Issues
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Cover Image
Cover Image
ON THE COVER
Radiotherapy results in upregulation of Piezo2, a mechanosensitive ion channel, in tumor cells, which contributes to radioresistance. The image shows the staining for cytoskeleton of B16F1, a radio-resistant mouse melanoma cell line, after ionizing radiation with Phalloidin (green), Cytokeratin (purple), and counterstained with Hoechst for nuclei (blue). Image © Miao et al., 2024. https://doi.org/10.1084/jem.20231486 - PDF Icon PDF LinkTable of Contents
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Insights
Iron TAMs: The fallen protectors
Folkert et al. define an “iron-rich” subset of tumor-associated macrophages (iTAMs). The metabolism of heme leads to the degradation of the transcriptional repressor Bach1 and shapes the transcriptional profile of iTAMs. The endothelin receptor B in iTAMs signals tumor-supportive functions.
Viewpoint
A path forward for Staphylococcus aureus vaccine development
Juliane Bubeck Wardenburg and Stephanie A. Fritz explore the biological linkage between microbial niche acquisition and host immunity as a basis to guide future vaccine efforts against Staphylococcus aureus infection.
Reviews
Transcriptional network dynamics in early T cell development
Multipotent blood progenitors begin T cell development in the thymus, activating a multistep gene regulatory network. This review explores how the dynamic interplay between Notch signals, Notch-induced factors, and progenitor-associated factors control T-development progression by synergizing and opposing each other’s action.
The partitioning of TCR repertoires by thymic selection
TCR rearrangement endows the preselection thymocyte repertoire with wide-ranging ligand specificity. Here, we discuss how thymic selection matures or eliminates clonotypes with particular specificities and develops T cell sublineages and microrepertoires according to their antigen-recognition capabilities.
Adjusting to self in the thymus: CD4 versus CD8 lineage commitment and regulatory T cell development
This review covers recent advances in our understanding of how developing T cells sense and adjust to their self-reactivity and how this impacts their decision to become a CD8 T cell, a CD4 T cell, or a regulatory T cell.
Generation and repair of thymic epithelial cells
Thymic epithelial cells (TECs) are essential for T-cell development, and their injury limits thymus function. We explain how TEC development creates multifunctional cortical and medullary microenvironments and describe regenerative pathways where TEC targeting creates therapeutic opportunities to restore T-cell immunity.
Rediscovering the human thymus through cutting-edge technologies
This review highlights how novel cutting-edge technologies, including high-resolution imaging, single-cell omics, and organoid cultures, have improved our understanding of human thymus biology, in terms of developmental trajectories, cellular heterogeneity, and spatial organization.
Brief Definitive Reports
Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients
Infection with tick-borne encephalitis (TBE) virus (TBEV) is usually benign but may cause severe encephalitis in rare cases. Pre-existing autoantibodies neutralizing type I IFNs underlie ∼10% of these severe cases, strongly increasing the risk of severe disease relative to the absence of these autoantibodies.
Technical Advances and Resources
Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies
Hahn et al., present data from a first-in-human HIV vaccine trial with a novel TLR-7/8-signaling adjuvant (3M-052AF/Alum). The vaccine appears safe and is the first vaccine reported to induce serum antibodies that neutralize non-lab-adapted HIV strains matched to the vaccine.
Modeling memory B cell responses in a lymphoid organ-chip to evaluate mRNA vaccine boosting
We developed a lymphoid organ-chip that models human recall responses to vaccination. This microfluidic-based system recapitulates antigen capture/expression, CD4+ T cell/B cell clustering, memory B cell amplification, plasmablast differentiation, and antibody secretion in response to perfused proteins or mRNA vaccines.
Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity
Trajectory analysis of CD4+ T cell differentiation during a type I inflammatory immune response identified two distinct differentiation paths for effector and precursor central memory T cells arising from heterogeneous naïve CD4+ T cells.
Articles
An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis
Iron-rich tumor-associated macrophages (iTAMs) are characterized by high intracellular iron, heme metabolism, and expression of the endothelin receptor type B. iTAMs promote angiogenesis and immunosuppression in tumors. Heme-mediated degradation of the transcriptional repressor BACH1 induces the iTAM transcriptional program in macrophages.
Tumor cell–intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance
Miao et al. report that tumor cell–intrinsic mechanical force sensor, Piezo2, impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.
SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma
SETD1B (KMT2G) is a histone H3K4 trimethyl transferase and a mutational target in lymphoma. SETD1B inactivation disables critical cell death programs and causes Venetoclax resistance. Inhibition of the corresponding histone demethylase KDM5 restores cell death and Venetoclax sensitivity.
Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer
The AMADEUS trial reveals key biomarkers in blood and tumor tissue that could predict patient response to immunotherapy, offering a potential breakthrough for treating various solid tumors. This discovery addresses the pressing need for personalized cancer treatment strategies.
RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation
This study shows NLRP3 inflammasome activation in circulating myeloid cells by human RAC2 gain-of-function variants that are linked to rare immune disorders. This work unravels a RAC2–PAK1–NLRP3 signaling axis as a potential drug target to treat patients.
Loss of ARID3A perturbs intestinal epithelial proliferation–differentiation ratio and regeneration
The transit-amplifying (TA) cells at the intestinal crypt have the capability to proliferate, differentiate, and undergo regeneration upon injury. Angelis et al. show that ARID3A functions to fine tune the proliferation–differentiation dynamics at the TA cells and regulate injury-induced regeneration.
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