Perivascular tissue resident memory T cells as therapeutic target in multiple sclerosis

Abstract

Introduction: Multiple sclerosis (MS) is characterized by inflammatory attacks of infiltrating leukocytes at onset but evolves into a smoldering, progressive disease within the central nervous system at its later stages. The authors discuss the contribution of white matter lesions to the pathology of advanced MS, thereby paying particular attention to the role of T cells. Areas covered: Diagnostic biopsy and autopsy studies of white matter lesions in early MS show different pathological patterns of demyelination and leukocyte infiltration. Brain autopsies from advanced MS display substantial inflammation without distinct patterns and suggest a role for perivascular CD8 + tissue-resident memory T (T RM) cells in active and mixed active/inactive MS white matter lesions. When compared to control and normal-appearing white matter, these lesions are enriched for parenchymal CD8 + T cells. In the perivascular space, cuffs containing CD8 + T RM cells are observed also in progressive MS, and could be sites of local reactivation. Expert opinion: Recent findings point toward the perivascular space as an immunological hotspot, which could be targeted in order to suppress a contribution of T RM cells to ongoing white matter lesion activity in advanced progressive MS. The authors discuss approaches, which may be explored to suppress T RM-cell reactivation in the perivascular space.

Different Perivascular Space Burdens in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinson’s Disease

“…PVS burden has been associated with brain atrophy with aging, inflammation leading to increased oxygen consumption, cerebrovascular reactivity and hypoperfusion, and disruption of the blood-brain barrier (Joutel et al, 2010;Aribisala et al, 2014;Adams et al, 2015;Rost et al, 2018;Ghali et al, 2020). Recent findings suggest that the PVS system may be an immunological hotspot, which is the site of antigen presentation and tissue-resident memory T-cell reactivation (Smolders et al, 2020). Moreover, higher level of inflammation markers (CRP,et al) are associated with MRI-visible EPVS burdens, but not with WMH (Aribisala et al, 2014;Hilal et al, 2018a;Yang et al, 2020).…”

CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?

“…Although majority of CD8+ T cells in active MS lesion are recruited from the periphery (160), CD8+ cells with features of tissue-resident memory T (Trm) cells are also present in these lesions (123,161) and suggested to have an important role (162)(163)(164)(165)(166).…”

“…Namely, the engagement of Toll-like receptor 2 on CD8+ Trm cells by toxic (o)Aβ variants may convert their partial activation to the full activation and proinflammatory cytokine production (199)(200)(201)(202). Thus, it seems that the role of CD8+ Trm cells in MS (166) and possibly AD pathogenesis could be dependent on the disease stage. Altogether, it may be hypothesized that not only effector/memory CD8+ T cells recruited from the periphery but also CD8+ Trm cells contribute FIGURE 1 | Schematic representation of the putative interactions between (re)activated CD8+ T cells and microglia in the progression of multiple sclerosis (MS) and Alzheimer's disease (AD).…”

Cerebral Organoids—Challenges to Establish a Brain Prototype

“…In previous studies of the nervous system development and function in health and human pathologies, the following models have been used: animal models in vivo [ 1 , 2 , 3 , 4 , 5 ]; intravital sections of the brain ex vivo [ 6 , 7 , 8 ]; primary neuronal culture of cells or brain tissue in vitro [ 9 , 10 , 11 , 12 , 13 ], and, to a lesser extent, post-mortem material [ 14 , 15 , 16 , 17 , 18 ]. All these experimental methodological approaches have their limitations.…”