Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis.
Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.
Shalev
Itay
I
Multi Organ Transplant Program, Department of Immunology, University of Toronto, Ontario, Canada.
Liu
Hao
H
Koscik
Cheryl
C
Bartczak
Agata
A
Javadi
Mojib
M
Wong
Kit Man
KM
Maknojia
Asif
A
He
Wei
W
Liu
Ming Feng
MF
Diao
Jun
J
Winter
Erin
E
Manuel
Justin
J
McCarthy
Doug
D
Cattral
Mark
M
Gommerman
Jennifer
J
Clark
David A
DA
Phillips
M James
MJ
Gorczynski
Reginald R
RR
Zhang
Li
L
Downey
Greg
G
Grant
David
D
Cybulsky
Myron I
MI
Levy
Gary
G
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D001835:Body Weight / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D005340:Fibrinogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; C080571:Fc gamma receptor IIB; C490637:Fgl2 protein, mouse; D012333:RNA, Messenger; D017452:Receptors, IgG; D005340:Fibrinogen