Featured
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Article
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Deep learning predictions of TCR-epitope interactions reveal epitope-specific chains in dual alpha T cells
Prediction of the specificity of a T cell receptor from amino acid sequence has been performed using different methods and approaches. Here the authors use TCRab sequences with known specificity to develop a deep learning TCR-epitope interaction predictor and use this method to predict specificity of dual alpha chain TCRs and TCRs specific for different antigens.
- Giancarlo Croce
- , Sara Bobisse
- & David Gfeller
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Article
| Open Access
Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant
Xenotransplantation in humans using pig organs could improve the transplant organ supply. Here the authors transplant pig kidneys into a brain-dead recipient and monitor the human immune cell response early after transplantation using spatial and single cell transcriptomics and show early myeloid cell infiltration.
- Matthew D. Cheung
- , Rebecca Asiimwe
- & Paige M. Porrett
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| Open Access
Dermal injury drives a skin to gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis in mice
The microbial community in the intestine can affect other organs such as the skin but it is not clear if the opposite can occur. Here the authors show that skin wounding affects the microbial composition of the intestinal flora which then enhances DSS induced colitis and intestinal inflammation.
- Tatsuya Dokoshi
- , Yang Chen
- & Richard L. Gallo
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| Open Access
Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells
Dupilumab-associated head and neck dermatitis has been described in a subset of patients treated with the IL4R-blocker dupilumab. Here the authors characterise the immune cell composition and single-cell transcriptome in comparison with untreated forms of atopic dermatitis in a small cohort showing increases in IL-22-associated genes.
- Christine Bangert
- , Natalia Alkon
- & Patrick M. Brunner
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| Open Access
BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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| Open Access
Single-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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| Open Access
COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.
- Matthew J. Cummings
- , Barnabas Bakamutumaho
- & Max R. O’Donnell
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| Open Access
Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing
Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia.
- Yabo Zhou
- , Dianheng Wang
- & Bo Huang
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Article
| Open Access
Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes
Natural killer (NK) cell maturation and function are regulated by multiple transcription factors (TF), but detailed molecular insights are scarce. Here the authors show that a TF, Eomes, is important for NK cell responses and cancer surveillance, in which Eomes expression is regulated by gp96 and Trim28 via the ubiquitination and degradation pathways.
- Yuxiu Xu
- , Xin Li
- & Songdong Meng
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Article
| Open Access
Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission
Immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are characterised by relapsing-remitting flares, which are difficult to study due to their unpredictable nature. Here the authors use an experimental model of immunomodulatory drug cessation in RA patients combined with multi-omic analysis of circulating leukocytes to characterise the immune response for those with arthritis flare versus drug-free remission.
- Kenneth F. Baker
- , David McDonald
- & John D. Isaacs
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Article
| Open Access
Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade
Single cell profiling of tissue from patients undergoing therapy has the potential to identify drug-induced immune changes. Here the authors show a skin scRNA-seq study of psoriasis patients treated with an IL-23 inhibitor and characterize changes in cell states during early treatment.
- Luc Francis
- , Daniel McCluskey
- & Satveer K. Mahil
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Article
| Open Access
Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity
Single cell transcriptomics can reveal at high resolution the body’s response to infection. Here the authors have applied this technology to a longitudinal SARS-CoV-2 infected cohort and identified gene expression changes that may predict disease severity and reveal the underlying molecular mechanisms.
- Quy Xiao Xuan Lin
- , Deepa Rajagopalan
- & Shyam Prabhakar
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| Open Access
Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis
Systemic sclerosis (SSc) is an autoimmune disease causing skin fibrosis and organ inflammation. Here the authors generate and analyze SSc skin single cell RNA sequencing data to propose contributions from both myofibroblasts and endothelial-to-mesenchymal -transitioning cells (EndoMT) to skin fibrosis, and to implicate the involvement of Hippo signaling pathways.
- Feiyang Ma
- , Pei-Suen Tsou
- & Johann E. Gudjonsson
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| Open Access
Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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Article
| Open Access
Distinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination
The ability of BCG vaccination to prevent pulmonary tuberculosis could be improved by targeting mucosal immunity within the lung. Here the authors compare latent Mtb-infected donors with intradermal or oral BCG vaccine recipients to show distinct systemic and pulmonary immune responses are induced by differing routes of natural infection or vaccination.
- Richard F. Silver
- , Mei Xia
- & Daniel F. Hoft
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| Open Access
Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Marking of recently activated T cells may help further our understanding of immunity against Mycobacterium tuberculosis (Mtb). Here the authors use Nur77-GFP reporter mice infected with Mtb and systems data approaches to implicate OX40 as a marker for recently activated, functionally and transcriptome-wise distinct CD4 T cells, and as a potential target for immunotherapy.
- Abigail R. Gress
- , Christine E. Ronayne
- & Tyler D. Bold
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| Open Access
Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Difficulties can be encountered when translating research between cells from animals and humans because of gene expression differences. Here the authors perform an integrative transcriptomic analysis from human and mouse neutrophils and identify a core inflammation program shared across inflamed contexts.
- Nicolaj S. Hackert
- , Felix A. Radtke
- & Ricardo Grieshaber-Bouyer
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Article
| Open Access
The transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure
Acute hypoxemic respiratory failure (AHRF) and the associated lung immune cell features are not well understood. Here the authors use CITE-Seq to analyse the transcriptomic and phenotypic profile of lung and blood cells from a longitudinal cohort of patients with AHRF to identify gene signatures and cell surface proteins associated with disease severity.
- Eric D. Morrell
- , Sarah E. Holton
- & Carmen Mikacenic
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| Open Access
RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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Article
| Open Access
Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity
Cell lineage specification involves substantial chromatin conformation reorganization. Here, the authors integrate in-situ Hi-C and PLAC-seq to map the dynamic changes in 3D chromatin structure during Treg cell differentiation. Furthermore, the authors further characterize the role of Foxp3 in the establishment of Treg-specific chromatin interactions by different Foxp3-mutant mouse lines.
- Zhi Liu
- , Dong-Sung Lee
- & Jesse R. Dixon
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Article
| Open Access
CREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
The mechanistic functions of neutrophils in skin inflammation are not fully understood. Here the authors use human psoriasis samples and a mouse model of skin inflammation to study neutrophils and find a CXCR4hi population of NET-forming, phagocytic neutrophils whose induction depends on the transcription factor CREB1.
- Jiaoling Chen
- , Yaxing Bai
- & Shuai Shao
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| Open Access
Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation
Effective CD8+ T cell immunity requires the generation of a long-lived memory pool and the maintenance of a non-exhausted effector T cell pool. The implementation of immune checkpoint blockade can reduced levels of exhaustion but lacks the ability to support memory formation in the effector pool. Here the authors suggest a role for Let-7 in the enhancement of the anti-tumor CD8+ T cell response by supporting memory via modulation of metabolic and differentiation state.
- Alexandria C. Wells
- , Kaito A. Hioki
- & Leonid A. Pobezinsky
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| Open Access
Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma
How the immune response is involved in the response to multiple myeloma after treatment is not fully understood. Here the authors investigate how lenalidomide treatment in newly diagnosed MM patients affects the immune microenvironment in the blood and bone marrow and compare between responses to treatment.
- David G. Coffey
- , Francesco Maura
- & Ola Landgren
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Article
| Open Access
Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development
Peripheral CD4+ T cells can develop into Intestinal intraepithelial lymphocytes (IEL) in the lamina propria. Here the authors characterise how IEL generation from CD4+ T cells is regulated and show using scRNA sequencing that Ccr9 is involved in this process through limiting IEL precursor differentiation.
- Keiko Ono
- , Tomohisa Sujino
- & Takanori Kanai
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Article
| Open Access
An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells
B cells pursue specific genetic programs to facilitate downstream cellular functions. Here the authors identify, using a combination of proteomic, transcriptomic and functional analyses, a group of mRNAs related to early activation and antibody production that are expressed in B cells without corresponding proteins, hinting a ‘poised’ state of B cells.
- Fiamma Salerno
- , Andrew J. M. Howden
- & Martin Turner
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| Open Access
A single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia
Achalasia is a rare motility disorder of the esophagus resulting from abnormal immune responses, but the immunologic mechanism is unclear. Here the authors use scRNA-seq of PBMC and esophageal lower sphincter tissue and find C1QC+ macrophages and tissue-resident memory T cells with expanded compositions and altered transcriptional profiles in achalasia.
- Zu-Qiang Liu
- , Hao Dai
- & Quan-Lin Li
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| Open Access
Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade
Age-associated B cells (ABC) have been shown to be associated with autoimmunity and ageing. Here the authors examine whether ABC are transcriptionally or functionally altered in participants with reduced immune cell function and show that, being transcriptionally similar, high pre-vaccine levels are associated with poor vaccine response.
- Juan Carlos Yam-Puc
- , Zhaleh Hosseini
- & James E. D. Thaventhiran
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Article
| Open Access
NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells
NBEAL2 loss of function mutations lead to grey platelet syndrome, a condition characterised by α-granule-deficient platelets and, in a proportion of cases, by autoimmunity. Here authors show that NBEAL2 physically interacts with CTLA-4 in human T cells, and NBEAL2 deficiency leads to reduced CTLA-4 surface expression in effector T cells, but not regulatory T cells, thus tipping the balance towards autoimmunity.
- Laure Delage
- , Francesco Carbone
- & Frédéric Rieux-Laucat
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| Open Access
Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate
It is debated how follicular helper T (Tfh) cells versus central memory CD4+ T cells arise from similar precursors, and little is known about the regulation of germinal-centre (GC)-Tfh cell differentiation. Here, authors establish markers in the early precursor stage that distinguish between the GC-Tfh and memory T cell fates and identify an important mechanism that regulates the competitive fitness of the GC-Tfh cells.
- Fangming Zhu
- , Ryan J. McMonigle
- & Hui Hu
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Article
| Open Access
Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity
Looking at genes that are differentially responsive to pathogens depending on the genetic background may help in the identification of therapeutic targets in personalized medicine. Here, using challenge of monocytes with three pathogens the authors identified eQTL that are shared between pathogens and loci that are pathogen specific.
- Antje Häder
- , Sascha Schäuble
- & Oliver Kurzai
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| Open Access
Igh and Igk loci use different folding principles for V gene recombination due to distinct chromosomal architectures of pro-B and pre-B cells
V gene recombination at the immunoglobulin heavy chain locus (Igh) is facilitated by extended loop extrusion. In this study, the authors find that, unlike Igh, the κ light chain locus does not involve extended loop extrusion but instead involves multiple, short-range loops for V gene combination.
- Louisa Hill
- , Gordana Wutz
- & Meinrad Busslinger
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Article
| Open Access
Single-cell analysis of peripheral blood from high-altitude pulmonary hypertension patients identifies a distinct monocyte phenotype
Single cell transcriptomic sequencing (scRNA) can identify genes that are differentially expressed in cell populations in specific diseases. Here the authors perform scRNA sequencing in a high-altitude pulmonary hypertension (HAPH) cohort and show transcriptional differences in monocyte populations.
- Xin-Hua Wu
- , Yang-Yang He
- & Zhi-Cheng Jing
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Article
| Open Access
The RNA-binding protein hnRNP F is required for the germinal center B cell response
The germinal centre (GC) response is characterized by regulated production of high affinity, class-switched antibodies in response to T-cell dependent antigens. Here authors show that the GC response is not only regulated at the transcriptional and protein levels, but also by the RNA-binding protein hnRNP F via alternative splicing of the co-stimulatory molecule CD40.
- Hengjun Huang
- , Yuxing Li
- & Xijun Ou
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Article
| Open Access
Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity
The regulation and direction of CD4+ T cells into phenotypic and functional lineages is coordinated by a complex set of mechanisms. Here the authors show a role for Aiolos as a regulator of the CD4+ cytotoxic and T follicular helper lineages.
- Kaitlin A. Read
- , Devin M. Jones
- & Kenneth J. Oestreich
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Article
| Open Access
CTCF controls three-dimensional enhancer network underlying the inflammatory response of bone marrow-derived dendritic cells
The role of 3D genome organization is not well understood in the transcriptional regulation of dendritic cells. Here the authors show that activation of dendritic cells in vitro induces dynamic reprogramming of the chromatin looping and enhancer activity linked to changes in gene expression and implicates a role for the chromatin architecture protein CTCF in the inflammatory response of dendritic cells.
- Bobae Yang
- , Sueun Kim
- & Hyoung-Pyo Kim
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Article
| Open Access
Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis
Th17 cells produce a range of characteristic Th17 type cytokines and express transcription factors governed by epigenetic regulation to engage the Th17 programme. Here the authors implicate the RNA 5- methylcytosine (m5C) methyltransferase Nsun2 in Th17 cells and the promotion of colitis in a murine model.
- Wen-Lan Yang
- , Weinan Qiu
- & Yun-Gui Yang
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Article
| Open Access
Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response
Circulating lipids can influence immune cell function, which could have implications for inflammatory diseases such as rheumatoid arthritis. Here, the authors use Mendelian randomization to identify genes whose expression is influenced by triglyceride levels in blood, implicating genes involved in lipid metabolism and allergic response.
- Koen F. Dekkers
- , Roderick C. Slieker
- & Bastiaan T. Heijmans
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Article
| Open Access
Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis
The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB+ CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing.
- Jae-Seung Moon
- , Shady Younis
- & William H. Robinson
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Article
| Open Access
Maturation and specialization of group 2 innate lymphoid cells through the lung-gut axis
The developmental process of group 2 innate lymphoid cells (ILC2) involves migration between different internal organs. Here the authors show that ILC2s migrate from the lung to the intestine to undergo maturation after treatment with IL-33 and that lung and intestine ILC2s have a different phenotype.
- Min Zhao
- , Fei Shao
- & Shuo Wang
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Article
| Open Access
Single-cell sequencing shows cellular heterogeneity of cutaneous lesions in lupus erythematosus
Discoid lupus erythematosus (DLE) and systemic LE (SLE) can present as cutaneous lesions. Here the authors characterise an scRNA dataset of cutaneous lesions from these patients and compare these to healthy controls showing differential immune cell recruitment, cell type and gene expression.
- Meiling Zheng
- , Zhi Hu
- & Ming Zhao
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Article
| Open Access
Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation
Treg cells can be functionally altered by epigenetic modulators. Here the authors show that the histone H3K36 methyltransferase Setd2 is important for the survival of Treg cells and for the regulation of IL-33 mediated Th2 responses in mice and SETD2 expression is increased in Treg cells from human colorectal cancer tissue.
- Zhaoyun Ding
- , Ting Cai
- & Ju Qiu
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Article
| Open Access
Integrated proteomic and transcriptomic landscape of macrophages in mouse tissues
Macrophage is located in different tissue to serve diverse functions. Here the authors use mass spectrometry and bulk RNA-sequencing to profile 11 mouse macrophage populations from 8 tissues, and combine their de novo data with public datasets to report an integrated proteomic and transcriptomic landscape of mouse macrophage as a valuable resource.
- Jingbo Qie
- , Yang Liu
- & Chen Ding
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Article
| Open Access
Deciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain
Perivascular macrophages (pvMs) are important for brain drainage and immune regulation. Here the authors analyse various reporter mouse strains for finer mapping of pvM subsets and lineage differentiation, and propose CX3CR1negative and CD45low as additional markers of intermediate pvMs for studying this heterogenous population.
- C. Siret
- , M. van Lessen
- & S. A. van de Pavert
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Article
| Open Access
The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis
Non-ischemic cardiomyopathy is a severe disease, characterized by interstitial fibrosis in the left ventricle of the heart. Here authors show that the E3 ubiquitin ligase WWP2 plays a pathogenic role in heart fibrosis via regulating a distinct monocyte population that initiates the process.
- Huimei Chen
- , Gabriel Chew
- & Enrico Petretto
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Article
| Open Access
Postnatal expansion of mesenteric lymph node stromal cells towards reticular and CD34+ stromal cell subsets
Lymph nodes in various locations of the body differ in their cell composition and gene expression signatures. Here authors show that the rapid postnatal expansion of lymph nodes is governed by CD34 + stromal cells and fibroblastic reticular stromal cell progenitors, distinguished by intrinsic, microbiome-independent core epigenetic blueprints.
- Joern Pezoldt
- , Carolin Wiechers
- & Jochen Huehn
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Article
| Open Access
Kinetics of mRNA nuclear export regulate innate immune response gene expression
The UCLA Ribonomics group reports that the nuclear export efficiency of innate immune mRNAs varies over a hundred-fold range such that for many genes only a small fraction of the newly synthesized premRNA reaches the cytoplasm. They show that nuclear export and cytoplasmic decay rates are correlated thereby ensuring similar expression levels of short-lived and long-lived mRNAs.
- Diane Lefaudeux
- , Supriya Sen
- & Sri Kosuri
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Article
| Open Access
Brain milieu induces early microglial maturation through the BAX-Notch axis
The mechanisms by which the brain milieu confers microglial development are not clear. Here, the authors show that the BAX-CaMKII-CREB-Notch signaling axis triggered by the neuronal milieu plays a role in early microglia maturation.
- Fangying Zhao
- , Jiangyong He
- & Li Li
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Article
| Open Access
Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
IL-9-producing CD4 T (Th9) cells have been implicated in allergy and tumor immunity, but how their differentiation is regulated by TGFβ is still unclear. Here the authors show that two transcription factors, DBP and E2F8, institute opposing effects on IL-9 expression downstream of TGFβ/Smad3 linker region-mediated signaling in activated mouse T cells to modulate antitumor responses.
- Sang-A Park
- , Yun-Ji Lim
- & WanJun Chen
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Article
| Open Access
The immune factors driving DNA methylation variation in human blood
Many studies assess epigenetic marks in white blood cells, but it is unclear how much immune factors affect the epigenome. Here, the authors show that fine-scale blood cell composition and cytomegalovirus infection affect the DNA methylome of adults.
- Jacob Bergstedt
- , Sadoune Ait Kaci Azzou
- & Lluis Quintana-Murci
Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection