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BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

ABSTRACT: The BCG (Bacille Calmette-Guérin) vaccine, introduced 100 years ago for tuberculosis prevention, has emerging therapeutic off-target benefits for autoimmunity. In randomized controlled trials, BCG vaccinations were shown to gradually improve two autoimmune conditions, type 1 diabetes (T1D) and multiple sclerosis. Here, we investigate the mechanisms behind the autoimmune benefits and test the hypothesis that this microbe synergy could be due to an impact on the host T cell receptor (TCR) and TCR signal strength. We show a quantitative TCR defect in T1D subjects consisting of a marked reduction in receptor density on T cells due to hypermethylation of TCR-related genes. BCG corrects this defect gradually over 3 years by demethylating hypermethylated sites on members of the TCR gene family. The TCR sequence is not modified through recombination, ruling out a qualitative defect. These findings support an underlying density defect in the TCR affecting TCR signal strength in T1D.

SUBMITTER: Takahashi H

PROVIDER: S-EPMC9668301 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

Takahashi Hiroyuki H Kühtreiber Willem M WM Keefe Ryan C RC Lee Amanda H AH Aristarkhova Anna A Dias Hans F HF Ng Nathan N Nelson Kacie J KJ Bien Stephanie S Scheffey Danielle D Faustman Denise L DL Faustman Denise L DL

Science advances 20221116 46

The BCG (Bacille Calmette-Guérin) vaccine, introduced 100 years ago for tuberculosis prevention, has emerging therapeutic off-target benefits for autoimmunity. In randomized controlled trials, BCG vaccinations were shown to gradually improve two autoimmune conditions, type 1 diabetes (T1D) and multiple sclerosis. Here, we investigate the mechanisms behind the autoimmune benefits and test the hypothesis that this microbe synergy could be due to an impact on the host T cell receptor (TCR) and TCR ...[more]

PMID: 36383663

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Project description:Background and aimsFollowing liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity.Approach and resultsWe applied the techniques of bulk RNA-sequencing (RNA-seq), single-cell RNA-seq, and assay for transposase-accessible chromatin with high-throughput sequencing to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGF-β signaling by profiling cells undergoing reprogramming in mice with hepatocyte-specific deletion in the downstream TGF-β signaling component mothers against decapentaplegic homolog 4 (Smad4). Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. Although some reprogrammed cells had molecular features of "fully differentiated" BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single-cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming.ConclusionHepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGF-β signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGF-β can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of BECs and bile ducts in the adult liver.

Dataset Information

BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

Publications

BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

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