title: T cell-intrinsic function of the noncanonical NF-κB pathway in the regulation of GM-CSF expression and experimental autoimmune encephalomyelitis pathogenesis.
abstract: The noncanonical NF-κB pathway induces processing of the NF-κB2 precursor protein p100, and thereby mediates activation of p52-containing NF-κB 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-κB2(lym1), we show that the noncanonical NF-κB 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-κB2(lym1) mutant T cells partially restores their ability to induce EAE. These results suggest that the noncanonical NF-κB pathway mediates induction of EAE by regulating the effector function of inflammatory T cells.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030;
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030;
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030;
authors.forename: Mako
authors.initials: M
authors.lastname: Nakaya
authors.affiliation: School of Life Sciences, Qinghua University, Beijing 100000, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030;
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030 ssun@mdanderson.org.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000276:immunology*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology*
chemical_list: D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D016178:Granulocyte-Macrophage Colony-Stimulating Factor