Biology subjects

Hamminger, P.

Publications and source records attributed to Hamminger, P..

3 recordsLinked to original sources

bioRxiv2022

Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function

FOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naive and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4+ T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naive NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naive Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXR{beta} in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naive and effector Treg cell subset composition independent from its ability to repress LXR{beta}-induced gene expression. Thus, our study reveals that NCOR1 maintains naive and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.

immunology↗

bioRxiv2021

24-Nor-Ursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation

Background & Aims24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8+ T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects. MethodsNorUDCA effects on CD8+ T cell function in vivo were investigated in a hepatic injury model system induced by excessive CD8+ T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8+ T cells in vitro. Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8+ T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients. ResultsIn vivo NorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8+ T cells. With MS, we identified that NorUDCA regulates CD8+ T cells via targeting mTORC1. NorUDCAs impact on mTORC1 signaling was further confirmed in circulating human CD8+ T cells. ConclusionsNorUDCA possesses a yet-unrecognized direct modulatory potency on CD8+ T cells and attenuates excessive CD8+ T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

molecular biology↗

bioRxiv2020

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK positive tumors show a loss of collaborative methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis. STATEMENT OF SIGNIFICANCEEpigenetic alterations are causally involved in tumorigenesis. Here we show that induction of a single human oncogene in murine T cells induces specific deregulation of epigenetic enzymes resulting in epigenomic alterations similar to human tumors. Our findings are of broader implication to understand how epigenomic processes are shaped by oncogene induced transformation.

cancer biology↗