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

ABSTRACT: 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.

SUBMITTER: Yu J

PROVIDER: S-EPMC4076693 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Yu Jiayi J Zhou Xiaofei X Nakaya Mako M Jin Wei W Cheng Xuhong X Sun Shao-Cong SC

Journal of immunology (Baltimore, Md. : 1950) 20140604 1

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 ...[more]

PMID: 24899500

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Project description:Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+IFN-γ+, IL-17+IFN-γ-, and IL-17-IFN-γ+ cells accompanied by higher frequency of IL-17-IFN-γ- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+IFN-γ+ Th17 cells in SC) on GM-CSF+IFN-γ+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+IFN-γ+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1β, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45hi cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto)reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE.

Dataset Information

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

Publications

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

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