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Utilizing ex vivo generated double negative T cells prevents the development and progression of nonalcoholic steatohepatitis

ABSTRACT: Methods: The DNT cells incubation with CD3/CD28 antibodies were stimulated with IL-10 (50 ng/ml) for 24 hours, then transcriptome sequencing studies were performed on DNT cells RNA. Results: The distributions of up- (107) and downregulated (114) genes (≥ 1.5-fold difference, padj < 0.05) compared with without IL-10-treated DNT were depicted in a volcano plot. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that changed genes from IL-10-stimulated monocytes were involved in the immune response; inflammatory response; regulation of apoptotic and proliferation; cytolysis; cytokine-cytokine receptor interaction; and T cell receptor signaling pathway, among others. Compared with control DNT cells, IL-10-treated DNT exhibited downregulated levels of cell survival and activation genes (Bcl-xl, Cytc, Epcam, and Spi1), cell cytotoxicity genes (Nkp46, Klrg1, Slamf6, Cd107a, Cd161, and Cd226), immune responses genes (Lta, Cd127, H2-Oa, and H2-Dma), and upregulated cell exhaustion genes (Pd-1, Ctla4, and Tim3).In this study, we found IL-10 stimulated DNT cells highly expressed PI3K-AKT signaling genes, such as Jak3, Pik3ap1, Pik3cb, and Sgk1, and MAPK pathway genes, such as Stmn1, Fos, Kras, Nras, and Map3k5, which indicated that IL-10 upregulated NKG2A expression in DNT cells may through these pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE134346 | GEO | 2020/11/11

REPOSITORIES: GEO

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Project description:Primary biliary cholangitis (PBC) is a liver-specific autoimmune disease. Treatment of PBC with ursodeoxycholic acid (UDCA) is not sufficient to prevent disease progression, new and creative approaches to treating patients with PBC are urgently required. Double-negative T (DNT) cells, unique regulatory T cells, play crucial roles in maintaining immune system homeostasis. However, both the absolute number and proportion of liver DNT cells were reduced in PBC patients. Hence, it is worth pursuing that whether replenishment of DNT cells can improve the hepatic function and pathology of PBC. In this study, adoptive transfer of DNT cells significantly decreases plasma levels of ALT, AST, AMA-M2 and IgM in both dnTGFβ RII and 2OA-BSA-immunized PBC mouse models. In addition, DNT cells exhibit a strong suppression on liver T cells. While combination therapy with DNT cells and UDCA predominantly ameliorate liver inflammation and extensively inhibit hepatic T and B cells. In vitro study further reveals that UDCA promotes the proliferation of DNT cells, increased functional molecule perforin and reduced inhibitory molecule NKG2A and EPCR expression, resulting in augmenting the suppressive function of DNT cells via FXR/JNK signaling pathway in both mice and human DNT cells. In conclusion, UDCA augments the suppressive function of DNT cells via FXR/JNK. A single transfer of DNT cells in combination with UDCA strongly ameliorates PBC in mice. This study provides a potential application of DNT cell-based therapy for PBC. Methods: The DNT cells incubation with anti-CD3/CD28 antibodies were stimulated with UDCA (60uM) for 48 hours, then transcriptome sequencing studies were performed on DNT cells RNA.Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced by the University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=1.41 and pvalue <= 0.05 between UDCA treated and control DNT cells were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment.

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Utilizing ex vivo generated double negative T cells prevents the development and progression of nonalcoholic steatohepatitis

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