Publications by authors named "Amanda Poholek"

Despite protective roles in various type of infection and in would healing, T helper (Th)2 cells are drivers of inflammation in allergic asthma. In this issue of Immunity, Zou et al. demonstrate the crucial involvement of hypoxia inducible factor (HIF)2α in promoting the differentiation of inflammatory Th2 cells, suggesting HIF2α as a promising therapeutic target for the treatment of allergic asthma.

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T cell exhaustion remains a significant barrier to immunotherapeutic success for many patients with solid tumors. Growing evidence suggests that enhanced survival and self-renewal properties of a stem-like precursor T cell population (Tpex) is correlated with a survival advantage in immunotherapy. In a recent study published in Science, Kang and colleagues find three epigenetic regulators commonly mutated in clonal hematopoiesis also control Tpex progression to exhaustion.

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CD8 T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (T) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid.

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  • - The study investigates how T helper 2 (T2) cells, involved in allergic reactions, differentiate in barrier tissues, focusing on house dust mite-specific T cells in mice.
  • - Key to T2 cell differentiation and migration is the early expression of a protein called Blimp-1, with its absence hindering T2 cell development in the lungs.
  • - The findings highlight the importance of IL-2 signaling and the local environment in lymph nodes, which support the initial formation of T2 cells by promoting Blimp-1 and GATA3, crucial for allergic asthma development.
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  • CART therapy is effective in treating leukemia, but many patients experience relapse, potentially due to the exhaustion of T cells during their expansion process.
  • Researchers explored using AMP-activated protein kinase (AMPK) regulation to enhance T cell function and persistence after their expansion in the lab.
  • The study found that T cells treated with the AMPK agonist Compound 991 showed improved survival and effectiveness against leukemia in mice, suggesting new ways to support CART therapy in long-term cancer treatment.*
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T cells are dynamically regulated immune cells that are implicated in a variety of diseases ranging from infection, cancer and autoimmunity. Recent advancements in sequencing methods have provided valuable insights in the transcriptional and epigenetic regulation of T cells in various disease settings. In this review, we identify the key sequencing-based methods that have been applied to understand the transcriptomic and epigenomic regulation of T cells in diseases.

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Spatial transcriptomics technologies have shed light on the complexities of tissue structures by accurately mapping spatial microenvironments. Nonetheless, a myriad of methods, especially those utilized in platforms like Visium, often relinquish spatial details owing to intrinsic resolution limitations. In response, we introduce TransformerST, an innovative, unsupervised model anchored in the Transformer architecture, which operates independently of references, thereby ensuring cost-efficiency by circumventing the need for single-cell RNA sequencing.

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  • Modern multiomic technologies can create complex profiles, but challenges like data variability and irrelevant information make analyzing these high-dimensional datasets difficult.
  • SLIDE is a new machine learning method that can identify important interactions in omic data without relying on specific assumptions, ensuring reliable results with controlled false discovery rates.
  • By using SLIDE on single-cell and spatial omic data, researchers found significant biological insights that surpass what existing methods provide, making it a powerful tool for biological research.
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Fungal infections are a global threat; yet, there are no licensed vaccines to any fungal pathogens. Th17 cells mediate immunity to Candida albicans, particularly oropharyngeal candidiasis (OPC), but essential downstream mechanisms remain unclear. In the murine model of OPC, IκBζ (Nfkbiz, a non-canonical NF-κB transcription factor) was upregulated in an interleukin (IL)-17-dependent manner and was essential to prevent candidiasis.

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  • High sugar diets in high-income countries may negatively impact the function of intestinal stem cells (ISCs) and transit-amplifying (TA) cells, which are crucial for maintaining the colonic epithelium and repairing damage.
  • Research using colonoids and a mouse model showed that excess sugar limits the development and proliferation of these cells by reducing the expression of growth-related genes and altering their metabolic pathways.
  • Findings suggest that short-term high-sucrose intake can inhibit the regenerative capabilities of ISCs and TA cells, potentially guiding dietary choices for better recovery from intestinal injuries.
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Regulation of interferon-γ is critical to constrain inflammation and mount effective responses to infection and anti-tumor immunity. In this issue of Immunity, Cui et al. identify a distal silencer element that disrupts promoter-enhancer looping, regulating IFN-γ expression and preventing inappropriate inflammation.

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  • Mammalian orthoreovirus, linked to celiac disease in humans, infects various mammals and affects mouse brains differently based on serotype.
  • A genome-wide CRISPRa screen identified the paired immunoglobulin-like receptor B (PirB) as a key receptor for reovirus that influences its neuropathogenicity.
  • The study found that PirB is essential for reovirus attachment and replication in the brain, especially for the neurotropic T3 serotype, highlighting its role in the virus's infectivity in neurons.
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Exhaustion is a state of CD8 T cell differentiation that occurs in settings of chronic Ag such as tumors, chronic viral infection, and autoimmunity. Cellular differentiation is driven by a series of environmental signals that promote epigenetic landscapes that set transcriptomes needed for function. For CD8 T cells, the epigenome that underlies exhaustion is distinct from effector and memory cell differentiation, suggesting that signals early on set in motion a process where the epigenome is modified to promote a trajectory toward a dysfunctional state.

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CD8 T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy.

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Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8 T cells throughout differentiation.

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Antigen-presenting cells (APCs) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory APCs that secrete IL-12, which is a driver of donor Th1 responses, causing graft-versus-host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cell responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD.

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In a recent issue of Nature, Melenhorst et al. perform an extensive analysis of CAR T cells that persist for ten years in CLL patients. They find a dominant cytotoxic CD4+ population, raising the possibility that CD4+ T cells play an important role in durable CAR T cell therapy.

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The multiligand receptors megalin () and cubilin () and their endocytic adaptor protein Dab2 () play essential roles in maintaining the integrity of the apical endocytic pathway of proximal tubule (PT) cells and have complex and poorly understood roles in the development of chronic kidney disease. Here, we used RNA-sequencing and CRISPR/Cas9 knockout (KO) technology in a well-differentiated cell culture model to identify PT-specific transcriptional changes that are directly consequent to the loss of megalin, cubilin, or Dab2 expression. KO of had the greatest transcriptional effect, and nearly all genes whose expression was affected in KO and KO cells were also changed in KO cells.

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Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor-α (TNFα) signaling axis. Both cytokines activate nuclear factor κB, but appropriate induction of downstream effector genes requires coordinated activation of other transcription factors, notably, CCAAT/enhancer binding proteins (C/EBPs). Here, we demonstrate the unexpected involvement of a posttranscriptional "epitranscriptomic" mRNA modification [N6-methyladenosine (mA)] in regulating C/EBPβ and C/EBPδ in response to IL-17A, as well as IL-17F and TNFα.

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T cells are critical for orchestrating appropriate adaptive immune responses and maintaining homeostasis in the face of persistent nonpathogenic Ags. T cell function is controlled in part by environmental signals received upon activation and derived from the tissue environment in which Ag is encountered. Indeed, tissue-specific environments play important roles in controlling the T cell response to Ag, and recent evidence suggests that tissue draining lymph nodes can mirror those local differences.

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Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models.

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MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-β.

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Regulatory T (T) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function. At the same time, T cells maintain a strong suppression of effector T cells within the TME.

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Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation.

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Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell-derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown.

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