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Gene expression in T cells from CD46-deficient patients and matcherd healthy controls

ABSTRACT: Recent data indicate that intracellularly activated and autocrine-functioning complement activation fragments - in conjunction with an NLRP3 inflammasome - is critical for normal human Th1 induction and contraction. More specifically, engagement of of the C3aR and CD46 by autocrine generated C3a and C3b, respectively, drives the metabolic reprogramming needed for IFN-gamma secrtion by human CD4+ T cells. It was not clear whether autocrine complement and/or the NLRP3 inflammasome are also needed for normal human cytotoxic CD8+ T cell (CTL) responses. During this study, we used CTLs isolated from patients with either CD46 deficiency or with NLRP3 hyperactivity to determine that CD46 is also required for normal IFN-gamma secretion as well as killing activity in CTLs, whilst a canonical NLRP3 inflammasome is not required for these key functions. The CD46-deficient patient utilized in this study has a mutation in the CD46 gene that leads to reduced cell surface CD46 expression and a dysfunction in Th1 induction. The patient suffers from episodes of atypical hemolytic uremic syndrome (aHUS) and common variable immune deficiency (CVID) and recurrent infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119913 | GEO | 2018/09/14

REPOSITORIES: GEO

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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Gene expression in T cells from CD46-deficient patients and matcherd healthy controls

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