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Gene expression profile of human Th17 cells

ABSTRACT: Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here we show that human T cells can express gasdermin E (GSDME), a membrane pore forming molecule, which has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunnelled release of the calpain-matured innate danger signal IL-1a. This property was restricted to a subset of human Th17 cells and regulated by the NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T cell receptor stimulation. Autocrine IL-1a signaling enforced a pro-inflammatory Th17 cell fate through continuous IL-10 suppression and showed an association of this T cell subset with the autoinflammatory Schnitzler syndrome. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This diversifies the functional repertoire and mechanistic equipment of T cells and thus provides new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in various diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214444 | GEO | 2022/10/24

REPOSITORIES: GEO

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Project description:IFNβ, an effective therapy against relapsing-remitting (RR) multiple sclerosis (MS) is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFNβ targeting innate immune response and their effects on DC-mediated regulation of T-cell differentiation. We found that IFNβ−1a in-vitro treatment of human monocyte-derived dendritic cells (DCs) induced the expression of TLR7 and the members of its downstream signaling pathway, including myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK)4, and TNF receptor-associated factor (TRAF)6, while it inhibited the expression of IL-1R. Using siRNA TLR7 gene silencing, we confirmed that IFNβ-1a-induced changes in MyD88, IRAK4 and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFNβ-1a-induced inhibition of IL-1β and IL-23, and the induction of IL-27 secretion by DCs. Supernatant (SN) transfer experiments confirmed that IFNβ-1a-induced changes in DCs’ cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C (RORC) and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFNβ−1a, that selectively targets the autoimmune response in MS. Overall design: Gene expression changes induced by IFNβ−1a were tested using Affymetrix Human Genome U133 (HG-U133) arrays (Affymetrix) that contain 45,000 probe sets representing 39,000 transcripts derived from approximately 33,000 human genes. 107 PBMCs per condition derived from 15 CIS patients were stimulated with plate-immobilized αCD3 (1 μg/ml) and αCD28 (5 μg/ml) mAb (BD Biosciences) in the absence or presence of IFNβ-1a (1000 U/ml) (EMD Serono Inc) for 24 h in serum-free medium (Gibco). Cells were harvested and the total RNA was isolated using a Rneasy kit (Quiagen). Arrays were hybridized for 16 hours at 45oC in the GeneChip® Hybridization Oven 640 (Affymetrix). The arrays were washed and stained with R-phycoerythrin streptavidin in the GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning and basic analysis.

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Gene expression profile of human Th17 cells

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