Inhibition of NF-kappa B in T cells blocks lymphoproliferation and partially rescues autoimmune disease in gld/gld mice

Citation
S. Vallabhapurapu et al., Inhibition of NF-kappa B in T cells blocks lymphoproliferation and partially rescues autoimmune disease in gld/gld mice, EUR J IMMUN, 31(9), 2001, pp. 2612-2622
Citations number
51
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Immunology
Journal title
EUROPEAN JOURNAL OF IMMUNOLOGY
ISSN journal
0014-2980 → ACNP
Volume
31
Issue
9
Year of publication
2001
Pages
2612 - 2622
Database
ISI
SICI code
0014-2980(200109)31:9<2612:IONBIT>2.0.ZU;2-Z
Abstract
The Fas ligand (FasL)/Fas pathway is crucial for the maintenance of homeost asis of the peripheral immune system. Its Importance is illustrated by the spontaneous mouse mutants gld and lpr which lack functional FasL and Fas re ceptor, respectively. These animals develop lymphadenopathy, splenomegaly, increased serum Ig and autoantibodies, leading to an autoimmune syndrome an d premature death. The Rel/NF-kappaB family of transcription factors plays an important role in peripheral lymphocyte proliferation and survival. In t his report, we studied the consequences of T cell-specific inhibition of NF -kappaB on the development of the gld phenotype. Transgenic gld/gld mice ex pressing a non-degradable form of I kappaB alpha under the control of T cel l-specific regulatory elements show dramatically reduced lymphadenopathy, s plenomegaly, 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. Interesting ly, the B cell abnormalities that are characteristic of gld/gld mice, such as the production of autoantibodies, high levels, of serum Ig, and the deve lopment of glomerulonephritis, are partially corrected. These results sugge st that the T cell-specific inhibition of NF-kappaB opens apoptotic pathway s distinct from FasL/Fas which, along with a diminished proliferative respo nse, blocks splenomegaly and lymphadenopathy and partially rescues autoimmu ne disease in gld/gld mice.