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

Figures & data

Figure 1. Characterization of postmortem MS white and gray matter lesions. (a) Immunohistochemical staining of formalin-fixed paraffin-embedded postmortem white matter MS tissue for HLA-DR (black) and PLP (brown). Panels show normal-appearing white matter (NAWM; no demyelination, no infiltration of HLA-DR⁺ cells), reactive site (no demyelination, infiltration of HLA-DR⁺ cells), active lesion (demyelination, infiltration of HLA-DR⁺ cells throughout the lesion), mixed active/inactive lesion (mA/I; demyelination, infiltration of HLA-DR⁺ cells at the lesion rim), inactive lesion (demyelination, no infiltration of HLA-DR⁺ cells), and inactive remyelinated/shadow plaque (partial demyelination/loose myelin, no infiltration of HLA-DR⁺ cells). Bar = 500 µM. (b) Double staining for MOG (red) and Iba-1 (blue), showing the original (left) and optimized (right) figures. The arrows show internalized MOG-positive fragments by Iba-1 positive cells, indicating active myelin uptake. Bar = 50 µM.

Figure 2. T-cell distribution in postmortem white matter control and MS tissue. (a) Staining for CD8 and CD4, showing perivascular distribution in control white matter, parenchymal localization of some CD8⁺ and CD4⁺ T cells in the rim of active lesions, and presence of both CD8⁺ and CD4⁺ T cells in perivascular MS clusters. (b) Double staining for CD8 (green) and laminin (red), confirming predominant localization of CD8⁺ T cells in the PVS of a control donor. In a mixed active/inactive white matter lesion, CD8⁺ T cells are observed in the parenchyma of the active rim and surrounding perilesional white matter. Bar = 50 µM.

Figure 3. Flow-cytometric analysis of brain CD8⁺ T_RM cells. (a) Gating procedure based on forward scatter (FSC), side scatter (SSC), viability, and expression of CD3, CD4, and CD8. (b) Expression of T_RM cell-associated surface markers on CD8⁺ T cells isolated from blood, MS normal-appearing white matter (NAWM), and an active MS lesion [42,66].

Figure 4. Concept of compartmentalized immune activation in advanced MS white matter lesions. In early MS, shown to the left, activated T_EM cells and effector T cells cross the endothelium of the blood brain barrier at the postcapillary venules and enter the perivascular space (PVS), forming perivascular infiltrates in acute lesions. These infiltrating T cells may give rise to a local T_RM-cell population. The extent to which T_RM cells contribute to acute infiltrates in early MS is incompletely understood. In chronic active lesions of advanced MS, shown to the right, T-cell trafficking is not evident, and perivascular cuffs are populated by T_RM cells. Perivascular T_RM cells are reactivated by APCs and contribute to inflammatory lesion formation, either locally in the PVS or upon entering the parenchyma, through producing soluble effector molecules and/or displaying cellular cytotoxicity.

Smolders J, Heutinck KM, Fransen NL, et al. Tissue-resident memory T cells populate the human brain. Nat Commun. 2018;9(1):4593.

 PubMedGoogle Scholar

Fransen NL, Hsiao -C-C, van der Poel M, et al. Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions. Brain 2020;143(6):1714–1730.

 Google Scholar