Biology subjects

Steinert, E. M.

Publications and source records attributed to Steinert, E. M..

5 recordsLinked to original sources

bioRxiv2026

Maintenance DNA methylation is necessary for age-related alterations in regulatory T cell transcriptional and DNA methylation signatures

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, restrain immune responses during inflammatory stimuli, and promote tissue function and repair. Treg cell lineage identity, stability, and function depend on specific DNA methylation patterns maintained by the epigenetic regulator, UHRF1. Aging disrupts DNA methylation patterns necessary for Treg cell-mediated lung repair in a cell-autonomous manner. Nevertheless, whether maintenance DNA methylation is necessary for age-related Treg cell transcriptional and methylation programs is unknown. Here, we performed transcriptional and DNA methylation profiling on young and old Treg cells isolated from mice with chimeric Treg cell-specific loss of UHRF1. We observed cell-autonomous, age-related alterations in transcriptional and DNA methylation signatures that were dependent on UHRF1. We conclude that maintenance DNA methylation is required for age-related alterations in Treg cell transcriptional and DNA methylation signatures.

immunology↗

bioRxiv2026

Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility

Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain -hydroxy acid, D--hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8+ T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

immunology↗

bioRxiv2025

Maintenance DNA methylation is required for induced regulatory T cell reparative function following viral pneumonia

FOXP3+ natural regulatory T cells (nTregs) promote resolution of inflammation and repair of epithelial damage following viral pneumonia-induced lung injury, thus representing a cellular therapy for patients with acute respiratory distress syndrome (ARDS). Whether in vitro induced Tregs (iTregs), which can be rapidly generated in substantial numbers from conventional T cells, also promote lung recovery is unknown. nTregs require specific DNA methylation patterns maintained by the epigenetic regulator, ubiquitin-like with PHD and RING finger domains 1 (UHRF1). Here, we tested whether iTregs promote recovery following viral pneumonia and whether iTregs require UHRF1 for their pro-recovery function. We found that adoptive transfer of iTregs to mice with influenza virus pneumonia promotes lung recovery and that loss of UHRF1-mediated maintenance DNA methylation in iTregs leads to reduced engraftment and a delayed repair response. Transcriptional and DNA methylation profiling of adoptively transferred UHRF1-deficient iTregs that had trafficked to influenza-injured lungs demonstrated transcriptional instability with gain of effector T cell lineage-defining transcription factors. Strategies to promote the stability of iTregs could be leveraged to further augment their pro-recovery function during viral pneumonia and other causes of ARDS.

immunology↗

bioRxiv2024

FOXP3+ Regulatory T Cells Require TBET to Regulate Activated CD8+ T Cells During Recovery from Influenza Infection

FOXP3+ regulatory T (Treg) cells are necessary to coordinate resolution of lung inflammation and a return to homeostasis after respiratory viral infections, but the specific molecular requirements for these functions and the cell types governed by Treg cells remain unclear. This question holds significance as clinical trials of Treg cell transfer therapy for respiratory viral infection are being planned and executed. Here, we report causal experiments in mice determining that Treg cells are necessary to control the numbers of activated CD8+ T cells during recovery from influenza infection. Using a genetic strategy paired with adoptive transfer techniques, we determined that Treg cells require the transcription factor TBET to regulate these potentially pro-inflammatory CD8+ T cells. Surprisingly, we found that Treg cells are dispensable for the generation of CD8+ lung tissue resident-memory T (Trm) cells yet similarly influence the transcriptional programming of CD8+ Trm and activated T cells. Our study highlights the role of Treg cells in regulating the CD8+ T cell response during recovery from influenza infection.

immunology↗

bioRxiv2020

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

immunology↗