About

Ulf H Beier, MD, is an Adjunct Associate Professor of Pediatrics (Nephrology) at the University of Pennsylvania's Perelman School of Medicine. He is affiliated with the Department of Pediatrics and is involved in research related to T cell metabolism, transplant immunology, and regulatory T cells. His research expertise includes the study of immune regulation, metabolic pathways in T cells, and their implications for autoimmune diseases and transplantation. Dr. Beier has contributed to understanding the roles of histone deacetylases, NAD metabolism, and chemokine expression in immune function and disease. His work has been published in various scientific journals, and he is actively engaged in advancing knowledge in immunology and nephrology.

Research topics

• Biology
• Cell biology
• Biochemistry
• Cancer research
• Medicine
• Endocrinology
• Internal medicine

Selected publications

• Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling

  Proceedings of the National Academy of Sciences · 2025-01-03 · 8 citations

  articleOpen access

  Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA–cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNA B6 and mtDNA NZB , where mtDNA NZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNA B6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNA NZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNA NZB mice exhibited strikingly impaired tumor growth while mtDNA B6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNA NZB Teff cells increased mitochondrial gene expression while activation of mtDNA NZB Treg cells impaired mitochondrial gene expression and resulted in mtDNA NZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNA NZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.

  PublisherDOI

• ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance

  Molecular Metabolism · 2025-02-08 · 17 citations

  articleOpen access

  OBJECTIVE: Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the Foxp3 locus and FoxP3 protein acetylation. Additionally, Tregs depend on specific metabolic programs for differentiation, yet the underlying molecular mechanisms remain elusive. We aimed to investigate the role of acetyl-CoA carboxylase 1 (ACC1) in the differentiation, stability, and function of regulatory T cells (Tregs). METHODS: We used either T cell-specific ACC1 knockout mice or ACC1 inhibition via a pharmacological agent to examine the effects on Treg differentiation and stability. The impact of ACC1 inhibition on Treg function was assessed in vivo through adoptive transfer models of Th1/Th17-driven inflammatory diseases. RESULTS: cells. Moreover, Tregs treated with an ACC1 inhibitor demonstrated superior long-term stability and an enhanced capacity to suppress Th1/Th17-driven inflammatory diseases in adoptive transfer models. CONCLUSIONS: We identified ACC1 as a metabolic checkpoint in Treg biology. Our data demonstrate that ACC1 inhibition promotes Treg differentiation and long-term stability in vitro and in vivo. Thus, ACC1 serves as a dual metabolic and epigenetic hub, regulating immune tolerance and inflammation by balancing de novo lipid synthesis and protein acetylation.

  PublisherDOI

• Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia–Reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain

  Transplantation · 2024-04-30 · 3 citations

  articleOpen access

  BACKGROUND: Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation. METHODS: Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors. RESULTS: Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage ( P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI ( P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia ( P < 0.01 for AST and P < 0.01 for ALT). CONCLUSIONS: Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.

  PublisherOA PDFDOI

• The poly(C)-binding protein Pcbp2 is essential for CD4+ T cell activation and proliferation

  iScience · 2022-12-21 · 5 citations

  articleOpen access

  Tconv cell activation in a T cell adoptive transfer colitis model system.

  PublisherDOI

• Thermogenic T cells: a cell therapy for obesity?

  American Journal of Physiology-Cell Physiology · 2022-04-27 · 5 citations

  reviewOpen access1st authorCorresponding

  Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardiovascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ("yo-yo effect" or weight cycling). Strategies that increase REE are attractive treatment options. Brown fat tissue engages in nonshivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g., 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (chimeric antigen receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacological mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.

  PublisherOA PDFDOI

• Distinct bioenergetic features of human invariant natural killer T (iNKT) cells enable retained functions in nutrient-deprived states

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-04-29

  preprintOpen access

  ABSTRACT Invariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (T CONV ), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect cytokine production or anti-tumor effector functions. We find that unlike T CONV , human iNKT cells are not dependent upon glucose or glutamine for cytokine production and cytotoxicity upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than T CONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to T CONV . Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated T CONV . Together, our data suggest that human iNKT cells possess different bioenergetic requirements from T CONV and display a more memory-like metabolic program relative to effector T CONV . Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.

  PublisherOA PDFDOI

• Distinct Bioenergetic Features of Human Invariant Natural Killer T Cells Enable Retained Functions in Nutrient-Deprived States

  Frontiers in Immunology · 2021-08-09 · 9 citations

  articleOpen access

  Invariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (T CONV ), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect effector functions such as production of cytokines and cytolytic proteins. We find that unlike T CONV , human iNKT cells are not dependent upon glucose or glutamine for these effector functions upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than T CONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to T CONV . Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated T CONV. Together, our data suggest that human iNKT cells possess different bioenergetic requirements from T CONV and display a more oxidative metabolic program relative to effector T CONV . Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.

  PublisherOA PDFDOI

• Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia–Reperfusion Injury

  American Journal of Respiratory and Critical Care Medicine · 2021-08-04 · 41 citations

  articleOpen access

  Abstract Rationale Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia–reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did (“inflammatory” HFD) or did not (“healthy” HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs’ suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18–treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18–driven impairment in Tregs’ suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs’ suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

  PublisherOA PDFDOI

• Cancer aided by greasy traitors

  Nature · 2021-02-24 · 1 citations

  letterSenior authorCorresponding
  PublisherDOI

• A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells

  Frontiers in Immunology · 2021-07-05 · 13 citations

  articleOpen access

  The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer. Beside their direct involvement in oncogenesis, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg (eTreg) phenotype and for the activation of an epigenetic program that suppresses the anti-tumor immune responses of conventional T and B cells. We now report that as with Mef2d, the deletion of Mef2c in Tregs switches off the expression of Il10 and Icos and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind the regulatory elements of Icos and Il10 , but its loss-of-function in Tregs induces the expression of the transcriptional repressor, Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is converted by Hdac9 into a transcriptional repressor on these loci. This leads to the impairment of Treg suppressive properties in vivo and to enhanced anti-cancer immunity. These data further highlight the central role played by the Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and adds a new level of complexity to the analysis and study of Treg biology.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K08AI095353

  NIH · $650k · 2017

Frequent coauthors

• Wayne W. Hancock

  University of Pennsylvania

  167 shared

• Liqing Wang

  Zhejiang Sci-Tech University

  103 shared

• Tatiana Akimova

  Children's Hospital of Philadelphia

  91 shared

• Rongxiang Han

  University of Pennsylvania

  78 shared

• Jing Jiao

  Zhanjiang Experimental Station

  59 shared

• Matthew H. Levine

  University of Pennsylvania

  52 shared

• Tricia R. Bhatti

  39 shared

• Yujie Liu

  Yantai University

  30 shared

Labs

• Ulf H Beier LabPI