Biology subjects

Steiner, K. K.

Publications and source records attributed to Steiner, K. K..

6 recordsLinked to original sources

bioRxiv2026

Tissues Guide Dependence of Treg on the Transferrin Receptor

Activated T cells increase transferrin-bound iron uptake via the transferrin receptor, also called CD71. We previously demonstrated that targeting CD71 with an antibody to reduce iron update can modify CD4 T cell function, with different effects on TH1, TH17, and regulatory T (Treg) cells. CD71 blocking antibody-treated Tregs had no loss of viability or differentiation, and Foxp3 expression was increased. However, a genetic deletion of Tfrc (the gene for CD71) driven by Foxp3-Cre was reported to cause a lethal autoimmunity. Whether altered immune homeostasis or insufficient early developmental tolerance drive the phenotype of CD71 knockout (KO) Treg mice were unclear. Here, we examined the Foxp3-YFP-Cre KO mouse model and a tamoxifen-inducible KO model in adults to determine the role of CD71 expression in Treg cells. We hypothesized that due to a lack of iron for mitochondrial metabolism, KO Treg adapt to rely heavily on glycolysis and become unstable, promoting pro-inflammatory exTreg cells. This effect was not universal, however, and necropsy analyses revealed tissue-specific inflammation. While the colons of mice with KO Treg cells appeared healthy, skin and lung tissue were severely inflamed. Metabolically, KO Treg cells had a significant decrease in their glycolytic capacity and instead increased oxidation of amino acids and fatty acids. In inflamed skin, which that promotes increased oxidative stress, CD71 expression in Treg cells suppressed tissue inflammation in a model of atopic dermatitis-like disease. These results indicate the CD71-iron axis as a new immunometabolic regulator of Treg cell functions in immune and non-immune organs. Capsule SummaryA loss of the transferrin receptor in Tregs causes severe autoimmunity and here we clarify how Tregs rely on this receptor for iron in specific tissues and disease settings including atopic dermatitis.

immunology↗

bioRxiv2025

Impaired oxidative phosphorylation drives primary tumor escape and metastasis

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

cancer biology↗

bioRxiv2024

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism

SummaryWe show that the mitochondrial fatty acid synthesis gene Mecr shapes CD4+ T cell metabolism and function. It may be targeted in inflammatory diseases and provides rationale to consider the immunological state of patients with mitochondrial disease. Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

immunology↗

bioRxiv2023

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities

Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1, are critical for T cell expansion and function. Interestingly, Gfpt1-deficient TH1 cells were more affected than TH17 cells, which had increased Nagk for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor Bcl11b promotes CD4+ T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders. HIGHLIGHTSO_LIInborn errors of immunity and metabolism have greater overlap than previously known C_LIO_LIGfpt1 deficiency causes an IEM but also selectively regulates T cell subset fate C_LIO_LILoss of Bcl11b causes a T cell deficiency IEI but also harms mitochondrial function C_LIO_LIMany IEM may have immune defects and IEI may be driven by metabolic mechanisms C_LI

immunology↗

bioRxiv2022

PD-1 is induced on tumor-associated macrophages in obesity to directly restrain anti-tumor immunity

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can also promote improved survival for some cancers3-5 and enhance responses to some immune checkpoint blockade therapies6-8. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described9-12, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner. PD-1+ TAMs had increased mitochondrial respiration and expression of genes regulating oxidative phosphorylation, lipid uptake and cell cycle while PD-1- TAMs showed greater signatures of phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis and phagocytic capacity, and this was reversed with blocking PD-1 antibody. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

immunology↗

bioRxiv2021

Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-{beta}, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

cancer biology↗