ON THE COVER
Michels et al. show that human colon organoids can identify novel biomarkers, such as HMGCS2, that specifically mark colorectal cancers. The cover shows the staining of HMGCS2 (HPA027442) in human early stage adenoma (T1/Dukes stage A) and adjacent normal tissue. The image was provided by the authors. See page 704.
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People & Ideas
Tuberculosis infection triggers ferroptosis
Despite great efforts to eradicate chronic viral infections, they still remain a global health problem. In this issue, Barnstorf et al. show that virus-unspecific bystander memory T cells are highly affected during chronic viral infection via IL-6/STAT1. Bystander memory T cells are strongly decimated in numbers and change in phenotype and function during chronic viral infection. These data provide new explanations for immune-mediated problems during chronic virus infections.
The role of guanylate-binding proteins in host defense.
This review discusses the generation of phagosomal cytotoxic reactive species by activated macrophages and neutrophils for the control of intracellular pathogens, and the mechanisms by which microbes combat host-derived oxidants via antioxidant networks that mitigate the redox-dependent control of infection.
Brief Definitive Reports
Gαs-coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells
This study demonstrates a regulatory role of Gαs-coupled receptor agonists (catecholamines, prostaglandins, and adenosine) and sleep on integrin activation on T cells in humans. The findings point to a mechanism by which T cell responses are altered in several conditions characterized by aberrant levels of these substances.
Rowe and colleagues show that hematopoietic cells with MLL translocations undergoing leukemogenesis in neonatal mice yield mixed-lineage early B-lymphoid/myeloid leukemia while identical cells in adults generate myeloid leukemia, demonstrating that the age of the hematopoietic microenvironment impacts lineage.
Technical Advances and Resources
Croft et al. demonstrate the use of recombinant adeno-associated viruses and organotypic brain slice cultures to study the central nervous system. This strategy can be used to model Alzheimer’s and Parkinson’s disease inclusion pathologies and determine mechanisms underlying neurodegeneration and therapeutic targets.
Necrotic tissue damage is a major pathological feature of tuberculosis. Here, Amaral et al. show that ferroptosis, a newly described regulated cell death pathway, plays an important role in Mycobacterium tuberculosis–induced cellular necrosis both in vitro and in vivo.
Chronic virus infection compromises memory bystander T cell function in an IL-6/STAT1-dependent manner
Barnstorf et al. demonstrate that chronic viral infections numerically reduce memory non–virus-specific (bystander) cytotoxic T lymphocytes and alter their phenotype and function. Phenotypic changes are induced by the inflammatory cytokine IL-6, and functional impairment is not cell-intrinsic but inferred by the chronically infected host.
The fibronectin EDA isoform sustains bone marrow fibrosis, binding to TLR4 on megakaryocytes and inducing NF-κB activation and IL-6 release. In primary myelofibrosis patients, the bone marrow fibrosis correlates with increased levels of fibronectin EDA isoform in plasma.
Tfr cells regulate Tfh-mediated antibody responses. Hou et al. demonstrate that FoxP3 and Ezh2 control the Tfr transcriptional program, and loss of this program results in dysfunctional ex-Tfr cells.
Denton et al. show that during influenza infection of mice, type I interferon can induce CXCL13 de novo in pulmonary PGDFRα+ fibroblasts. This chemokine drives CXCR5-dependent recruitment of B cells to the lung, thereby supporting pulmonary germinal center formation.
During β-selection, T cells without productive TCRβ rearrangements are eliminated. Klein et al. show that the transcription factor Duxbl regulates this process by inducing apoptosis through activation of the Oas/RNaseL pathway. Successful TCRβ rearrangement rescues cells by pre-TCR–mediated Duxbl suppression.
EHF transcriptionally inhibits the expressions of TGFβ1 and GM-CSF to decrease T reg cell and MDSC accumulation, making it a promising biomarker to evaluate the immune microenvironment in PDAC. EHF overexpression may improve the efficacy of checkpoint immunotherapy in PDAC.
By blocking an important signaling pathway (called NOTCH) and interfering with expression of two tumor suppressor genes in cells derived from human embryonic stem cells, Chen et al. have developed a model for studying small cell lung cancers.
The study provides insights in HGSOC by identifying that ascitic CAFs selectively recruit ITGA5high ascitic tumor cells to form heterotypic spheroids named metastatic units (MUs), which actively engage in peritoneal metastasis, discriminates HGSOC from LGSOC, and act as therapeutic targets in hampering OC metastasis.
Transcriptome and proteome profiling in isogenic CRISPR/Cas9 engineered human colon organoids reveals qualitatively distinct Wnt responses in APC-deficient adenoma and normal stem/progenitor cells. The data represent a comprehensive resource for molecular markers that are linked with colon cancer prognosis.