid plexus participate in the periventricular inflammation typical for MS patients. However, it is still uncertain whether such processes involve cell trafficking into the CNS and/or the secretion of pro- or antiinflammatory factors.

Here, we used single-cell mass cytometry (CyTOF) to profile the immune landscape of periventricular MS brain regions and to better understand their pathology and routes of immune cell infiltration into the CNS. For this purpose, we isolated immune cells from the human postmortem periventricular brain areas (septum), the choroid plexus and the blood. With our 37-marker panel, we defined the main innate and adaptive immune cell populations and their phenotype in MS, dementia, and control donors without neurological disease. Besides detecting the accumulation of T cells and antibody-secreting cells typical of MS in the periventricular brain regions, we also identified an NK signature consisting of CD56^bright NK cells. CD56^bright NK cells are known for their immunoregulatory properties and were also detected in the blood of the same MS donors with a migratory and activated phenotype, similarly to those in the brain. Using multispectral immunofluorescence, we validated these findings in an independent cohort of periventricular brain and choroid plexus tissue, which indicated that NK cells expressing granzyme K, typical of the CD56^bright subset, are enriched in MS lesions and the choroidal tissue from MS donors. Together, our study brings NK cells back to the spotlight of MS pathology by suggesting a local immunoregulatory role of the CD56^bright subset within periventricular MS brain regions.

In this study, we used a CyTOF multi-parameter approach to provide a comprehensive overview of the immune landscape in human periventricular brain tissue from donors with MS, dementia and controls.

Here, we revealed the involvement of CD56^bright NK cells in MS periventricular pathology. Since periventricular areas of the brain are a predilection site for MS lesions (Brownell and Hughes, 1962; Jehna et al., 2015; Palmer et al., 1999), we focused on the septum as it separates the two lateral ventricles and is highly exposed to CSF. Although magnetic resonance imaging studies demonstrated the presence of MS lesions in the septum (Gean-Marton et al., 1991; Palmer et al., 1999; Palotai et al., 2018; Simon et al., 1986), the composition of the inflammatory infiltrates remained unknown. We found an expansion of CD56^bright NK cells within the septum of MS donors, and these CD56^bright NK cells expressed higher levels of proteins involved in NK cell activation and migration. Using multiplex immunohistochemistry, we validated the accumulation of NK cells expressing GrK, typical of the CD56^bright subset (Bratke et al., 2005), in periventricular MS lesions from an independent cohort. Putative CD56^bright NK cells abound in the rim of the lesions, where the highest activity is present in terms of immune cell activation and demyelination. The centre of MS lesions is characteristically hypocellular, and this is reflected in the number of NK cells present. We also found a slight increase in the density of GrB⁺ NK cells — the putative CD56^dim cells — in MS lesions versus NAWM and healthy controls that was not detected with the CyTOF. Next to NK cells, we detected higher frequencies of ASCs, CD4⁺ and CD8⁺ T cells in the septum from MS donors compared to controls, which is similar to other periventricular regions (Machado-Santos et al., 2018). The distribution of general immune cell populations in the septum was consistent with previous literature (Korin et al., 2017; Smolders et al., 2018).

NK cells are lymphocytes of the innate immune system with the ability to regulate adaptive responses. There are two main NK cell subsets based on the expression of CD56 and CD16: CD56^bright NK cells express low levels of CD16 and are specialised immunoregulators, while CD56^dim NK cells have a potent cytolytic capacity, which may be mediated by CD16 (Mimpen et al., 2020). Importantly, we relied on the markers CD56 and NKp46 to identify human NK cells by CyTOF and immunohistochemistry, respectively. However, NK cells belong to the broader group of innate lymphoid cells (ILCs), which also include ILC1, ILC2 and ILC3 subsets. ILC subpopulations are highly plastic and their identification remains a challenge; it has been proposed that they belong to a single, highly plastic population, but this debate is beyond the scope of this study. Although NK cells are thought to predominate in the brain parenchyma (Sedgwick et al., 2020), we cannot exclude the presence of other ILCs. Particularly, certain subsets of ILC3s share the expression of CD56 with NK cells (Trabanelli et al., 2018). The extent and pathological consequences of the presence of ILC3s in MS should be determined in future studies.

A beneficial role of CD56^bright NK cells in MS was first discovered with the anti-inflammatory drug daclizumab. Daclizumab is an anti-CD25 antibody therapy that leads to the expansion of circulating CD56^bright NK cells (Bielekova et al., 2006; Wynn et al., 2010), an increase that was later reported with other disease-modifying treatments for MS as well (Gross et al., 2016b; Saraste et al., 2007; Smith et al., 2018). In line with this, a protective role for NK cells was shown in animal models of MS (Hao et al., 2010; Xu et al., 2005) through cytotoxicity against autoreactive T cells (Xu et al., 2005). Despite the beneficial immunomodulatory role assigned to CD56^bright NK cells in the context of MS, the presence of NK cells in the CNS can also be detrimental (Jin et al., 2021; Lagumersindez-Denis et al., 2017; Liu et al., 2016; Liu and Shi, 2019; Morse et al., 2001). Thus, while NK cells may act as a double-edged sword in MS (Gross et al., 2016a), we postulate that the presence of specifically CD56^bright NK cells in the periventricular areas primarily has a beneficial effect on MS pathology by limiting neuroinflammation.

To date, studies of NK cells in the MS brain parenchyma did not distinguish between the CD56^bright and CD56^dim NK subsets. NK cells were detected in the brains from MS donors (Gross et al., 2016a; Lagumersindez-Denis et al., 2017; Liu et al., 2016; Traugott and Raine, 1984), while absent from controls (Gross et al., 2016a; Liu et al., 2016). Within active MS lesions, NK cells express GrK polarised towards neighbouring T cells (Gross et al., 2016a; Jiang et al., 2011). Thus, the expansion of the CD56^bright NK cell population we observed in MS brains may mediate a protective response to neuro-inflammation by killing autoreactive T cells through the release of GrK. Moreover, we observed higher expression of the ligand PDL1 in CD56^bright NK cells from MS brains compared to those from controls, suggesting an involvement of the PD1-PDL1 axis. PDL1 is an NK cell activation marker associated with enhanced cytotoxicity (Dong et al., 2019) and binds the T cell co-inhibitory molecule PD1 inducing suppression of PD1⁺ autoreactive T cells (Riley, 2009).

Proportions of circulating CD56^bright NK cells remained the same in MS and control donors, as described before (Gross et al., 2016a; Laroni et al., 2016). Interestingly, CD56^bright NK cells in both the MS brain and blood expressed higher levels of proteins associated with cell migration. As such, the enrichment of CD56^bright NK cells in the CNS of MS patients could result from selective infiltration from the blood towards the brain rather than being the result of accumulation in the circulation. In line with this, migration studies showed that CD56^bright NK cells have a higher capacity to transmigrate across a blood-brain barrier in vitro model than their CD56^dim counterparts (Gross et al., 2016a). However, this study did not show enhanced migration of CD56^bright NK cells from MS donors compared to controls.

Direct infiltration from the circulation through the local brain vasculature is a likely route for MS immune infiltrates. Besides, abundant periventricular veins drain to the ventricles (Pardini et al., 2016), resulting in an indirect peripheral-brain connection through the choroid plexus via the CSF. Here, we described the presence of NK cells in the human choroid plexus and identified the upregulation of the adhesion molecule CD54 in CD56^dim NK cells in MS. The higher ratio of CD56^bright/CD56^dim cells in the choroid plexus compared to the blood indicates enrichment of CD56^bright NK cells in the choroid plexus. Accordingly, we could not detect GrB⁺ NK cells, presumptive CD56^dim NK cells, within the choroid plexus stroma from controls, and rarely in MS cases, using multiplex immunohistochemistry. The upregulation of CD54 in CD56^dim NK cells in MS was unique to the choroid plexus and differed from CD56^dim NK cells in the circulation and the septum. However, the proportion of CD56^dim NK cells did not differ between groups. Although the higher frequency of CD56^bright NK cells measured by CyTOF in the choroid plexus from MS donors relative to controls was not significant, multiplex immunohistochemistry confirmed the accumulation of GrK⁺ NK cells in the choroid plexus stroma of MS donors from an independent cohort. Future studies should uncover if CD56^bright NK cells continue their journey across the blood-CSF barrier and the ependymal layer lining the periventricular brain. Supporting this idea, the CSF ratio of CD56^bright/CD56^dim NK cells is higher in MS patients than in controls (Rodríguez-Martín et al., 2015; Schafflick et al., 2020), and it is further increased upon treatment with the anti-CD25 antibody therapy daclizumab (Bielekova et al., 2011). In conclusion, circulating CD56^bright NK cells in MS may infiltrate into periventricular brain areas directly across the blood-brain barrier, and indirectly via the choroid plexus-CSF route.

Our study has two main limitations, first scarcity of fresh human tissue prevented having sex and age-matched groups with large sample sizes for the CyTOF analysis. To overcome the underpowered design and possible effects of confounders, we have validated our main finding by multiplex immunohistochemistry in a separate cohort with a similar age and female/male ratio. Secondly, there is a strong contribution of blood-derived immune cells in the choroid plexus, which precluded a clear distinction between circulating and stromal immune cells. This may have prevented the detection of choroid-plexus specific changes in the stroma, such as an accumulation of CD8⁺ T cells in the choroid plexus from MS donors, previously described by our group using immunohistochemistry (Rodríguez-Lorenzo et al., 2020b). In addition, the high proportion of granulocytes in the CP as detected by our CyTOF analysis likely originates from the circulation (Rodríguez-Lorenzo et al., 2020b; Vercellino et al., 2008). Contrariwise, the scarcity of B cells, despite the high vascularisation, is in line with previous reports (Rodríguez-Lorenzo et al., 2020b; Vercellino et al., 2008); and the detection of rare ASCs in the choroid plexus but not in the blood reassures their tissue specificity (Vercellino et al., 2008).

Notably, our study with postmortem blood uncovered a higher frequency of B cells in MS donors relative to controls and dementia cases. While the efficacy of peripheral B cell-depleting therapies suggests a pathogenic role of circulating B cells in MS (Hauser et al., 2017; Montalban et al., 2017), we could not find evidence in the literature showing an accumulation of B cells in the blood of MS patients, and a recent study showed similar frequencies relative to controls (Schafflick et al., 2020). Although most B cells lack T-bet expression, a small subset of T-bet⁺ B cells shows a trend towards more abundance in MS postmortem blood, in line with recent literature (Couloume et al., 2021; van Langelaar et al., 2019). Moreover, the expression of T-bet within T-bet⁺ B cells was higher in MS donors relative to control and dementia donors. T-bet expression on B cells has been associated with increased pathogenic responses (Barnett et al., 2016; Piovesan et al., 2017). The relevance of T-bet⁺ B cells in MS should be further confirmed in fresh blood samples.

In addition, we aimed to uncover MS-specific immune changes by comparing our findings in MS donors to an extra neurological control group consisting of demented cases next to our non-neurological controls. All but one of our demented controls were diagnosed with Alzheimer’s disease (AD). We found that the increase in CD56^bright NK cells and ASCs were specific to MS compared to both dementia and controls. Although our study was not powered for focusing on dementia, we found that the abundance of CD8⁺ T cells in the septal periventricular area was higher compared to the controls, following the trend seen in MS donors. The most notable increase was seen in CD8⁺ tissue-resident memory T cells, a population that has been found in the ageing brain before (Smolders et al., 2018). In AD, higher numbers of circulating CD8⁺ T_EMRA cells relative to healthy donors were negatively associated with cognition (Gate et al., 2020). In addition, clonally expanded CD8⁺ T cells were more abundant in the CSF of AD patients compared to healthy controls (Gate et al., 2020). Although our findings were not statistically significant, they highlight a role for periventricular CD8⁺ T cells in AD pathology. Moreover, we identified an activated phenotype of periventricular B cells in demented donors, consisting of higher expression of CD25 and CD49d. Interestingly, an accumulation of activated B cells was found in the circulation of AD mouse models before, together with infiltration of B cells into the brain parenchyma (Kim et al., 2021). Future studies with increased sample size should confirm these results and reveal how T and B cells play a role in AD pathogenesis.

FCS CyTOF files are uploaded to http://flowrepository.org with IDs FR-FCM-Z4JJ (raw) and FR-FCM-Z4JK (normalised). Code used in this analysis is available on the github repository https://github.com/MolecularCellBiologyImmunology/cytof-periventricular-ms, (copy archived at swh:1:rev:70e973c2d935e4ff2cb080d7feef0dd08c23e061).

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Author details

1. Sabela Rodríguez-Lorenzo

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Lynn van Olst

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5956-4519

2. Lynn van Olst

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Sabela Rodríguez-Lorenzo

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7569-0470

3. Carla Rodriguez-Mogeda

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Investigation, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7849-9302

4. Alwin Kamermans

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Formal analysis, Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3601-395X

5. Susanne MA van der Pol

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Methodology

   Competing interests

   No competing interests declared

6. Ernesto Rodríguez

   1. MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
   2. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands

   Contribution

   Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

7. Gijs Kooij

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Funding acquisition

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9488-2918

8. Helga E de Vries

   MS Center Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

   Contribution

   Funding acquisition, Supervision, Writing – review and editing

   For correspondence

   he.devries@amsterdamumc.nl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7904-7124

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