Issues

Jiang et al. leveraged KRAS-induced iron addiction in cancer cells to design a clever drug delivery approach to enable selective inhibition of KRAS signaling in mutant KRAS tumors but not in normal tissues, offering a new strategy for treating this largely incurable disease.

In this issue of JEM, Diny et al. identify the aryl hydrocarbon receptor (AHR) as a key orchestrator of eosinophil tissue adaptation in the small intestine.

Using single-cell RNA and TCR sequencing, Snyder et al. show that during acute cellular rejection there is an allograft-specific clonal expansion of cytotoxic recipient-derived tissue resident memory T cells that are reprogrammed but persist despite high-dose glucocorticoid therapy.

Human autoantibodies neutralizing specific cytokines can underlie specific infectious diseases in otherwise healthy patients. The autoantibodies mimic inborn errors of the corresponding cytokines or their response pathways. Four autoimmune phenocopies of inborn errors of cytokine immunity have already been reported.

FGFR3 gain-of-function mutation leads to learning and memory impairments independently of skull abnormalities. Cornille et al. suggest that modulation of the FGFR3 signaling pathway might be of value for treating the neurological and cognitive impairments observed in craniosynostosis.

Jiang et al. report that oncogenic KRAS signaling induces ferrous iron (Fe²⁺) accumulation throughout mutant KRAS-mediated transformation. Converting an FDA-approved MEK inhibitor into a ferrous iron–activatable drug conjugate (FeADC) achieves potent MAPK blockade in tumor cells with superior systemic tolerability.

Eosinophils undergo tissue adaptation in the small intestine. Aryl hydrocarbon receptor–deficient eosinophils fail to induce the full intestinal gene expression program, are functionally impaired in extracellular matrix interactions, are more prone to degranulation, and have an extended life span.

During acute cellular rejection after lung transplantation, there is an intra-allograft oligoclonal expansion of cytotoxic CD8⁺ T cells. Despite treatment with systemic glucocorticoids, expanded T cell clones persist as transcriptionally reprogrammed, airway-centric tissue resident memory T cells.

HBV exposure in children usually causes chronic infection, and HBsAg-specific CD8⁺ T cells are rarely detected in this situation. We find that mMDSCs, cross-presenting HBsAg, migrate to the thymus and eliminate HBsAg-specific CD8⁺ thymocytes, resulting in a specific tolerance to HBV.

Kafai et al. describe neutralizing murine and human mAbs targeting the Venezuelan equine encephalitis virus E2 glycoprotein that protect mice against lethal aerosol virus challenge. These mAbs exhibit distinct epitope specificity and block multiple steps in the virus replication cycle.

Martin-Fernandez et al. describe patients with partial USP18 deficiency, which underlies both type I interferonopathy and Mendelian susceptibility to mycobacterial disease (MSMD). This work delineates the lack of negative regulation of the IFN-I signaling pathway leading to depression of the IFN-γ–IL12 loop as a cause of MSMD.

Capsules are essential for the virulence of invasive bacteria, but how they enhance disease potential is largely undefined. This work shows that capsules enable bacteria to circumvent molecular recognition and phagocytic killing of Kupffer cells in the liver.

Giordano et al. establish human AGS iPSC-based models of TREX1 or RNASEH2B deficiencies. They uncover DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes that can be uncoupled from aberrant type I IFN responses and identify novel targets to curtail AGS neuroinflammation.

In the early, limited time frame of neuropathic pain, mGluR5 reemerges in cortical astrocytes, causing drastic increases in synapse and network remodeling, leading to intractable mechanical allodynia. Despite its restricted expression, astrocytic mGluR5 plays a determinant role in subsequent brain functions.

Mechanisms for synaptic pruning of adult-born neurons remain unknown. In this study, Kurematsu et al. demonstrate that phosphatidylserine is involved in microglial spine pruning and functional maturation of adult-born neurons in the olfactory bulb and hippocampus.

Liu et al. demonstrate that the PERK-triggered HSPC preconditioning in the spleen is essential for their myeloid descendant cells to become immune suppressors in response to subsequent tumor microenvironmental stimulation. A spleen-targeted PERK blockade could be an effective strategy of immunotherapy.

Here, the authors identified a novel lncRNA, lncEry, that was highly expressed in erythroid-related progenitors and erythrocytes. They found that lncEry combined with Wdr82 to promote Klf1 and globin gene expression to regulate the early and late stages of erythropoiesis, respectively.

Matsubara et al. identify an endothelial subtype that orchestrates hardening of teeth, the hardest tissue of the body. The reciprocal feedback between these capillaries and odontoblasts highlights both the similarities and differences between bones and teeth, the two primary components of the skeletal system.