ON THE COVER
Qin et al. develop a genome-editing tool that combines the versatility of prime editors and unconstrained PAM requirement of SpRY, which is able to rescue retina functionality and restore vision in mice. Th e cover shows a section of a Pde6bT to C mouse retina immunostained for GFP (green), rhodopsin (red), and nuclei (blue). Image © Qin et al., 2023. https://doi.org/10.1084/jem.20220776
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IFNγ score–based neoadjuvant immunotherapy for stage III melanoma
In this issue of JEM, Reijers et al. demonstrate that pre- and post-treatment IFNγ-related gene expression scores are promising markers for choosing neoadjuvant immunotherapy for stage III melanoma.
Sidestepping SHP2 inhibition
A genome-wide CRISPR/Cas9 knockout screen uncovered novel mechanisms of adaptive resistance to pharmacologic inhibition of SHP2.
Eye on genome editing
CRISPR/Cas9 genome editing techniques have the potential to treat previously untreatable inherited genetic disorders of vision by correcting mutations that cause these afflictions. Using a prime editor, Qin et al. restored visual functions in a mouse model (rd10) of retinitis pigmentosa.
FRC-derived retinoic acid: The key to unlocking milky spots
Milky spots of the omentum enable lymphocyte access to the peritoneal cavity. In this issue of JEM, Yoshihara and Okabe demonstrate how secretion of retinoic acid by fibroblastic reticular cells allows lymphocyte entry into milky spots and the peritoneal cavity.
License to kill: Retinoic acid programs T cells for tissue residency
In this issue of JEM, Qiu et al. show that retinoic acid signaling during priming in the mesenteric lymph node licenses CD8+ T cells to develop into small intestinal tissue-resident memory cells, a finding that provides key insights into tissue-specific vaccination strategies.
Brief Definitive Reports
Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia
MyD88- and IRAK-4–deficient patients have a higher risk of hypoxemic COVID-19 pneumonia than individuals of similar age in the general population, due to impaired TLR7-dependent type I IFN production.
IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma
In the DONIMI trial, a baseline IFN-γ signature enables prospective selection of patients who can benefit from anti-PD-1 monotherapy. In contrast to results of our murine melanoma model, domatinostat (a class I HDAC inhibitor) does not add benefit to neoadjuvant anti-PD-1 ± anti-CTLA-4 in patients.
Genome-wide CRISPR/Cas9 screens reveal shared and cell-specific mechanisms of resistance to SHP2 inhibition
Genome-wide and focused CRISPR/Cas9 screens for SHP2i resistance in multiple cancer lines identified novel in vitro and in vivo resistance genes. Deletion of these genes results in ERK activation and cross-resistance to FLT3-ITD/BCR-ABL inhibition in FLT3-ITD or BCR-ABL–driven AML lines.
Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas
Qin and colleagues develop a genome-editing tool characterized by the versatility of prime editors and unconstrained PAM requirement of SpRY. In vivo gene correction is successfully implemented in the mouse model of Pde6b-associated retinitis pigmentosa, leading to substantial functional rescue of vision.
Aldh1a2+ fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots
This study unveils a subset of fibroblastic reticular cells that play an essential role in the formation of milky spots of visceral adipose tissue omentum by regulating lymphocyte recruitment.
Retinoic acid signaling during priming licenses intestinal CD103+ CD8 TRM cell differentiation
Qiu et al. demonstrate that retinoic acid signaling during T cell priming in the mesenteric lymph nodes licenses the differentiation of CD103+ CD8 tissue-resident memory T cells after entry into the small intestine, which may improve rational vaccine design.
Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease
Sharma et al. define a new primary atopic disorder caused by heterozygous gain-of-function variants in STAT6. This results in severe, early-onset allergies, and is seen in 16 patients from 10 families. Anti–IL-4Rα antibody and JAK inhibitor treatment were highly effective.
Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice
Age-associated B cells are heterogeneous with respect to expression of memory and plasmablast markers. Unlike resting memory, ABCs are chronically activated, with the capacity for self-renewal or differentiation. Depletion of CD11c+ ABCs improved renal disease in the MRL/lpr lupus model.
AP-1–independent NFAT signaling maintains follicular T cell function in infection and autoimmunity
Follicular T helper (Tfh) cells coordinate optimal germinal center responses, but abnormal Tfh cell function contributes to autoantibody-dependent autoimmunity. Seth et al. demonstrate that AP-1–independent NFAT gene expression, typically associated with hyporesponsive T cells, is required for Tfh cell maintenance and is a therapeutic target in murine lupus.
RELA tunes innate-like interferon I/III responses in human T cells
A transcriptional rheostat orchestrated by RELA is found to control the expression of type I/III interferon in T cells. Unlocking IFN-I/III expression in T cells confers self-defense against HIV infection and increases the antitumor activity of CAR T cells.
Pleiotrophin drives a prometastatic immune niche in breast cancer
Metastatic cancer cells thrive in secondary organs by producing PTN and activating the NF-κB pathway. This leads to increased cytokine production, neutrophil recruitment, and T cell dysfunction. Targeting PTN presents a promising addition to the current regimen for treating metastatic TNBC.
Intestinal cell type-specific communication networks underlie homeostasis and response to Western diet
Intercellular communications across different layers of the intestine remain poorly understood. Here, Wang et al. show the heterogeneity and developmental trajectories of intestinal intraepithelial lymphocytes, lamina propria lymphocytes, and intestinal epithelial cells, and the cell type-specific homeostatic interactomes in response to a Western diet.