Inhibition of NF-kappaB in T cells blocks lymphoproliferation and partially rescues autoimmune disease in gld/gld mice.
The Fas ligand (FasL)/Fas pathway is crucial for the maintenance of homeostasis of the peripheral immune system. Its importance is illustrated by the spontaneous mouse mutants gld andlpr which lack functional FasL and Fas receptor, respectively. These animals develop lymphadenopathy, splenomegaly, increased serum Ig and autoantibodies, leading to an autoimmune syndromeand premature death. The Rel/NF-kappaB family of transcription factors plays an important role in peripheral lymphocyte proliferation and survival. In this report, we studied the consequences of T cell-specific inhibition of NF-kappaB on the development of the gld phenotype. Transgenic gld/gld mice expressing a non-degradable form of IkappaBalpha under the control of T cell-specific regulatory elements show dramatically reduced lymphadenopathy, splenomegaly, and an almost complete elimination of Thy-1(+)B220(+)CD4(-)CD8(-) abnormal T cells, correlating with reduced proliferative responses and increased apoptosis of peripheral T cells upon TCR triggering. Interestingly, the B cell abnormalities that are characteristic of gld/gld mice, such as the production of autoantibodies, high levels of serum Ig, and the development of glomerulonephritis, are partially corrected. These results suggest that the T cell-specific inhibition of NF-kappaB opens apoptotic pathways distinct from FasL/Fas which, along with a diminished proliferative response, blocks splenomegaly and lymphadenopathy and partially rescues autoimmune disease in gld/gld mice.
Vallabhapurapu
S
S
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Karlsruhe, Germany.
Ryseck
R P
RP
Malewicz
M
M
Weih
D S
DS
Weih
F
F
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D053222:Fas Ligand Protein; D015433:Glomerulonephritis, Membranous / Q000276:immunology*; D020672:I-kappa B Proteins; D008206:Lymphatic Diseases / Q000276:immunology; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013163:Splenomegaly / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011948:Receptors, Antigen, T-Cell; D000072000:NF-KappaB Inhibitor alpha