Soluble fibrinogen-like protein 2/fibroleukin exhibits immunosuppressive properties: suppressing T cell proliferation and inhibiting maturation of bone marrow-derived dendritic cells.
Fibrinogen-like protein 2 (fgl2)/fibroleukin is a member of the fibrinogen-related protein superfamily. In addition to its established role in triggering thrombosis, it is known to be secreted by T cells. The soluble fgl2 ((s)fgl2) protein generated in a baculovirus expression system bound to both T cells and bone marrow-derived dendritic cells (DC) in a specific manner. (s)fgl2 exhibited immunomodulatory properties capable of inhibiting T cell proliferation stimulated by alloantigens, anti-CD3/anti-CD28 mAbs, and Con A in a dose-dependent manner; however, it had no inhibitory effects on CTL activity. The time- and dose-dependent inhibitory effect of (s)fgl2 on alloreactive T cell proliferation could be neutralized by a mAb against mouse fgl2. Polarization toward a Th2 cytokine profile with decreased production of IL-2 and IFN-gamma and increased production of IL-4 and IL-10 was observed in (s)fgl2-treated allogeneic cultures. Exposure of immature DC to (s)fgl2 abrogated the expression of CD80(high) and MHC class II(high) molecules and markedly inhibited NF-kappaB nuclear translocation, thus inhibiting their maturation. (s)Fgl2-treated DC had an impaired ability to stimulate allogeneic T cell proliferation. Maximal inhibition of proliferation was observed when allogeneic T cells were cultured with (s)fgl2-treated DC and (s)fgl2 protein was added in the culture. These data provide the first evidence to demonstrate that (s)fgl2 exerts immunosuppressive effects on T cell proliferation and DC maturation.
Chan
Camie W Y
CW
Multi Organ Transplant Program, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada.
Kay
Lyndsey S
LS
Khadaroo
Rachel G
RG
Chan
Matthew W C
MW
Lakatoo
Sophia
S
Young
Kevin J
KJ
Zhang
Li
L
Gorczynski
Reginald M
RM
Cattral
Mark
M
Rotstein
Ori
O
Levy
Gary A
GA
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis; D016367:Baculoviridae / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005822:Genetic Vectors; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D011485:Protein Binding / Q000276:immunology; D012995:Solubility; D013491:Suppressor Factors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018122:B7-1 Antigen; D016207:Cytokines; C490637:Fgl2 protein, mouse; D006131:Growth Inhibitors; D000949:Histocompatibility Antigens Class II; D013491:Suppressor Factors, Immunologic; D005340:Fibrinogen; D013925:Thromboplastin