Transcriptomics,Genomics

Dataset Information

38

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. Overall design: Total CD8+ T cells of the patient and a sex- and age-matched healthy donor were isolated and activated for 6 hrs in vitro with immobilised antibodies to CD3 and CD3+CD46 in the presence of 25 U/ml IL-2. Toral RNA was isolated and gene array analyses pereformed as technical replicates of three.

INSTRUMENT(S): Illumina HumanHT-12 V4.0 expression beadchip

SUBMITTER: Mehdi Pirooznia  

PROVIDER: GSE119913 | GEO | 2018-09-14

REPOSITORIES: GEO

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Publications


The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and f  ...[more]

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