Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis

J Immunol. 2008 Jan 1;180(1):249-60. doi: 10.4049/jimmunol.180.1.249.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Antigens, CD / metabolism
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / pathology
  • B-Lymphocytes / immunology
  • Body Weight / genetics
  • Dendritic Cells / immunology
  • Fibrinogen / antagonists & inhibitors
  • Fibrinogen / genetics
  • Fibrinogen / metabolism*
  • Gene Deletion
  • Glomerulonephritis / genetics*
  • Glomerulonephritis / pathology
  • Lymph Nodes / immunology
  • Mice
  • Mice, Mutant Strains
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, IgG / metabolism
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Thymus Gland / immunology

Substances

  • Antibodies
  • Antigens, CD
  • Fc gamma receptor IIB
  • Fgl2 protein, mouse
  • RNA, Messenger
  • Receptors, IgG
  • Fibrinogen