4333 total record number 24 records this year

T cell-intrinsic function of the noncanonical NF-B pathway in the regulation of GM-CSF expression and experimental autoimmune encephalomyelitis pathogenesis.

Yu, J;Zhou, X;Nakaya, M;Jin, W;Cheng, X;Sun, SC;

The noncanonical NF-B pathway induces processing of the NF-B2 precursor protein p100, and thereby mediates activation of p52-containing NF-B complexes. This pathway is crucial for B cell maturation and humoral immunity, but its role in regulating T cell function is less clear. Using mutant mice that express a nonprocessible p100, NF-B2(lym1), we show that the noncanonical NF-B pathway has a T cell-intrinsic role in regulating the pathogenesis of a T cell-mediated autoimmunity, experimental autoimmune encephalomyelitis (EAE). Although the lym1 mutation does not interfere with naive T cell activation, it renders the Th17 cells defective in the production of inflammatory effector molecules, particularly the cytokine GM-CSF. We provide evidence that p52 binds to the promoter of the GM-CSF-encoding gene (Csf2) and cooperates with c-Rel in the transactivation of this target gene. Introduction of exogenous p52 or GM-CSF to the NF-B2(lym1) mutant T cells partially restores their ability to induce EAE. These results suggest that the noncanonical NF-B pathway mediates induction of EAE by regulating the effector function of inflammatory T cells.