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) —

 

Yes but wherever there is inflammation for more than a day there will be T cells, just as there will be neutrophils. It tells us nothing interesting about the origin of the inflammation.

In Long Covid we have no clinical evidence of brain stem or cord inflammation. If brain stem gets inflamed you fairly rapidly develop impairment of consciousness or at least major neurological dysfunction. So far I have not heard of any features of long Covid that might be due to hidden focal inflammatory lesions in brain or cord.

 

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 —