Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

TY - JOUR

T1 - Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

AU - Kaufmann, Max

AU - Evans, Hayley

AU - Schaupp, Anna-Lena

AU - Engler, Jan Broder

AU - Kaur, Gurman

AU - Willing, Anne

AU - Kursawe, Nina

AU - Schubert, Charlotte

AU - Attfield, Kathrine E

AU - Fugger, Lars

AU - Friese, Manuel

PY - 2021/3/12

Y1 - 2021/3/12

N2 - Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB).Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes).Findings: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients.Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.Funding: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome.

AB - Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB).Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes).Findings: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients.Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.Funding: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome.

UR - https://www.cell.com/med/fulltext/S2666-6340(21)00036-2

U2 - 10.1016/j.medj.2021.01.006

DO - 10.1016/j.medj.2021.01.006

M3 - SCORING: Journal article

C2 - 33748804

VL - 2

SP - 296-312.e8

JO - MED-CAMBRIDGE

JF - MED-CAMBRIDGE

SN - 2666-6340

IS - 3

ER -