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.

KEYWORDS:

• Autopsy
• demyelination
• microglia
• multiple sclerosis
• pathology
• t cells
• therapy
• tissue-resident memory T cells

Article highlights

• The phenotype of MS evolves in the majority of patients from a relapsing–remitting onset, characterized by inflammatory attacks of leukocytes infiltrating the CNS, into a smoldering, slowly progressing inflammatory disease.

• Diagnostic biopsy and autopsy studies of white matter lesions in early MS show distinct profiles of demyelination and leukocyte infiltration, while autopsy studies in advanced MS lack clear separate pathological patterns.

• In advanced MS, the presence of active and mixed active/inactive white matter lesions correlates with a faster accumulation of disability, disease progression, and an unfavorable genetic risk profile.

• Active and mixed active/inactive lesions are enriched for CD8⁺ and to a lesser extent CD4⁺ T cells, proportionally infiltrating the parenchyma and having a T_RM-cell phenotype, the latter suggests mobilization from the PVS rather than recruitment from the circulation.

• In progressive MS, perivascular cuffs containing T_RM cells are observed and may be sites of antigen presentation and T_RM-cell reactivation.

• Targeting the reactivation and mobilization of perivascular brain T_RM cells could be effective in controlling a T cell-mediated contribution to white matter lesions and related disability progression in advanced MS.

Declaration of interest

J Smolders received speaker and/or consultancy fees from Biogen, Merck, Novartis, and Sanofi-Genzyme. I Huitinga received speaker and/or consultancy fees from of Biogen and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This project is funded by Stichting MS Research [MS 14-888], the Vriendenloterij, the German Research Foundation [FOR 2149], and the Nationaal MS Fonds [OZ2018-003].