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Article
| Open AccessSingle-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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Article
| Open AccessTargeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis
Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.
- Xudong Tang
- , Yangyang Shang
- & Lei Chen
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Article
| Open AccessAdjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
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Article
| Open AccessImmune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.
- Anja W. Olsen
- , Ida Rosenkrands
- & Frank Follmann
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Article
| Open AccessPorphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/Treg cell balance axis
Periodontitis is closely linked with inflammatory bowel disease (IBD) and may have overlapping characteristics. Here the authors show that a periodontal pathogen P. gingivalis promotes intestinal inflammation by affecting the microbiome metabolite linoleic acid and Th17/Treg cell balance in the intestine.
- Lu Jia
- , Yiyang Jiang
- & Yi Liu
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Article
| Open AccessM2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1
Adipose beiging is a positive biological change, which is often thought to be primarily sympathetically induced. Here, the authors show that M2 macrophages can independently promote beige adipogenesis, further revealing the adipocyte transcription factor Ets1 as a negative regulator of this process.
- Suyang Wu
- , Chen Qiu
- & Xiao Han
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Article
| Open AccessStructure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open AccessGlobal evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection
Human Papillomaviruses (HPV) are classified in lineages based on their sequence. Here, the authors test neutralizing activity of sera from naturally infected women against vaccine-preventable HPV variants, delineating lineage-specific antibody responses.
- Gathoni Kamuyu
- , Filomeno Coelho da Silva
- & Simon Beddows
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Article
| Open AccessConverging and evolving immuno-genomic routes toward immune escape in breast cancer
Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.
- Juan Blanco-Heredia
- , Carla Anjos Souza
- & Leticia De Mattos-Arruda
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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Article
| Open AccessEfficient encoding of large antigenic spaces by epitope prioritization with Dolphyn
Profiling antibody responses to vast antigenic spaces has been challenging using programmable phage display (PhIP-Seq). Here, authors develop a methodology for compressing large proteomic spaces and have discovered human antibodies targeting gut bacteria-infecting phages.
- Anna-Maria Liebhoff
- , Thiagarajan Venkataraman
- & H. Benjamin Larman
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Article
| Open AccessChronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.
- Sarah Rösing
- , Fabian Ullrich
- & Claudia Günther
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Article
| Open AccessRegulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue
Regulatory T cell (Treg) maintenance and function require IL-2, yet this cytokine is only present in low levels in vivo. In this study, the authors demonstrate that that Treg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.
- Hunter A. Martinez
- , Ievgen Koliesnik
- & Hedwich F. Kuipers
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Article
| Open AccessA single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Article
| Open AccessDemographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study
The antibody response to COVID-19 vaccines varies among individuals. Here the authors find that older age, male sex, smoking, higher BMI, vaccine type, and certain comorbidities are associated with lower anti-S1 antibody levels after COVID-19 vaccinations, indicating that certain groups might benefit from higher frequency or doses of vaccination.
- John S. Kim
- , Yifei Sun
- & Elizabeth C. Oelsner
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Article
| Open AccessSingle-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis
Anti-integrin therapy inhibits lymphocyte trafficking in ulcerative colitis. Here Mennillo et al. use single-cell and spatial -omics to show modulation of mononuclear phagocytes and other networks, identifying gene sets related to treatment response.
- Elvira Mennillo
- , Yang Joon Kim
- & Michael G. Kattah
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Article
| Open AccessCOVID-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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Article
| Open AccessMucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease
Here, through parallel profiling of the mucosal transcriptome and microbiome of intestinal biopsies derived from patients with IBD and from non-IBD controls, the authors characterize interactions between gene expression and microbiota composition associated with traits of patients with inflammatory bowel diseases. Peer Review Information: Nature Communications thanks Robert Häsler, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.
- Shixian Hu
- , Arno R. Bourgonje
- & Rinse K. Weersma
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Article
| Open AccessNon-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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Article
| Open AccessMosquito midgut stem cell cellular defense response limits Plasmodium parasite infection
Here, the authors study the cellular response of midgut progenitors in Anopheles stephensi to Plasmodium berghei infection. They show that midgut stem cells are able to detect Plasmodium oocysts and eliminate them in a Jak/STAT pathway dependent manner.
- Ana-Beatriz F. Barletta
- , Jamie C. Smith
- & Carolina Barillas-Mury
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Article
| Open AccessPAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma
MYC drives S-phase progression and immune invasion in pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms are not fully understood. Here, the authors show that the transcription elongation complex PAF1c controls the competition of different gene sets for RNA polymerase and elongation factors to regulate these MYC-associated mechanisms in PDAC.
- Abdallah Gaballa
- , Anneli Gebhardt-Wolf
- & Martin Eilers
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Article
| Open AccessCell 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 AccessTGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo
Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques.
- Jinhee Kim
- , Deepanwita Bose
- & Elena Martinelli
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Article
| Open AccessGene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer
Immune checkpoint inhibitor treatment improves overall survival in metastatic urothelial cancer, but response of individual patients varies significantly. Authors here perform whole-genome DNA and bulk RNA sequencing on samples from metastatic tumours and based on these data, they set up a single metric, T cell-to-stroma enrichment (TSE) score, that reflects the relative abundance of T cells versus stromal cells and their products, accurately predicting therapeutic outcome.
- Maud Rijnders
- , J. Alberto Nakauma-González
- & Martijn P. Lolkema
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Article
| Open AccessEpigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.
- Jiye Liu
- , Lijie Xing
- & Kenneth C. Anderson
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Article
| Open AccessTYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes
TYK2 is a candidate susceptibility gene for type 1 diabetes (T1D) and a beneficial effect has been reported for TYK2 inhibitors for other autoimmune diseases. In this study, the authors generate Tyk2 KO mice on a NOD background and demonstrate that TYK2 signaling drives CD8+ T cell autoreactivity and T1D.
- Keiichiro Mine
- , Seiho Nagafuchi
- & Keizo Anzai
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Article
| Open AccessA general computational design strategy for stabilizing viral class I fusion proteins
The authors present a generalisable computational approach to stabilize class I fusion proteins in the prefusion state. The method was used to stabilize the fusion proteins of RSV, hMPV, and SARS-CoV-2 viruses, with the designs structurally validated and RSV F protein assessed in a neutralization assay.
- Karen J. Gonzalez
- , Jiachen Huang
- & Eva-Maria Strauch
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Article
| Open AccessDubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway
Here, Zhang et al. identify a metabolic axis by which Lys-producing commensal bacterium Dubosiella newyorkensis mediates a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in dendritic cells.
- Yanan Zhang
- , Shuyu Tu
- & Shu Jeffrey Zhu
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Article
| Open AccessHKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression
Aberrant expression of the human hexokinase HKDC1 has been observed in patients with cancer. Here the authors report that HKDC1 expression is associated with hepatocellular carcinoma progression and PD-L1 mediated immune evasion.
- Yi Zhang
- , Mingjie Wang
- & Ping Gao
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Article
| Open AccessApplying valency-based immuno-selection to generate broadly cross-reactive antibodies against influenza hemagglutinins
Here the authors develop a DNA vaccine, mixing 18 hemagglutinin (HA) subtypes monovalently into heterodimeric molecules, and show that it induces broadly reactive antibodies against subdominant HA epitopes and heterologous protection against influenza A viruses in mice.
- Daniëla Maria Hinke
- , Ane Marie Anderson
- & Ranveig Braathen
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Article
| Open AccessEFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death
Physiologically, the host suppresses intestinal epithelial cell death to prevent intestinal inflammation. Here, the authors show that EF-hand domain-containing protein D2 (EFHD2) endogenously suppresses intestinal epithelial cell death by blocking TNFR1 internalization and protects the intestine from excessive inflammation.
- Jiacheng Wu
- , Xiaoqing Xu
- & Xuetao Cao
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Article
| Open AccessA hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs
Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers.
- Kieran English
- , Rain Kwan
- & Patrick Bertolino
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Article
| Open AccessT-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms
Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.
- Eileen Rauch
- , Timm Amendt
- & Philipp Yu
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Article
| Open AccessCAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes
A main challenge for the use of CAR-T in solid tumours is the identification of surface proteins as feasible targets. Here, the authors show TYRP1 as a target for CAR-T cell therapy in preclinical models of cutaneous, acral and uveal melanoma.
- Sameeha Jilani
- , Justin D. Saco
- & Cristina Puig-Saus
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Article
| Open AccessAmyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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Article
| Open AccessMotility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function
Invariant natural killer T (iNKT) cells are important contributors to anti-tumour immunity, but they often become dysfunctional in cancers. Here authors show that inhibited iNKT intra-tumour motility and iNKT cell exclusion from tumours by macrophages both contribute to their diminished function in cancer, and by therapeutic interference with the respective motility and iNKT-macrophage interaction pathways, their function can be restored.
- Chenxi Tian
- , Yu Wang
- & Li Bai
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Review Article
| Open AccessThe genetic basis of autoimmunity seen through the lens of T cell functional traits
Genetic risk variants for autoimmune diseases are largely enriched in T cell-specific regulatory regions. In this review, Raychaudhuri and colleagues summarise the findings of recent studies evaluating the genetic regulation of T cell molecular and functional traits in these diseases.
- Kaitlyn A. Lagattuta
- , Hannah L. Park
- & Soumya Raychaudhuri
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Article
| Open AccessAssessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy
HLA-I plays a key role in triggering an immune response and predicting immune checkpoint efficacy. Here the authors develop a method for quantifying HLA-I neoantigen presentation capacity by integrating HLA-I allele divergence and neoantigens numbers, termed HAPS, to describe how immune checkpoint response may be mediated by HLA.
- Jiefei Han
- , Yiting Dong
- & Zhijie Wang
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Article
| Open AccessThe role of extracellular vesicle fusion with target cells in triggering systemic inflammation
Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules from donor to recipient cells. Here, the authors show that EVs play a crucial role in activating immune responses through cell fusion, shedding light on their impact on inflammation.
- Praveen Papareddy
- , Ines Tapken
- & Heiko Herwald
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Article
| Open AccessStructural basis for the oligomerization-facilitated NLRP3 activation
NLRP3 is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Here, the authors determined Cryo-EM structures of human NLRP3 in its closed and open states, elucidating the mechanism of NLRP3 inflammasome activation.
- Xiaodi Yu
- , Rosalie E. Matico
- & Sujata Sharma
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Article
| Open AccessHeat 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 AccessSmith-specific regulatory T cells halt the progression of lupus nephritis
Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.
- Peter J. Eggenhuizen
- , Rachel M. Y. Cheong
- & Joshua D. Ooi
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Article
| Open AccessTumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient
Immune checkpoint blockade cancer therapy has been designed to enable tumor killing by conventional αβ T cells. Here authors show that in a Merkel cell carcinoma patient showing complete response to anti-PD-1 treatment, innate-like γδ T cells that specifically recognize the tumor cells expand, and likely contribute to therapeutic success.
- Scott C. Lien
- , Dalam Ly
- & Pamela S. Ohashi
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Article
| Open AccessA phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate-severe acute respiratory distress syndrome
Invariant natural killer T (iNKT) cells recognize abnormal cells, but their T cell receptor is not variable and kill cancerous or infected target cells without MHC I restriction. Here, the authors show that in a clinical trial, donor-unrestricted allogeneic iNKT cells could be safely administered to human COVID-19 patients suffering from acute respiratory distress syndrome and trigger an anti-inflammatory response.
- Terese C. Hammond
- , Marco A. Purbhoo
- & Mark A. Exley
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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessBystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity
Many viral infections are linked to the development of neurological disorders. Here, Balint et al use a mouse model of Zika virus infection to show that it is immune cells (NKG2D+CD8+ T cells) that cause infection-associated paralysis, rather than the virus itself.
- Elizabeth Balint
- , Emily Feng
- & Ali A. Ashkar
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Article
| Open AccessSingle-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 AccessLeukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche
The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.
- Amy Dawson
- , Martha M. Zarou
- & G. Vignir Helgason
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Article
| Open AccessA monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity
Characterisation of monoclonal antibodies against SARS-CoV-2 are useful for potential therapeutics or to understand more about the immune response to this virus. Here the authors characterise a monoclonal antibody that has a broad range of reactivity against SARS-CoV-2 variants and measure how it binds to its specific target region of the receptor binding domain.
- Leire de Campos-Mata
- , Benjamin Trinité
- & Giuliana Magri
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