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Arsenic trioxide in combination with IFNα is able to deplete MPN stem cells, leading to reduced transplantation and even long-term treatment-free remission in disease control.

Leukemia stem cells are heterogeneous and reside within the phenotypic hematopoietic stem cell and progenitor cell compartments in juvenile myelomonocytic leukemia.

The pathways involved in the persistence of memory B cells are largely unknown. In this issue, two groups (Müller-Winkler et al. and Lau et al.) take complementary approaches to identify an essential role for BAFFR in the survival of memory B cells.


JEM 125th Anniversary

JEM has been a launching pad for scientific careers since its inception. Here is a collection of testimonials attesting to the diversity of the scientific community it serves.


Neuroendocrine, immune, and structural cells establish circadian circuits that optimize immune and physiological responses. In this review, Palomino-Segura and Hidalgo discuss the architecture of these circuits and speculate that immune cells can be a source of circadian signals in physiology.

In Special Collection: Neuroscience Collection 2021

Diet is an important modulator of systemic and central nervous system inflammation, with profound effects in metabolism, immunity, and the gut microbiome. Fontana et al. discuss recent findings on the relationship between calorie intake and the mechanisms underlying neuroinflammation and neurodegeneration.

Brief Definitive Reports

Myeloproliferative neoplasms are partly sensitive to interferon α therapy. Dagher et al. demonstrate that arsenic trioxide sharply potentiates interferon’s ability to eliminate patients’ progenitors or disease-initiating cells from mouse models by targeting PML, an interferon target and key senescence gene.

Mycobacterium tuberculosis (Mtb) infects macrophages and eventually leads to their death. Zhang et al. find that type I IFN signaling contributes to the death of Mtb-infected macrophages through an apparently novel mechanism.

ST2 expression was largely dispensable for T reg cell accumulation and maintenance in tissues at steady state. However, ST2 deficiency limited to T reg cells was important in limiting the size of IL-17A–producing γδT cells in a mouse model of neuroinflammation.

T reg cells are essential for establishing immunological tolerance, and their development in the thymus is tightly regulated. This study demonstrates that miR-155, a miRNA known for conferring T reg cell competitive fitness, can also promote T reg cell differentiation by targeting the TGFβ pathway in the thymic medulla.

Technical Advances and Resources

This work presents robust tools for the transduction and expansion of murine CAR-T cells and demonstrates the impact of murine IL-15 co-expression on CAR-T cell expansion, phenotype, function, and tumor microenvironment reprogramming in immunocompetent mice.

By using genomic and transcriptomic sequencing technologies, Ye et al. identify AID-dependent and/or polymerase η-associated mechanisms of mutagenesis in human germinal center–derived/related B cell lymphomas and link aberrant immunoglobulin gene diversification processes to different disease subtypes.


Early, germinal center–independent, memory B cell responses are exquisitely sensitive to upregulation and downregulation of cell-intrinsic BAFFR signaling. However, germinal center function, including production of memory B cells, is unaffected by modulations of this pathway.

Memory B cells are long-lived components of humoral immunological memory. Müller-Winkler et al. show that the survival of MBCs is critically dependent on signaling from the BCR, BAFF, BAFFR, and IKK2 kinase.

Immunodominance can be a major impediment to the development of neutralizing antibody responses. This study reveals that the proportion of rare, neutralizing B cells in the germinal center can be enhanced by augmenting the quantity of antigen-specific CD4 T cells.

Distinct protective humoral signatures are induced by Vi-conjugate and Vi-polysaccharide vaccines. Shared humoral features across both vaccines suggest that protection against typhoid fever is mediated through a combination of qualitative features of the polyclonal humoral response (avidity and innate immune cell functional responses) in addition to antibody quantity.

Single-cell analysis reveals an accumulation of short-lived disease-specific as well as non–disease-specific intestinal plasma cells in untreated and short-term–treated celiac disease. Plasma cells differ transcriptionally depending on specificity, longevity, and disease status and may contribute to formation of the celiac lesion.

Enforced RANK signaling in B cells drives systemic autoimmunity and CLL development. The survival of CLL cells depends on microenvironmental RANKL, and inhibition of RANKL–RANK signaling kills murine and human CLL cells.

Juvenile myelomonocytic leukemia is a rare cancer of childhood with a poor prognosis. Through phenotypic, functional, and molecular analyses of blood and bone marrow samples, Louka et al. identify and characterize the disease-propagating population(s), paving the way for leukemia stem cell–directed disease monitoring and therapy.

Mice with Nfkb2 mutations that cause accumulation of the inhibitory NF-κB2/p100 (p100) precursor protein relative to the active NF-κB2/p52 (p52) product develop severe autoimmunity, whereas mice lacking p100 and p52 do not, indicating a role for p100 in pathogenesis.

In Special Collection: Metabolism in Homeostasis and Disease

Wang et al. demonstrate that AMPK is downstream of IL-33 signaling, and feedback inhibits IL-33–induced activation of NF-κB in ILC2s. This study uncovers that adiponectin via AMPK acts as a negative regulator of ILC2s and exerts an antithermogenic effect.

Novel multi-transcription factor reporter mice were generated via CRISPR/Cas9 to dissect the developmental progression of ILC and LTi lineages. This study identifies lineage-specified precursors, indicating earlier bifurcation of ILC and LTi lineages than formerly proposed.

The lysosomal protease cathepsin L uses pancreatic secretory granule protein precursors and a reverse proteolysis mechanism, transpeptidation, to generate chimeric super-epitopes specific for diabetogenic CD4 T cells.

Mori et al. established the composition of the LAT, CD5, and CD6 signalosomes of primary T cells. Positive and negative functions were solely assigned to the LAT and CD5 signalosomes, respectively, whereas the CD6 signalosome conveys antithetical functions with implications for autoimmune diseases.

RIAM, which is required for conventional T cell homing and activation, is dispensable for regulatory T cell suppressive functions, thereby nominating RIAM as a focus for inhibiting conventional T cells while sparing regulatory T cells.

The mechanisms governing autophagy initiation in T reg cells remain unclear. Wang et al. identify a ZFP91-dependent mechanism promoting TCR-initiated autophagosome maturation to restrict hyperglycolysis and maintain T reg cell homeostasis and function.

Maccari et al. identify a physiological population of highly proliferative CD38+CD45RA+, IL-10–producing TCRαβ+ T cells. They can be CD4+, CD8+, or double-negative and are controlled by FAS and CTLA4, while their survival is enhanced by mTOR and STAT3 signals.

We developed mice expressing Tlr4 SNPs homologous to those expressed in humans and associated with infectious and inflammatory diseases. Cellular and molecular analyses of TLR4 signaling in wild-type vs. TLR4-SNP mice revealed novel mechanisms of LPS hyporesponsiveness and altered disease susceptibility.

CAR T cell therapy remains suboptimal for the treatment of solid tumors. Xu et al. demonstrate that CAR T cell migration and persistence in locally advanced breast cancer are enhanced by coadministration of CAR T cells with STING agonists.

Ma et al. uncovers an essential role of AR signaling in melanoma cell expansion and tumorigenesis, with loss of AR activity inducing cellular senescence, genomic DNA breakage, a STING-dependent inflammatory cascade, and immune cell recruitment, providing an attractive venue for new combination approaches to disease management.

Podocyte injury is a common hallmark in various glomerular diseases. Upregulated LRRC55 promotes BK channel activation and aggravates podocyte injury in focal segmental glomerulosclerosis, diabetic nephropathy, and membranous nephropathy. LRRC55 inhibition attenuates podocyte injury, thus representing a new therapeutic approach for progressive glomerular disease.


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