Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions, 2020, Fransen et al.

Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions
Fransen, Nina L; Hsiao, Cheng-Chih; van der Poel, Marlijn; Engelenburg, Hendrik J; Verdaasdonk, Kim; Vincenten, Maria C J; Remmerswaal, Ester B M; Kuhlmann, Tanja; Mason, Matthew R J; Hamann, Jörg; Smolders, Joost; Huitinga, Inge

Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases.

We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3 + , CD4 + , and CD8 + T cells in 140 subcortical white matter lesions. The location of CD8 + T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8 + T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-appearing white matter (n = 7), and control white matter (n = 10), by flow cytometry.

In normal-appearing white matter, the number of T cells was increased compared to control white matter. In active and mixed active/inactive lesions, the number of T cells was further augmented compared to normal-appearing white matter. Active and mixed active/inactive lesions were enriched for both CD4 + and CD8 + T cells, the latter being more abundant in all lesion types. Perivascular clustering of T cells in the medulla oblongata was only found in cases with a progressive disease course and correlated with a higher percentage of mixed active/inactive lesions and a higher lesion load compared to cases without perivascular clusters in the medulla oblongata. In all white matter samples, CD8 + T cells were located mostly in the perivascular space, whereas in mixed active/inactive lesions, 16.3% of the CD8 + T cells were encountered in the brain parenchyma. CD8 + T cells from mixed active/inactive lesions showed a tissue-resident memory phenotype with expression of CD69, CD103, CD44, CD49a, and PD-1 and absence of S1P1. They upregulated markers for homing (CXCR6), reactivation (Ki-67), and cytotoxicity (GPR56), yet lacked the cytolytic enzyme granzyme B.

These data show that in chronic progressive multiple sclerosis cases, inflammatory lesion activity and demyelinated lesion load is associated with an increased number of T cells clustering in the perivascular space. Inflammatory active multiple sclerosis lesions are populated by CD8 + tissue-resident memory T cells, which show signs of reactivation and infiltration of the brain parenchyma.

Link | PDF (Brain, paywall)

 

Posting in relation to evidence in a preprint that there is T cell trafficking into brainstem and spinal cord in Long Covid. See Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to Two Years Following COVID-19 (2023) —

 

Could there be limited T cell migration to the perivascular spaces of brainstem and cord, without necessarily infiltrating parenchyma and causing more profound dysfunction? Although maybe pain (cord), dysautonomia, abnormal breathing (brainstem) symptoms could possibly relate if those particular centres tended to be more vulnerable/closer to perivascular spaces??

 

A few quotes from the paper's discussion —

 

See also —

Twin study identifies early immunological and metabolic dysregulation of CD8+ T cells in multiple sclerosis (Sep 2024)
Vladyslav Kavaka; Luisa Mutschler; Clara de la Rosa del Val; Klara Eglseer; Ana M. Gómez Martínez; Andrea Flierl-Hecht; Birgit Ertl-Wagner; Daniel Keeser; Martin Mortazavi; Klaus Seelos; Hanna Zimmermann; Jürgen Haas; Brigitte Wildemann; Tania Kümpfel; Klaus Dornmair; Thomas Korn; Reinhard Hohlfeld; Martin Kerschensteiner; Lisa Ann Gerdes; Eduardo Beltrán

Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI).

We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8+ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS.

Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.

EDITOR’S SUMMARY
Multiple sclerosis (MS) is an inflammatory disease of the nervous system in which CD8 T cells are present in MS lesions, but their role in disease progression remains unclear. Kavaka et al. analyzed CD8 T cells from the blood and cerebrospinal fluid of monozygotic twins, where one twin had MS and the other showed no signs or subclinical signs of neuroinflammation (SCNI). CD8 T cells from individuals with MS and cotwins with SCNI exhibited proinflammatory immunological and metabolic features consistent with enhanced activation and migration. These findings were validated in a separate cohort of individuals with MS, providing insights into the role of CD8 T cells in MS progression.

Link | PDF (Science Immunology) [Paywall]