B7-H1 shapes T-cell-mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity.
Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4+T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Luisa
L
Klotz
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Ivan
I
Kuzmanov
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Stephanie
S
Hucke
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Catharina C
CC
Gross
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Vilmos
V
Posevitz
Department of Neurology, University Hospital Würzburg, 97080 Wuerzburg, Germany.
Angela
A
Dreykluft
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Andreas
A
Schulte-Mecklenbeck
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Claudia
C
Janoschka
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Maren
M
Lindner
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Martin
M
Herold
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Nicholas
N
Schwab
Institute of Experimental Immunology, University of Bonn, 53127 Bonn, Germany.
Isis
I
Ludwig-Portugall
Institute of Experimental Immunology, University of Bonn, 53127 Bonn, Germany.
Christian
C
Kurts
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany.
Sven G
SG
Meuth
Institute for Neuropathology, University of Münster, 48149 Muenster, Germany.
Tanja
T
Kuhlmann
Department of Neurology, University Hospital Münster, 48149 Muenster, Germany; heinz.wiendl@ukmuenster.de.
Heinz
H
Wiendl
D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental; D042783:Endothelial Cells / Q000378:metabolism*; D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease; D051379:Mice; D008822:Mice, Transgenic; D009026:Mortality; D010539:Permeability; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D060890:B7-H1 Antigen
CNS lesion distribution; blood–brain barrier; multiple sclerosis; neuroinflammation; spontaneous EAE
J Immunol. 2009 Oct 15;183(8):4984-93
19794071
Nat Med. 2008 Mar;14(3):337-42
18278054
J Immunol. 2006 Dec 1;177(11):7698-706
17114440
J Clin Invest. 2006 Sep;116(9):2385-92
16955140
Nat Immunol. 2007 Mar;8(3):239-45
17304234
Ann Neurol. 2014 Oct;76(4):594-608
25088017
Nat Med. 2007 Oct;13(10):1173-5
17828272
Arch Dermatol. 2011 May;147(5):579-84
21576578
PLoS One. 2010 Nov 29;5(11):e15531
21209700
Brain Res. 2012 Dec 3;1487:78-87
22789903
Mult Scler. 2002 Dec;8(6):479-84
12474987
Rheumatology (Oxford). 2011 Oct;50(10):1809-13
21791547
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2741-6
19202065
J Clin Invest. 2006 Sep;116(9):2393-402
16955141
J Exp Med. 2003 May 5;197(9):1083-91
12719480
Am J Pathol. 2014 Jul;184(7):2056-65
24819960
Circulation. 2013 Mar 5;127(9):1028-39
23395974
J Immunol. 2015 Oct 15;195(8):3584-95
26378076
FASEB J. 2010 Apr;24(4):1023-34
19940258
J Cell Sci. 2003 May 1;116(Pt 9):1837-46
12665564
Lab Invest. 1997 Mar;76(3):355-64
9121118
Brain. 2000 Aug;123 ( Pt 8):1667-76
10908196
Eur J Immunol. 2010 Dec;40(12):3581-90
21108477
Brain Res. 2005 Aug 16;1053(1-2):162-74
16040011
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10691-6
15249675
J Immunol. 2009 Jul 1;183(1):129-36
19535643
Tissue Antigens. 2000 Mar;55(3):199-205
10777094
Nat Med. 2013 Sep;19(9):1161-5
23933981
J Exp Med. 2011 Nov 21;208(12):2465-76
22025301
Annu Rev Immunol. 2005;23:515-48
15771580
J Autoimmun. 2014 Nov;54:33-50
25175979
J Immunol. 2014 Dec 15;193(12):5809-15
25367116
Nat Genet. 2013 Nov;45(11):1353-60
24076602
Am J Transplant. 2005 Mar;5(3):494-9
15707403
Cell Mol Immunol. 2015 Mar;12(2):213-21
25027969
Cell Immunol. 2014 Jul;290(1):72-9
24908630
J Exp Med. 1998 Jul 6;188(1):169-80
9653093
J Clin Endocrinol Metab. 2009 Dec;94(12 ):5139-45
19850680
J Exp Med. 2003 May 5;197(9):1073-81
12732654
Glia. 2011 May;59(5):841-56
21360758
Clin Neuropharmacol. 2009 May-Jun;32(3):121-32
19483479
Ann Neurol. 2005 Jul;58(1):50-7
15912506
Int Immunol. 2015 Jan;27(1):47-53
25326459
J Vis Exp. 2014 Nov 14;(93):e52204
25489873
Inflamm Res. 2003 Apr;52 Suppl 1:S39-40
12755402
J Immunol. 2002 Jul 1;169(1):117-25
12077236
Nat Immunol. 2009 May;10(5):514-23
19305396
Am J Pathol. 2009 Jun;174(6):2290-9
19443704
Immunity. 2012 Jun 29;36(6):1017-30
22726954
Cell Immunol. 1982 Nov 1;73(2):299-310
6891621
Eur J Immunol. 2008 Jun;38(6):1734-44
18421793
Circ Res. 2015 Aug 28;117(6):502-12
26199323