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Gut microbiome has been linked to cavernous angioma (CA), a common vascular disease, but the role in humans remains unclear. Here, the authors combine 16S rRNA sequencing and shotgun metagenomics to profile the microbiome in a large cohort of human subjects with and without CA, and among subjects with different CA clinical features.

Haimon et al. examine the function of microglia in a relapsing–remitting mouse model of multiple sclerosis, finding that these cells preferentially interact with regulatory T cells compared with effector T cells, and that these cognate interactions require interferon-γ signaling and are critical to maintain regulatory T cell activity.

Single-cell and spatial analyses of conserved regulatory T (T_reg) cell-dependent transcriptional states of diverse accessory cell types in mouse and human lung cancer suggest rational T_reg cell targeting-based combination therapy for PD-1 blockade-resistant tumors.

Alternative cell death pathways are revealed in the absence of caspase-8-dependent apoptosis and MLKL-dependent necroptosis.

Experiments at the Joint European Torus tokamak show improved thermal ion confinement in the presence of highly energetic ions and Alfvénic instabilities in the plasma.

Wherry and colleagues provide a comparative analysis of paired single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin sequencing profiles of CD8⁺ T cells in acute and chronic lymphocytic choriomeningitis virus infections, identifying new features about T_ex cell subsets and epigenetic differences from acutely infected precursors seen at early time points in infection.

Van Gisbergen and colleagues show that tissue-resident memory T cells, genetically marked in Hobit reporter mice, can exit tissues upon reinfection and contribute to systemic memory responses.

Acton and colleagues examine the mechanics of lymph node swelling during the course of an immune response. They find tissue tension regulates fibroblastic reticular cell (FRC) proliferation during lymph node expansion and that podoplanin (PDPN)–CLEC-2 signaling in FRCs regulates this process, which in turn regulates T cell activation.

Farrar and colleagues perform an extensive analysis of Ncor1/2 function in B cell development. Loss of both genes results in defective pre-BCR signaling, increased accessibility of STAT5 chromatin motifs and inappropriate Rag gene expression, leading to accelerated leukemic transformation.

The inhibitory receptor CTLA-4 recognizes two ligands on opposing antigen-presenting cells, CD80 and CD86. Sansom and colleagues show CTLA-4 captures ligands by transendocytosis, whereupon low-affinity CD86 releases CTLA-4 at low pH to promote CTLA-4 recycling; however, high-affinity CD80 remains bound and targets CTLA-4 for ubiquitination and destruction.

Dempsey et al. present a graphene-based biosensor technology to detect enzyme activity in serum samples. A model is developed based on the activity of a panel of these biosensors to classify 90% of patients with lung cancer across all stages of disease, providing a potentially useful screening technology.

Peyer’s patches (PPs) are sites of antibody production in the gut mucosa. Carroll and colleagues show the mechanosensory channel protein Piezo1 is required for the homeostatic maintenance of PPs. Specific loss of Piezo1 in FRCs disrupt PP structure and function, resulting in reduction of fecal IgA production and gut immunity.

The authors describe a functional crosstalk between the p53 network and the integrated stress response through the p53 repressor PPM1D. Inhibition of PPM1D potentiates p53-dependent transactivation and apoptosis via induction of the HRI-eIF2α-ATF4 pathway.

Patients with cancer undergoing anti-PD-1 immune checkpoint blockade can experience immune-related adverse effects. Wherry and colleagues examined the immunity elicited upon immunization of patients with cancer and report that anti-PD-1 immunotherapy dynamically affects influenza vaccine-induced immune responses.

Ghosh et al. report findings showing that the atypical kinase RIOK2 functions as a winged helix-turn-helix domain containing transcription factor that regulates the differentiation of human hematopoietic stem and progenitor cells toward erythroid, myeloid and megakaryocytic lineages. RIOK2 enhances GATA1 and KLF1 expression, while suppressing other transcription factors like RUNX3, SPI1 and GATA2.

The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.

Growing evidence suggests that immune dysregulation is involved in the pathogenesis of myelodysplastic syndromes (MDSs). Glimcher and colleagues report haplosufficiency of the serine–threonine kinase RIOK2 leads to increased IL-22 production that, in turn, suppresses erythropoiesis. Blocking IL-22 rescues this defect in mice, suggesting that IL-22 blockade might be of therapeutic value in treating MDSs.

Henao-Mejia and colleagues provide a detailed characterization of the 3D genome architecture of ILCs and demonstrate that ILC2 development and progression of allergic inflammation are controlled by a unique 3D DNA topology at the Id2 locus.

Schumacher and colleagues have designed a reporter system that allows in vivo tracking of replicative history over many cell generations. Using this system to study acute T cell responses, they uncover substantial diversity in past division of central memory CD8⁺ T cells and its link to cell state and recall potential.

Regulatory T cells are functional in a broad-spectrum systemic autoimmune disease and are capable of suppressing innate and adaptive immune responses, reversing established tissue inflammation and enabling long-term restoration of immunological health.

Segal and colleagues identify a neuroprotective immature-like neutrophil subset that participates in dectin-1-dependent axon repair and regeneration in the central nervous system.

Romagnani and colleagues discover an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.

The deubiquitinase A20 is a potent inhibitor of NF-κB signaling pathways. Ma and colleagues identify distinct roles for A20 ubiquitin-binding ZF4 and ZF7 domains, which exhibit different phenotypes upon mutation, but play synergistic roles in regulating inflammatory responses.

Elemento, Melnick and colleagues examine the chromatin and transcriptional changes that occur during differentiation of human primary B cells into antibody-secreting cells. In naive B cells, the transcription factor OCT2 is preloaded at high-affinity super-enhancer sites present in repressed ‘silent’ chromatin; upon activation, OCAB is recruited to these regions, where it facilitates arrays of OCT2 binding to lower-affinity octamer motifs, leading to active formation of germinal center B cell-specific super-enhancers.

Ludewig and colleagues show that adenovirus immunization fosters the formation of pulmonary immune-stimulating niches underpinned by fibroblastic stromal cells that maintain ‘inflating’ memory CD8⁺ T cells through the provision of interleukin-33.

Mutations in the RNA-binding proteins Roquin-1 or Regnase-1 cause systemic autoimmunity. Heissmeyer and colleagues show that Roquin-1 and Regnase-1 physically interact and thereby regulate CD4⁺ and CD8⁺ T cell metabolism and functionality.

Within a human cohort, wide variation can occur with constitutively expressed proteins. Aschenbrenner and colleagues found that individuals with lower CRELD1 expression have decreased frequencies of naive CD4⁺ T cells. Mice with conditional Creld1 deficiency also exhibit a phenotype associated with immunological aging.

Fessler and colleagues report that loss of the IFN-γ-induced GTPase IRGM1 results in autoinflammatory disease. Deficient IRGM1 activity led to defective lysosomal maturation and impaired mitophagy, prompting the release of cytosolic mtDNA and thereby activating the cGAS–STING pathway.

Fibroblastic reticular cells (FRCs) provide structural support and soluble factors necessary for proper lymph node organization and function. Turley and colleagues use scRNA-seq to identify a unique Gremlin1-expressing FRC subset that is found in T cell zones. Grem1⁺ FRCs support the survival of resident cDCs and are necessary to promote T cell immunity.

Cerebral ischemia activates innate immune responses in injured brain lesions. Andreasson and colleagues show TREM1 is upregulated after stroke and amplifies these proinflammatory responses by peripheral CD11b⁺ myeloid cells in both the ischemic brain and distally in the intestine.

Melnick and colleagues show that the cohesin complex exhibits dose-dependent regulation of chromatin remodeling that accompanies the transition of germinal center B cells to plasma cells, which is necessary to prevent lymphomagenesis.

Vijayanand and colleagues show highly suppressive CD4⁺CTLA-4⁺PD-1⁺ follicular regulatory T (T_FR) cells reside within tumor microenvironments. Depleting T_FR cells or blocking their activity with CTLA-4-depleting antibodies before anti-PD-1 checkpoint blockade therapy improved the efficacy of anti-PD-1 treatment in mouse tumor models and was also associated with better survival outcomes in a large cohort of patients with melanoma.

Early humoral responses to malaria fail to induce durable protective antibodies. Butler and colleagues report that low-affinity, short-lived plasmablasts become nutrient sinks for glutamine and starve germinal center B and T cells, thereby reducing the generation of high-affinity B cells and long-lived plasma cells and memory B cells.

The zinc-finger transcription factor IKAROS is essential for B cell development. Taniuchi, Morio and colleagues identify a human kindred presenting with B cell immunodeficiency that was caused by a heterozygous missense mutation in IKZF3 encoding the related AIOLOS protein. AIOLOS^G159R is a mutant protein that interferes with both wild-type AIOLOS and IKAROS by forming heterodimers that bind to aberrant DNA-binding sites and prevent normal expression of IKAROS-dependent genes.

Stretch-activated ion channel Piezo1 contribures to mechanotransduction in many tissues, but its output is mostly measured indirectly. Here, the authors introduce GenEPi, a fluorescent reporter for directly visualizing Piezo1 activation-dependent calcium influx.

Heeger and colleagues report that activated B cells dynamically regulate the expression of complement regulatory proteins via the transcription factor BCL6. C3 convertase activity and C3aR1–C5aR1 signaling were both necessary for optimal B cell activation and germinal center formation.

The transcription factor ThPOK is critical for homeostasis and differentiation of mature helper T cells. Here, Kappes and colleagues describe a ThPOK-mediated positive autoregulatory loop that is crucial for tissue-specific T_reg cell differentiation, maintenance of intestinal T_reg cell integrity and conversion of these cells into CD4⁺ intraepithelial lymphocytes.

Gounari and colleagues examine how the Wnt–β-catenin signaling axis in regulatory T cells promotes inflammatory bowel disease and colonic dysplasia. Activated β-catenin induces epigenetic changes that alter expression of genes co-regulated by Foxp3 and TCF-1.

TCR ligation activates the tyrosine kinase ZAP-70 to phosphorylate the adapter LAT, which then coordinates TCR proximal signaling cascades. Weiss and colleagues show LAT-Y132 is critical to TCR ligand discrimination, as its phosphorylation represents a rate-limiting step in T cell activation due to a conserved glycine residue at position 131.

Wang et al. show that the Rictor-dependent mTORC2–Akt pathway is needed to maintain CD4⁺ memory cells. This axis acts, in part, by suppressing mitoROS generation and subsequent oxidation of membrane phospholipids, which then triggers cell death by ferroptosis.

Wherry and colleagues examine whether exhausted T cells (T_EX) can differentiate into functional memory T cells (T_MEM) when chronic antigen is withdrawn. Using the chronic LCMV infection mouse model, they show that ‘recovering’ T_EX cells (REC-T_EX) only partially recover immunophenotypic and functional characteristics of T_MEM cells. The epigenomic status of REC-T_EX cells more closely resembles that of T_EX cells, and, upon rechallenge, the REC-T_EX cells were still compromised in their ability to respond to virus.

Oxidative stress can promote neurodegeneration. Akassoglou and colleagues describe Tox-seq, a functional single-cell RNA sequencing method to identify oxidative stress transcriptional signatures in CNS-resident cells. Tox-seq identified coagulation and glutathione-redox pathway genes that are coupled to oxidative stress and that could be targeted by the glutathione-regulating small molecule acivicin.

A20, encoded by TNFAIP3, is a negative-feedback inhibitor of NF-κB. Grey and colleagues identify natural human variants of TNFAIP3, which lower A20 activity and increase autoinflammatory responses. These alleles were inherited by descendants of Denisovans who crossed the Wallace Line to inhabit Oceania.

Fibroblastic reticular cells (FRCs) are dynamic regulators of lymphoid tissue structure. Turley and colleagues show FRCs also support activated T cells by producing IL-6, which confers an advantage to CD8+ T cell memory responses.

Thompson and colleagues show that repetitive antigenic stimulation within the tumor environment triggers mitochondrial dysfunction by inhibiting oxidative phosphorylation, which leads to T cell exhaustion.

Croker and colleagues show that the phosphatase Ptpn6 functions to suppress neutrophil cell death pathways and IL-1 release, thereby limiting autoinflammatory responses.

Protein transcription factor paralogs are not equivalent and serve distinct roles in immune cells. Merkenschlager and colleagues show that RUNX1 and RUNX3 differ in binding strength to motif sequences and how this leads to differential functional activities.

Germinal centers are typically divided into dark and light zones. Clark and colleagues identify ‘gray zone’ cyclin B1⁺ B cell clusters as sites of ongoing cell proliferation, and these cells are distinct from dark zone B cells that undergo AID-dependent somatic hypermutation. This separation of function safeguards B cells undergoing DNA replication against potential mutagenic events that could result in neoplastic transformation.