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Brief Definitive Report

Conventional dendritic cells (cDCs) bridge antigen detection to the induction of adaptive immunity, playing crucial roles in host defense. Vanderkerken, Baptista, et al. show that LTα1β2-expressing ILC3s, together with B cells, control the size of the splenic cDC compartment and cDC2 differentiation.

Germline stop-gain variants in SAMD9L encode truncated gain-of-function proteins that result in a multisystem human disorder with autoinflammatory features. The interferon-inducible dominant proteins interfere with global protein synthesis via inhibition of translational elongation.

Using a mouse model of congenital cytomegalovirus infection, evidence is provided for a pathogenic role of NK and ILC1 cells in the brain. Although brain-infiltrating innate immune cells fail to control infection, they orchestrate pathological inflammatory responses that lead to altered cerebellar development.

Article

Macrophages in the bone marrow erythroblastic island (EIM) and splenic red pulp (RPM) are required for terminal erythropoiesis and removal of aged erythrocytes, respectively. This manuscript shows that EIM and RPM development require both PPARγ and Spi-C.

Soft extracellular matrix protects breast cancer cells from apoptosis and reduces the efficacy of chemo- and radiation therapies through enhanced NF-κB signaling and diminished proapoptotic JNK activity. Therapeutic targeting of the NF-κB–JNK axis may thwart treatment resistance in breast cancer.

Sudo et al. demonstrate that group 2 innate lymphoid cells (ILC2s) in the bone marrow become activated following chemotherapy-induced stress and support hematopoietic recovery by producing GM-CSF. Adoptive transfer of ILC2s has therapeutic potential for myelosuppressive conditions.

Stuani et al. demonstrate that IDH mutant AML cells display an enhanced mitochondrial phenotype, which is not reversed by IDH mutant inhibitors. This study provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Bhat et. al. describe an essential role of Regnase-1 in B cell immune homeostasis at multiple developmental stages and, using several mouse models, show that disrupting Regnase-1 expression in B cells leads to severe immunopathology.

In Special Collection:
JEM Immunology Collection 2021

Null mutations in secreted nuclease DNASE1L3 cause monogenic systemic lupus erythematosus (SLE). This study shows that many patients with sporadic SLE with nephritis manifest reduced DNASE1L3 activity, which is associated with blocking autoantibodies to the enzyme.

Rupérez et al. report the discovery of the protein Metrnβ as a new cardiokine with cardioprotective actions. They established that the heart produces Metrnβ, which in turn protects against cardiac hypertrophy. Metrnβ is also a new prognostic biomarker in heart failure patients.

Systematic analysis of the neuronal receptor interactome in multiple sclerosis brains reveals the metabotropic glutamate receptor 8 as a disbalanced hub. Its activation constitutes a novel treatment strategy to enhance neuronal resilience by inhibiting pathological calcium overload in inflammation-induced neurodegeneration.

Starobova et al. demonstrate that vincristine-induced peripheral neuropathy (VIPN) is driven by activation of the NLRP3 inflammasome and release of IL-1β. Moreover, inhibition of NLRP3-mediated IL-1β release prevents VIPN in a murine model without affecting chemotherapy efficacy.

Through transcriptomic and epigenomic analysis, Wu et al. identify a glucocorticoid/Gadd45β/TET1-dependent pathway promoting PGC-1α gene transcription and, thereby, triggering gluconeogenesis, hepatic glucose production, and hyperglycemia.

Ferez et al. show that during a viral infection, the levels of Qa-1b expression are decreased in infected cells and increased in some bystander immune cells to respectively promote or inhibit their killing by activated NK cells.

In this study, Ma et al. demonstrate that AIM2 negatively regulates the DNA-PK–AKT3 in microglia to control neuroinflammation synergistically induced by cGAS and DNA-PK, thereby preventing the pathogenesis of EAE independent of inflammasome activation.

This study demonstrates that nuclear DEK governs quiescence and metabolic homeostasis of HSC and preserves HSC potential. Mechanistically, DEK dampens chromatin accessibility in HSC by inducing deacetylation of H3K27 and governs gene expression, including Akt1/2.

Aging is associated with the development of human idiopathic pulmonary fibrosis (IPF), a lethal fibrotic lung disease. In this study, the investigators identify a novel molecular target with therapeutic potential against age-related persistent lung fibrosis in mice.

By using a rapid whole-blood T cell activation assay measuring cytokines released by SARS-CoV-2–specific T cells, Le Bert et al. show that individuals who clear SARS-CoV-2 infection without symptoms mount a highly functional virus-specific cellular immune response.

VanBlargan et al. describe a novel panel of neutralizing monoclonal antibodies against the emerging tick-borne Powassan virus, including domain III– and fusion loop–binding cross-reactive antibodies that confer broad protection in vivo against Powassan and other tick-borne flaviviruses.

Agudelo et al. discover expanded clones of similar antibodies from the memory B cells of tick-borne encephalitis virus–infected and vaccinated donors; however, the most potent and broadly neutralizing antibodies derive from donors recovering from natural infection.

Review

This review summarizes the pleiotropic functions of leptin, whose capability to regulate both energy homeostasis and inflammation has unveiled the biological determinants of human obesity and the interconnection among dysmetabolic conditions, the onset of autoimmune diseases, and cancer in more affluent countries.

The enteric virome is composed of a staggering diversity of eukaryotic and prokaryotic viruses that can interact with the intestinal immune system. Li et al. discuss how resident enteric viruses directly or indirectly affect intestinal homeostasis and modulate innate and adaptive immune responses.

This review highlights the emergent role of the cytokine IL-17 in orchestrating cellular and organismal metabolism. Metabolism is thereby integrated into the protective and pathogenic aspects of IL-17 responses in a temporally and spatially regulated manner.

Viewpoint

Miriam Merad and Nicolas Vabret reflect on the lessons learned from a year in the COVID-19 pandemic.

Rappuoli and Andreano highlight that, in humans, neutralizing antibodies deriving from germlines IGHV3-53/IGHV3-66 dominate the immune response to SARS-CoV-2 infection and discuss potential correlations with self-reacting antibodies in COVID-19.

Insights

AIM2 is widely known for its role as a cytosolic dsDNA receptor that activates the inflammasome. In this issue of JEM, Ma et al. describe an inflammasome-independent function of AIM2 in microglia that restrains neuroinflammation via a novel crosstalk between AIM2 and cGAS signaling.

Vincristine-induced peripheral neuropathy is driven by innate immune system activation. This could be prevented by repurposing the IL-1 receptor antagonist anakinra as a co-treatment strategy.

Loss-of-function mutations in DNaseL13, the enzyme that restricts the amount of microparticle-associated DNA, cause SLE in humans and mice. In this issue of JEM, Hartl et al. uncover a reduction in plasma DNASE1L3 enzymatic activity due to the presence of autoantibodies in patients with non-familial SLE.

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