Natalizumab Treatment Induces Proinflammatory CD4 T Cells Preferentially in the Integrin β7+ Compartment.
Journal
Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
received:
20
03
2023
accepted:
19
07
2023
medline:
25
9
2023
pubmed:
23
9
2023
entrez:
22
9
2023
Statut:
epublish
Résumé
Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin α4β1 with V-CAM expressed on brain vascular endothelial cells. Although natalizumab treatment reduces the clinical relapse rate in patients with relapsing-remitting MS, its discontinuation after reactivation of the JC virus is associated with a rebound of the disease in 20% of patients. The mechanisms of this rebound are not elucidated, but natalizumab increases the frequencies of circulating CD4 T cells expressing proinflammatory cytokines as well as the proportion of circulating Th17/Th1 cells (Th1-like Th17 cells). Gut-derived memory CD4 T cells are a population of growing interest in the pathogenesis of MS, but whether and how their properties are affected by natalizumab is not known. Here, we studied the phenotype and cytokine expression profile of circulating gut-derived memory CD4 T cells in patients with relapsing-remitting MS under natalizumab. We identified gut-derived memory CD4 T cells by their expression of integrin β7 and compared their properties and those of integrin β7- memory CD4 T cells across healthy donors and patients with relapsing-remitting MS treated or not with natalizumab. We also compared the capacity of integrin β7- and integrin β7+ CD4 T-cell subsets to transmigrate in vitro across a model of blood-brain barrier. The proportions of proinflammatory Th17/Th1 cells as well as of IL-17A+IFNγ+ and IL-17A+GM-CSF+ cells were higher in memory CD4 T cells expressing integrin β7 in patients receiving natalizumab compared with healthy donors and patients with relapsing-remitting MS not receiving natalizumab. By contrast, integrin β7 negative memory CD4 T cells only presented a modest increased in their proportion of Th17/Th1 cells under natalizumab. We further observed that integrin β7+ Th17/Th1 cells migrated as efficiently as integrin β7- Th17/Th1 across a monolayer of brain microvascular endothelial cells. Our study shows that circulating integrin β7+ memory CD4 T cells of patients with relapsing-remitting MS under natalizumab are enriched in proinflammatory cells supporting the hypothesis that integrin β7+ memory CD4 T cells could play a pathogenic role in the disease rebound observed at natalizumab discontinuation.
Sections du résumé
BACKGROUND AND OBJECTIVES
Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin α4β1 with V-CAM expressed on brain vascular endothelial cells. Although natalizumab treatment reduces the clinical relapse rate in patients with relapsing-remitting MS, its discontinuation after reactivation of the JC virus is associated with a rebound of the disease in 20% of patients. The mechanisms of this rebound are not elucidated, but natalizumab increases the frequencies of circulating CD4 T cells expressing proinflammatory cytokines as well as the proportion of circulating Th17/Th1 cells (Th1-like Th17 cells). Gut-derived memory CD4 T cells are a population of growing interest in the pathogenesis of MS, but whether and how their properties are affected by natalizumab is not known. Here, we studied the phenotype and cytokine expression profile of circulating gut-derived memory CD4 T cells in patients with relapsing-remitting MS under natalizumab.
METHODS
We identified gut-derived memory CD4 T cells by their expression of integrin β7 and compared their properties and those of integrin β7- memory CD4 T cells across healthy donors and patients with relapsing-remitting MS treated or not with natalizumab. We also compared the capacity of integrin β7- and integrin β7+ CD4 T-cell subsets to transmigrate in vitro across a model of blood-brain barrier.
RESULTS
The proportions of proinflammatory Th17/Th1 cells as well as of IL-17A+IFNγ+ and IL-17A+GM-CSF+ cells were higher in memory CD4 T cells expressing integrin β7 in patients receiving natalizumab compared with healthy donors and patients with relapsing-remitting MS not receiving natalizumab. By contrast, integrin β7 negative memory CD4 T cells only presented a modest increased in their proportion of Th17/Th1 cells under natalizumab. We further observed that integrin β7+ Th17/Th1 cells migrated as efficiently as integrin β7- Th17/Th1 across a monolayer of brain microvascular endothelial cells.
DISCUSSION
Our study shows that circulating integrin β7+ memory CD4 T cells of patients with relapsing-remitting MS under natalizumab are enriched in proinflammatory cells supporting the hypothesis that integrin β7+ memory CD4 T cells could play a pathogenic role in the disease rebound observed at natalizumab discontinuation.
Identifiants
pubmed: 37739811
pii: 10/6/e200166
doi: 10.1212/NXI.0000000000200166
pmc: PMC10519437
pii:
doi:
Substances chimiques
Natalizumab
0
integrin beta7
0
Interleukin-17
0
Antibodies, Monoclonal
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Références
Cells. 2020 Feb 19;9(2):
pubmed: 32093011
J Immunol. 2015 Jun 1;194(11):5085-93
pubmed: 25917097
J Immunol. 2009 Oct 15;183(8):4984-93
pubmed: 19794071
J Immunol. 2011 Dec 15;187(12):6176-9
pubmed: 22084440
Ann Neurol. 2005 Jul;58(1):50-7
pubmed: 15912506
Eur J Immunol. 2011 Mar;41(3):813-21
pubmed: 21341265
J Neurol. 2014 Jun;261(6):1170-7
pubmed: 24728334
J Exp Med. 2014 Aug 25;211(9):1833-46
pubmed: 25135296
Brain. 2019 Apr 1;142(4):916-931
pubmed: 30770703
J Immunol. 1994 Jul 15;153(2):517-28
pubmed: 7517418
J Immunol. 2014 Jun 15;192(12):5610-7
pubmed: 24850724
Ann Neurol. 2009 May;65(5):499-509
pubmed: 19475668
J Immunol. 1993 Jul 15;151(2):717-29
pubmed: 7687621
Ann Neurol. 2009 Sep;66(3):390-402
pubmed: 19810097
Cell. 2019 Apr 4;177(2):492-493
pubmed: 30951673
Immunol Rev. 2007 Aug;218:65-81
pubmed: 17624944
Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4615-22
pubmed: 20660719
Nat Med. 2007 Oct;13(10):1173-5
pubmed: 17828272
Clin Exp Immunol. 2014 Jun;176(3):320-6
pubmed: 24387139
J Exp Med. 2011 Nov 21;208(12):2465-76
pubmed: 22025301
J Neuroimmunol. 2000 Mar 1;103(2):146-52
pubmed: 10696909
Nature. 2001 Jan 4;409(6816):97-101
pubmed: 11343121
Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2209944120
pubmed: 36574650
N Engl J Med. 2003 Jan 2;348(1):24-32
pubmed: 12510039
Sci Transl Med. 2015 May 13;7(287):287ra74
pubmed: 25972006
J Neuroimmune Pharmacol. 2015 Dec;10(4):528-46
pubmed: 25946987
J Neuroimmunol. 2007 Jan;182(1-2):124-34
pubmed: 17182110
BMC Immunol. 2006 Jul 07;7:14
pubmed: 16824229
Fluids Barriers CNS. 2020 Feb 3;17(1):3
pubmed: 32008573
J Clin Invest. 1998 Dec 15;102(12):2096-105
pubmed: 9854045
Sci Transl Med. 2010 Oct 27;2(55):55ra78
pubmed: 20980695
J Neuroimmunol. 2011 May;234(1-2):148-54
pubmed: 21450349
J Immunol. 2013 Mar 1;190(5):1961-73
pubmed: 23365083
J Immunol. 1996 May 15;156(10):3727-36
pubmed: 8621908
Nature. 2011 Oct 26;479(7374):538-41
pubmed: 22031325
Clin Exp Immunol. 2015 Mar;179(3):378-91
pubmed: 25113810
Neurol Ther. 2015 Dec;4(2):147-57
pubmed: 26647006
Cold Spring Harb Perspect Med. 2018 Mar 1;8(3):
pubmed: 29358320
Lancet Neurol. 2010 Apr;9(4):438-46
pubmed: 20298967
J Immunol. 2013 Oct 1;191(7):3673-80
pubmed: 23980210
Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25860-25869
pubmed: 31796589
Neurology. 2009 Jun 2;72(22):1922-30
pubmed: 19487650
Immunity. 2016 Nov 15;45(5):1078-1092
pubmed: 27851911
Genes Immun. 2009 Jan;10(1):5-10
pubmed: 18971939
Sci Immunol. 2020 Nov 20;5(53):
pubmed: 33219152
Brain. 2018 May 1;141(5):1334-1349
pubmed: 29659729
Mult Scler. 2017 Jan;23(1):114-118
pubmed: 27003947
J Leukoc Biol. 2014 Dec;96(6):1155-64
pubmed: 25097195
Immunity. 2016 Apr 19;44(4):875-88
pubmed: 27096318
J Immunol. 2005 Aug 1;175(3):1558-65
pubmed: 16034094