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Dodiya et al. characterize an APPPS1-21 mouse model of Aβ amyloidosis with an antibiotic-perturbed microbiome. Fecal transplantation approaches and microglial depletion studies are employed to establish the causality between the gut microbiota, microglia, Aβ, and neurodegeneration.

Single-cell transcriptomics from paired autologous peripheral and tumor lymphocytes from melanoma patients reveal an understudied population of metabolically active, dysfunctional CD8 T cells. This subpopulation is associated with immunotherapy resistance and was leveraged to develop a therapeutic response predictive model.

S1PR5 impairs TRM cell differentiation by limiting T cell entry and promoting T cell egress from peripheral tissues. Local TGF-β signaling coordinates suppression of the T-bet–ZEB2–S1PR5 emigration axis, thus enforcing tissue residency.

Regenerative inflammation in skeletal muscle drives macrophage specification via a regeneration-promoting program. A growth factor–expressing macrophage population develops, producing GDF-15 under the control of RXR and PPARγ. GDF-15 acts as an autocrine and paracrine factor coordinating myoblast proliferation and myeloid cell invasion and activity.

WEE1 inhibition modulates the efficacy of cancer immunotherapy by regulating dsRNA and interferon responses, which increases recruitment of anti-tumor T cells with concurrent PD-L1 elevation. This study provides a rationale for combination strategies between WEE1 inhibitors and anti–PD-L1 therapies.

Computational screening identifies a novel agonist for NR2F1, a master activator of cancer cell dormancy. Agonist-mediated activation of NR2F1 induces a novel long-lived dormancy program with neural crest-like features and prevents disseminated squamous carcinoma cancer cell progression to overt metastasis.

Using in vivo intravital microscopy and biochemical and cell biological studies, we demonstrate that neutrophil DREAM enhances neutrophil adhesive function in vascular inflammation. Our results suggest that targeting DREAM might be a novel therapeutic strategy to attenuate excessive neutrophil recruitment in inflammatory diseases.

3K3A-APC has shown promise in human ischemic stroke. Present data support that 3K3A-APC could very well be the first therapeutic agent at our disposal to prevent and/or treat white matter strokes, a major cause of human disability, including cognitive dysfunction.

A stem-loop RNA (SLR) RIG-I agonist is effective in preventing and treating acute SARS-CoV-2 infection in mice. A single injection of SLR can clear chronic SARS-CoV-2 in immunocompromised mice. SLR is effective against the ancestral virus as well as variants of concern.

Brief Definitive Report

Single-cell RNA and ATAC sequencing identify transcriptomic and epigenomic features of acute- and memory-phase virus-responding CD4+ T cells and show that, unlike follicular helper T cells, memory CD4+ T cells develop despite lacking Bcl6 and Blimp1 transcription factors.

By manipulating and quantifying the dynamics of PU.1 protein expression in live differentiating adult HSPCs in vitro, Ahmed et al. report that PU.1 upregulation is not caused by fast direct autoregulation but occurs as a later consequence of hematopoietic differentiation.

The intestinal helminth Heligmosomoides polygyrus suppresses development of epithelial tuft cells, which are essential for the type 2 immune response, through secreted factors that block tuft cells both in intestinal organoids and when administered in vivo.

Found in Translation

Hao Wu, Li Wang, and Michael A. Crackower discuss recent advances in structure-based drug design to target NLRP3 and NLRP1.

Insights

Evrard et al. find that sphingosine 1-phosphate receptor 5 (S1PR5) powerfully impairs tissue-resident memory T cell (TRM cell) formation, and that tissue-derived TGF-β limits S1pr5 expression by infiltrating T cells.

Mutual antagonism between the transcriptional repressors Bcl-6 and Blimp-1 has been appreciated as a key mechanistic determinant of lymphoid differentiation programs. Now, in this issue of JEM, Ciucci et al. demonstrate that this relationship is central to the generation of T cell memory.

Drurey et al. show that excretory/secretory products from the parasitic helminth Heligmosomoides polygyrus suppress the host-protective small intestinal epithelial response.

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