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Pieters et al. establish a novel mouse model of MCL driven by overexpression of cyclin D2 and identify fetal-derived B1a cells as putative cell of origin for MCL.

Interferon responses in the nasopharyngeal epithelium are critical to prevent severe COVID-19. Epithelial cells alone are unable to stop SARS-CoV-2 growth, but sufficient early interferon can be provided by non-epithelial cells or a co-infecting virus. Autoantibodies block early interferon, enhancing the risk of severe COVID-19.

In this issue of JEM, Gschwend et al. reveal the indispensable role of alveolar epithelial cells type 2 in controlling the density of alveolar macrophages. This study highlights the intricate crosstalk that lung stroma and macrophages undergo to maintain homeostasis.

A peptide derived from the airborne mold species Aspergillus nidulans that stimulates T cells of Löfgren's syndrome patients has been identified.

Brief Definitive Reports

In Special Collection:
Cytokines Collection 2021

Lepelley et al. describe dominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, to cause mitochondrial DNA–dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.

Remyelination requires the clearance of cholesterol-rich myelin debris within demyelinating lesions by phagocytes. Gouna et al. found that TREM2-dependent formation of lipid droplets is necessary to buffer excess lipids released by myelin injury and required for myelin repair to occur.

The coadministration of imatinib with standard of care (dihydroartemisinin plus piperaquine) to P. falciparum malaria patients in drug-resistant regions of Vietnam results in an accelerated decline in parasite density and pyrexia, with no apparent drug-related toxicities.

In response to bacterial inflammation, hepatic fibroblast growth factor 21 (FGF21), an endocrine hormone that mediates adaptive responses to metabolic stresses such as starvation, promotes disease tolerance and survival by supporting thermoregulation and cardiovascular function.

Host resistance to Mycobacterium tuberculosis infection is mediated through cellular type I immunity. Bohrer et al. reveal an unexpected association between type II immunity-related eosinophils and TB in humans, nonhuman primates, and mice, where eosinophil deficiency results in increased disease susceptibility.

CAPS is an IL-1β–mediated autoinflammatory disease due to gain-of-function mutations in NLRP3. This work shows that skin-infiltrating neutrophils represent a substantial source of IL-1β in CAPS patients. In mice, gain-of-function mutations in Nlrp3 restricted to neutrophils are sufficient to trigger severe CAPS.

Technical Advances and Resources

Single-cell RNA sequencing of human follicular dendritic cells (FDCs) provides insights in germinal center biology and enhances our understanding of these enigmatic cells. Data suggest regulation of B cell antigen availability by FDCs and T cell interactions with FDCs.

Articles

Mantle cell lymphoma (MCL) is an incurable aggressive B cell lymphoma for which mouse models are currently lacking. Pieters et al. show that Ccnd2 overexpression and p53 loss in mice induce B1a-derived MCL-like lymphomas that are sensitive to MALT1 inhibition.

In Special Collection:
Cytokines Collection 2021

SARS-CoV-2 infection induces strong type I IFN immunity in the nasopharyngeal cavity of mildly symptomatic COVID-19 patients, but this response is compromised in critically ill patients with autoantibodies against type I IFNs.

In Special Collection:
Cytokines Collection 2021

This study identifies AT2s as the relevant source of GM-CSF for the development and maintenance of alveolar macrophages. During organogenesis, nascent AT2s induce GM-CSF expression in a perfectly timed manner to support the proliferation and differentiation of fetal monocytes that contemporaneously seed the embryonic lungs.

We identify a peptide derived from Aspergillus nidulans recognized by CD4+ T cells derived from the lungs of Löfgren’s syndrome (LS) patients and provide evidence that A. nidulans plays a role in the pathogenesis of LS.

TB results in 1.5 million deaths per year, yet a low percentage of M. tuberculosis–infected individuals progress to TB. Knowledge of the early immune response during TB progression and on treatment will inform clinical management of the disease.

This study shows that RNA virus persistence in mice requires continuous viral spread such that a substantial proportion of the liver consists of formerly infected hepatocytes, which have cleared the virus in a cell-intrinsic manner yet exhibit persistent transcriptional alterations.

Xenograft cancer studies using rag2Δ/Δ, il2rga−/− zebrafish allow facile, single-cell imaging of T cell–mediated tumor killing by CAR T cell, BiTE, and APEC immunotherapies and identified EGFR-targeted immunotherapies as an effective treatment for rhabdomyosarcoma muscle cancers.

MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues. MERTK acts through a mechanism that reduces the sensitivity of scanning for antigen by T cells, leading to reduced T cell responsiveness to antigen.

This work shows that JAML–CXADR interactions promote γδ T cell activation and limit CD8 T cell dysfunction within the tumor microenvironment and identifies JAML costimulation as a novel target for improved cancer immunotherapy.

In Special Collection:
JEM Cancer Immunotherapy 2021

The present study shows in murine models that autoimmunity, which targets normal cholangiocytes upon primary biliary cholangitis, fuels the immunosurveillance of malignant cholangiocytes and protects from the emergence of cholangiocarcinoma.

The mechanism controlling lineage commitment in early hematopoiesis is unclear. Cova et al. show that the Helios transcription factor is required to actively suppress megakaryocyte priming in hematopoietic stem and progenitor cells, which contributes to increased stem cell pluripotency and lymphoid commitment.

Grenov et al. show that the m6A methyltransferase is an important regulator of the germinal center (GC) reaction through the functions of the m6A readers, IGF2BP3 and YTHDF2, that control key GC-related pathways including MYC-induced proliferation and oxidative phosphorylation.

Studies of novel RAG1 N-terminal region mutants reveal a role for the first 215 amino acids in establishing the balance between short- and long-range V(D)J recombination and a distinct role for RAG1 ubiquitin ligase activity in promoting efficient recombination and lymphocyte development.

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