Issues
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Cover Image
Cover Image
ON THE COVER
Tanaka et al. investigate the role of C-type lectin Mincle in promoting cell death and acute kidney injury. The cover image shows the triple staining of macrophages, laminin, and filipin in the corticomedullary junction area of the injured kidney. Image provided by the authors and modified by the editorial office. Image © Tanaka et al., 2020. https://doi.org/10.1084/jem.20192230. - PDF Icon PDF LinkTable of Contents
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People & Ideas
Charles E. Egwuagu: Going with the flow
Charles E. Egwuagu: Going with the flow
Insights
Cancer metastasis linked to macrophage size, shape, and metabolism
Macrophage morphology could be used to stratify metastasis risk for CRC patients.
COPA silences STING
COPA mutations prevent STING’s Golgi–ER trafficking and promote STING activation and interferonopathy.
Mutations make gut antibodies promiscuous
Intestinal antibodies from healthy subjects or patients with Crohn’s disease cross-target distinct communities of the gut microbiota by a mechanism involving somatic hypermutation.
β-Catenin regulates tumor-derived PD-L1
Tumor-intrinsic AKT–β-catenin axis regulates the expression of PD-L1, and blocking the AKT pathway synergizes with anti–PD-1 in glioblastoma.
Viewpoint
Immigration in science
JEM’s academic editors discuss the benefits of immigration in science.
SARS-CoV-2 vaccine development, access, and equity
A COVID-19 vaccine must first be proven to be safe and effective, but making billions of doses of high quality vaccine and using it equitably and accessibly may present an equal if not greater challenge to the global community.
Brief Definitive Reports
Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease
Barthélemy et al. use mass spectrometry to characterize plasma tau isoforms and assess their diagnosis utility for Alzheimer’s disease. They demonstrate plasma tau phosphorylation measures of p-tau-217 and p-tau-181 are increased with amyloid. Their results support p-tau-217 is superior to p-tau-181 as an AD plasma biomarker.
Imaging resident and recruited macrophage contribution to Wallerian degeneration
This work describes the spatiotemporal orchestration of recently recruited monocyte-derived and resident macrophages during Wallerian degeneration induced by chronic constriction injury of the sciatic nerve and unveils distinct contribution of these two macrophage subsets in myelin degradation and neurofiber regeneration.
Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis
Morphometric characterization of TAMs in human colorectal liver metastases captures individual populations, corresponding to single-cell clusters and associated with distinct clinical outcome and transcriptional profiles. Quantitative analysis of macrophage morphology can serve as a simple readout of functional diversity with prognostic significance.
A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome
A defect in COPI transport due to mutant COPA causes multimerization of STING on the Golgi and type I interferon–driven immune dysregulation in mice. Small-molecule inhibition of STING activation is a new molecular target for treating COPA syndrome.
Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling
Heterozygous missense mutations in COPA underlie constitutive interferon signaling through STING, thereby defining a novel type I interferonopathy and emphasizing the importance of the ER–Golgi axis in interferon homeostasis. Based on these results, three patients have been treated with interferon signaling (JAK1) inhibitors.
Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection
Antibody-mediated clearance of circulating HBsAg has minimal impact on the expansion of HBV-specific CD8+ T cells undergoing intrahepatic priming. It does not alter their differentiation into dysfunctional cells, nor does it enhance their functional restoration by immunotherapeutic strategies.
Necroptosis restricts influenza A virus as a stand-alone cell death mechanism
Necroptosis is considered a fail-safe death modality deployed when apoptosis pathways are compromised, but whether necroptosis can limit a virus in the absence of apoptosis is unknown. This study demonstrates that necroptosis drives highly effective antiviral immunity when apoptosis is absent.
Requirements for cDC2 positioning in blood-exposed regions of the neonatal and adult spleen
Splenic cDCs must be positioned for blood-borne antigen encounter. This study shows that cDC2 localization in bridging channels versus the marginal zone (MZ) is dictated by MZ B cells. Further, it establishes that integrins are necessary for cDC2 retention in blood-exposed regions.
Technical Advances and Resources
Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses
The emergence of SARS-CoV-2 has created a need for robust assays of plasma and monoclonal antibody neutralization potency. Pseudotyped HIV-1– and vesicular stomatitis virus–based reporter viruses and a replication-competent vesicular stomatitis virus/SARS-CoV-2 chimera represent useful tools to assess neutralizing antibodies.
Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection
Diagnosis of EBV-driven T/NK-cell lymphoproliferative disorders and chronic active EBV diseases is often difficult. Fournier et al. report a flow-FISH cytometry assay allowing rapid identification of EBV-infected cells in blood and accurate diagnoses. It represents a powerful tool to study pathophysiological mechanisms of EBV-LPD.
Articles
High microbiota reactivity of adult human intestinal IgA requires somatic mutations
The authors reveal a mechanism of SIgA–microbiota interaction in the adult human gut. They describe antibodies with a high capacity to bind phylogenetically distant members of the microbiota. Such cross-species reactivity does not correlate with antibody polyreactivity but crucially depends on somatic mutations.
Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth
This study identifies a novel population of CD204+IL4R+ bone metastasis–associated macrophages (BoMAMs) in mouse models and patient samples. These BoMAMs, derived from CCR2-recruited monocytes but not from CD169+ resident macrophages, significantly promote metastatic outgrowth of breast cancer in vivo.
β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Our findings reveal an important mechanism of PD-L1 up-regulation elicited by AKT-dependent β-catenin activation and highlight the clinical significance of β-catenin activation in tumor immune evasion.
A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity
Molecular characterization of inhibitory and non-inhibitory antibodies contributes to vaccine design. Here, we show that the high-affinity mAb 5D5 against the PfCSP N-terminus of sporozoites does not inhibit Pf invasion. This information is critical for the prioritization of functional sites of vulnerability to include in next-generation malaria immunogen designs.
Repression of the B cell identity factor Pax5 is not required for plasma cell development
Due to cross-antagonism of the B cell factor Pax5 and plasma cell regulator Blimp1, it was hypothesized that plasma cells develop only upon Pax5 repression by Blimp1. Unexpectedly, Liu et al. show that ectopic Pax5 expression in plasma cells does not interfere with their development and function.
Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
Mutations in ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. Helfricht et al. demonstrate that the loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination, proving a molecular basis for the immunodeficiency in ICF patients.
C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury
This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death–triggered sustained inflammation after renal ischemia–reperfusion injury.
Constructing and deconstructing GATA2-regulated cell fate programs to establish developmental trajectories
By elevating levels of the GATA2 transcription factor in hematopoietic progenitor cells, a transcriptional enhancer establishes multilineage differentiation potential. During embryogenesis, deleting the enhancer upregulates innate immune machinery and deconstructs multilineage potential to favor monocytic differentiation.
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