ON THE COVER
The cover shows in situ hybridization for Znf382 mRNA (magenta) and immunohistochemistry of glutamine synthetase (yellow) and DAPI (blue) in mouse dorsal root ganglion. Image © Ma et al., 2021. https://doi.org/10.1084/jem.20210920
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Bone marrow runs the (bone) show
Clonal hematopoiesis of indeterminate potential (CHIP) promotes osteoporosis via bone-resorbing osteoclasts.
Can repurposing drugs play a role in malaria control?
Laura Kirkman and Roland Cooper discuss how repurposing drugs can play a role in controlling malaria.
Signature required: The transcriptional response to tuberculosis
Here, Katrin Mayer-Barber and Clifton Barry III discuss patterns and pathways associated with individuals infected with Mycobacterium tuberculosis who develop clinical symptoms.
Brief Definitive Reports
Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis
Somatic mutations such as in DNMT3A accumulate in hematopoietic stem cells in CHIP. Kim et al. show that CHIP promotes osteoporosis via bone-resorbing osteoclasts. Mutant macrophages with altered methylation and inflammatory signaling secrete cytokines such as IL-20.
Posttranscriptional regulation of ILC2 homeostatic function via tristetraprolin
Tristetraprolin (TTP) negatively regulates constitutive IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) through mRNA degradation. In Zfp36−/− mice, eosinophilopoiesis was dysregulated by IL-5 overproduction in ILC2s, suggesting that TTP is crucial in regulating ILC2 homeostatic function.
Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis
The authors report inborn error of TLR3 or MDA5 in two unrelated children with enterovirus rhombencephalitis. TLR3 and MDA5 may control anti-enterovirus immunity in central nervous system cells via the maintenance of basal or virus-induced type I IFN production, respectively.
Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress
Activation of PI3Kδ signaling in B cells impairs autophagy, leading to increased ER stress and plasma cell death in an mTORC1-dependent mechanism.
T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients
We report four patients in a multigenerational family carrying a novel heterozygous variant in AIOLOS/IKZF3 associated with T and B cell developmental and functional defects, CID, PJP, and CLL. Identification of germline IKZF3 mutations introduces us to hereditary AIOLOS-associated diseases in humans.
Glycan engineering of the SARS-CoV-2 receptor-binding domain elicits cross-neutralizing antibodies for SARS-related viruses
Shinnakasu et al. show that the glycan engineering immunogens of SARS-CoV-2 spike receptor-binding domain (RBD) elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibodies, thereby manifesting significant neutralizing activity not only for SARS-CoV-2 but also for more broad SARS-related viruses.
Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients
Through single-cell TCR and RNA sequencing, the authors identified public cTfh clonotypes expanded in recovered COVID-19 patients and determined their epitopes in the specific regions of spike protein conserved among emerging SARS-CoV-2 variants, which are candidates for booster antigens.
Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity
Antibodies are central to long-term protection after infection or vaccination but often compromised in infancy. This study identifies a mechanism by which this compromise occurs and shows how it can be targeted to boost antibodies in early life and provide protection from reinfection.
Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence
This study combines HIV-1 sequence analysis and integration site discovery to show a preponderance of integrations into ZNF genes in expanded latent clones. ZNF genes, unlike other integration targets, are downregulated upon T cell activation, which may facilitate latency maintenance.
Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness
Isringhausen et al. demonstrate that chronic viral infection causes durable destruction of BM mesenchymal stromal networks and leads to long-lasting impairment of the competitive fitness of HSCs. In vivo blockage of IFN pathways protects BM and HSC function from viral-induced damage.
The histone demethylase Lsd1 regulates multiple repressive gene programs during T cell development
The histone demethylase Lsd1 is required for down-regulation of stem cell and early progenitor genes and for the activity of several repressive transcription factors, including Bcl11b, Gfi1, and Bcl6, during T cell development.
ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice
The authors find that lung and skin pathogenic CD4+ T cells express high levels of ACC1. ACC1 controls the inflammatory function of the pathogenic CD4+ T cell population to promote type 2 inflammation in the lung and skin.
LYVE1+ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth
Zhang, Kim, and colleagues reveal two macrophage subpopulations lining peritoneal surfaces that are distinct from peritoneal fluid macrophages. One population expresses LYVE1, resembles omental macrophages, and promotes expansion of ovarian cancer within the cavity in the absence of the omentum.
HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160
HVEM is a TNF family receptor that binds a TNF protein and Ig family proteins. Using structural biology and mutagenesis, we identified HVEM muteins with selective ligand binding. We verified their function in vivo in models of inflammation and infection.
DCIR and its ligand asialo-biantennary N-glycan regulate DC function and osteoclastogenesis
Asialo-biantennary N-glycan is identified as a ligand for the inhibitory C-type lectin receptor DCIR, which is important for the homeostasis of the immune and bone system. The interaction between DCIR and asialo-biantennary N-glycans negatively regulates antigen presentation by DCs and osteoclastogenesis.
ZNF382 controls mouse neuropathic pain via silencer-based epigenetic inhibition of Cxcl13 in DRG neurons
This study demonstrates that peripheral nerve injury–induced downregulation of ZNF382 in DRG contributes to neuropathic pain likely through silencer-based epigenetic disinhibition of CXCL13, a key neuropathic pain player, in DRG neurons.