Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.
CNS-homing
T cells
Tfh
Th17
multiple sclerosis
natalizumab
scRNA-seq
spatial transcriptomics
therapeutic resistance
Journal
Med (New York, N.Y.)
ISSN: 2666-6340
Titre abrégé: Med
Pays: United States
ID NLM: 101769215
Informations de publication
Date de publication:
12 03 2021
12 03 2021
Historique:
entrez:
22
3
2021
pubmed:
23
3
2021
medline:
23
3
2021
Statut:
ppublish
Résumé
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). 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 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. As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. 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.
Sections du résumé
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
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.
Identifiants
pubmed: 33748804
doi: 10.1016/j.medj.2021.01.006
pii: S2666-6340(21)00036-2
pmc: PMC7966680
doi:
Substances chimiques
Natalizumab
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
296-312.e8Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00008/3
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100308/Z/12/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
Références
Immunity. 2015 Dec 15;43(6):1160-73
pubmed: 26682987
Science. 2016 Jul 1;353(6294):78-82
pubmed: 27365449
Sci Signal. 2017 Dec 12;10(509):
pubmed: 29233918
Sci Rep. 2016 Nov 16;6:37137
pubmed: 27849009
Lancet Neurol. 2020 Apr;19(4):307-316
pubmed: 32199096
Immunity. 2011 Dec 23;35(6):986-96
pubmed: 22177922
J Immunol. 2009 Apr 1;182(7):4036-45
pubmed: 19299701
JAMA. 2019 Jan 15;321(2):175-187
pubmed: 30644981
Genome Biol. 2018 Dec 19;19(1):224
pubmed: 30567574
PLoS One. 2009 Dec 08;4(12):e8212
pubmed: 19997559
Br J Pharmacol. 2013 Oct;170(3):602-13
pubmed: 23869659
Nat Rev Cancer. 2010 Dec;10(12):858-70
pubmed: 21102636
PLoS One. 2012;7(12):e52208
pubmed: 23284936
Eur J Immunol. 2010 Aug;40(8):2174-81
pubmed: 20486123
Nat Rev Immunol. 2015 Sep 15;15(9):545-58
pubmed: 26250739
J Exp Med. 2012 Sep 24;209(10):1743-52
pubmed: 22927550
Ann Neurol. 2010 Oct;68(4):477-93
pubmed: 20976767
Nat Methods. 2017 Sep;14(9):865-868
pubmed: 28759029
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Bioinformatics. 2018 Jun 1;34(11):1966-1968
pubmed: 29360929
Genome Biol. 2014;15(12):550
pubmed: 25516281
Neurology. 2018 Jun 12;90(24):e2107-e2118
pubmed: 29769373
Nat Biotechnol. 2020 Mar;38(3):276-278
pubmed: 32055031
Genome Biol. 2019 Dec 23;20(1):296
pubmed: 31870423
Nat Commun. 2020 Jan 14;11(1):247
pubmed: 31937773
Nat Methods. 2017 Nov;14(11):1083-1086
pubmed: 28991892
Nat Immunol. 2018 May;19(5):497-507
pubmed: 29662170
Immunity. 2008 Jan;28(1):29-39
pubmed: 18164222
J Neuroimmunol. 2001 Nov 1;120(1-2):1-9
pubmed: 11694313
PLoS One. 2012;7(9):e45095
pubmed: 23028778
N Engl J Med. 2006 Mar 2;354(9):899-910
pubmed: 16510744
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Cell. 2016 Feb 11;164(4):770-9
pubmed: 26830879
Nat Biotechnol. 2018 Jun;36(5):411-420
pubmed: 29608179
Eur J Hum Genet. 2011 Oct;19(10):1100-3
pubmed: 21610746
Neurology. 2006 Sep 26;67(6):960-7
pubmed: 17000961
Nature. 2012 Aug 30;488(7413):675-9
pubmed: 22914092
J Immunol. 2011 Sep 1;187(5):2067-71
pubmed: 21795595
J Exp Med. 2013 Jul 1;210(7):1301-9
pubmed: 23797093
Adv Exp Med Biol. 2010;706:128-37
pubmed: 21618832
Cell Syst. 2019 Apr 24;8(4):329-337.e4
pubmed: 30954475
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Lancet Neurol. 2018 May;17(5):405-415
pubmed: 29545067
Front Immunol. 2013 Apr 08;4:84
pubmed: 23579783
J Immunol. 2008 Mar 15;180(6):3746-56
pubmed: 18322180
Nature. 2019 Sep;573(7772):75-82
pubmed: 31316211
Lancet Neurol. 2018 May;17(5):467-480
pubmed: 29656742
Cell Rep. 2019 Feb 5;26(6):1627-1640.e7
pubmed: 30726743
Nat Methods. 2019 Sep;16(9):875-878
pubmed: 31471617
Nat Immunol. 2009 Feb;10(2):167-75
pubmed: 19098919
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Eur J Immunol. 2000 Aug;30(8):2372-7
pubmed: 10940928
Nat Commun. 2020 Nov 30;11(1):6077
pubmed: 33257685
Gigascience. 2018 Jun 1;7(6):
pubmed: 29846586
JAMA Neurol. 2020 Feb 1;77(2):184-191
pubmed: 31589278