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  •   BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-23
    Zsófia Agnes Bittner, Xiao Liu, Maria Mateo Tortola, Ana Tapia-Abellán, Sangeetha Shankar, Liudmila Andreeva, Matthew Mangan, Marianne Spalinger, Hubert Kalbacher, Peter Düwell, Marta Lovotti, Karlotta Bosch, Sabine Dickhöfer, Ana Marcu, Stefan Stevanović, Franziska Herster, Yamel Cardona Gloria, Tzu-Hsuan Chang, Francesca Bork, Carsten L. Greve, Markus W. Löffler, Olaf-Oliver Wolz, Nadine A. Schilling

    Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton’s tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK directly interacts with NLRP3 in immune cells and phosphorylates

  •   Gut epithelial IL-27 confers intestinal immunity through the induction of intraepithelial lymphocytes.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-23
    Chia-Hao Lin,Mei-Chi Chen,Ling-Li Lin,David A Christian,Booki Min,Christopher A Hunter,Li-Fan Lu

    IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically

  •   Encephalitis patient-derived monoclonal GABA A receptor antibodies cause epileptic seizures
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-21
    Jakob Kreye, Sukhvir K. Wright, Adriana van Casteren, Laura Stöffler, Marie-Luise Machule, S. Momsen Reincke, Marc Nikolaus, Scott van Hoof, Elisa Sanchez-Sendin, Marie A. Homeyer, César Cordero Gómez, Hans-Christian Kornau, Dietmar Schmitz, Angela M. Kaindl, Philipp Boehm-Sturm, Susanne Mueller, Max A. Wilson, Manoj A. Upadhya, Divya R. Dhangar, Stuart Greenhill, Gavin Woodhall, Paul Turko, Imre Vida

    Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor

  •   Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-21
    Vishwas Mishra, Avipsa Bose, Shashi Kiran, Sanghita Banerjee, Idrees A. Shah, Pooja Chaukimath, Mudasir M. Reshi, Swarna Srinivas, Anaxee Barman, Sandhya S. Visweswariah

    Activating mutations in receptor guanylyl cyclase C (GC-C), the target of gastrointestinal peptide hormones guanylin and uroguanylin, and bacterial heat-stable enterotoxins cause early-onset diarrhea and chronic inflammatory bowel disease (IBD). GC-C regulates ion and fluid secretion in the gut via cGMP production and activation of cGMP-dependent protein kinase II. We characterize a novel mouse model

  •   Implication of folate deficiency in CYP2U1 loss of function.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-21
    Claire Pujol,Anne Legrand,Livia Parodi,Priscilla Thomas,Fanny Mochel,Dario Saracino,Giulia Coarelli,Marijana Croon,Milica Popovic,Manon Valet,Nicolas Villain,Shahira Elshafie,Mahmoud Issa,Stephane Zuily,Mathilde Renaud,Cécilia Marelli-Tosi,Marine Legendre,Aurélien Trimouille,Isabelle Kemlin,Sophie Mathieu,Joseph G Gleeson,Foudil Lamari,Daniele Galatolo,Rana Alkouri,Chantal Tse,Diana Rodriguez,Claire

    Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes

  •   Takes one to B1a: Dismantling the origin of mantle cell lymphoma
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-16
    Anna E. Beaudin

    Therapeutic discovery for mantle cell lymphoma (MCL) has been hindered by a lack of preclinical mouse models that recapitulate human disease. In this issue, Pieters and colleagues (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202280) establish a novel mouse model of MCL driven by overexpression of cyclin D2 and identify fetal-derived B1a cells as putative cell of origin for MCL.

  •   TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-17
    Chris D Hermann,Benjamin Schoeps,Celina Eckfeld,Enkhtsetseg Munkhbaatar,Lukas Kniep,Olga Prokopchuk,Nils Wirges,Katja Steiger,Daniel Häußler,Percy Knolle,Emily Poulton,Rama Khokha,Barbara T Grünwald,Ihsan Ekin Demir,Achim Krüger

    Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased

  •   Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-16
    Annika Hausmann,Boas Felmy,Leo Kunz,Sanne Kroon,Dorothée Lisa Berthold,Giverny Ganz,Ioana Sandu,Toshihiro Nakamura,Nathan Sébastien Zangger,Yang Zhang,Tamas Dolowschiak,Stefan Alexander Fattinger,Markus Furter,Anna Angelika Müller-Hauser,Manja Barthel,Katerina Vlantis,Laurens Wachsmuth,Jan Kisielow,Luigi Tortola,Danijela Heide,Mathias Heikenwälder,Annette Oxenius,Manfred Kopf,Timm Schroeder,Manolis

    Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages

  •   A fungal antigenic driver for Löfgren's syndrome sarcoidosis.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-13
    Clarice X Lim,Thomas Weichhart

    Löfgren's syndrome is an acute form of sarcoidosis that is characterized by the activation of CD4+ T helper cells. In this issue of JEM, Greaves et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210785) identified a peptide derived from an airborne mold species that stimulates T cells of Löfgren's syndrome patients in an HLA-DR3-restricted manner. An increased serum IgG antibody response to the

  •   Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-08
    Juliette Paillet, Céleste Plantureux, Sarah Lévesque, Julie Le Naour, Gautier Stoll, Allan Sauvat, Pamela Caudana, Jimena Tosello Boari, Norma Bloy, Sylvie Lachkar, Isabelle Martins, Paule Opolon, Andrea Checcoli, Agathe Delaune, Noémie Robil, Pierre de la Grange, Juliette Hamroune, Franck Letourneur, Gwennhael Autret, Patrick S.C. Leung, M. Eric Gershwin, Jie S. Zhu, Mark J. Kurth, Bouchra Lekbaby

    Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance

  •   Alveolar macrophages and epithelial cells: The art of living together
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-07
    Derek Clements, Juliana Idoyaga

    In this issue of JEM, Gschwend et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210745) reveal the indispensable role of alveolar epithelial cells type 2 in controlling the density of alveolar macrophages. This study highlights the intricate crosstalk that lung stroma and macrophages undergo to maintain homeostasis.

  •   Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-07
    Olivier Tabone, Raman Verma, Akul Singhania, Probir Chakravarty, William J. Branchett, Christine M. Graham, Jo Lee, Tran Trang, Frederic Reynier, Philippe Leissner, Karine Kaiser, Marc Rodrigue, Gerrit Woltmann, Pranabashis Haldar, Anne O’Garra

    Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time

  •   Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-03
    Julien Stackowicz, Nicolas Gaudenzio, Nadine Serhan, Eva Conde, Ophélie Godon, Thomas Marichal, Philipp Starkl, Bianca Balbino, Axel Roers, Pierre Bruhns, Friederike Jönsson, Philippe Moguelet, Sophie Georgin-Lavialle, Lori Broderick, Hal M. Hoffman, Stephen J. Galli, Laurent L. Reber

    Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production

  •   Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-03
    Yael Goldfarb, Tal Givony, Noam Kadouri, Jan Dobeš, Cristina Peligero-Cruz, Itay Zalayat, Golda Damari, Bareket Dassa, Shifra Ben-Dor, Yael Gruper, Bergithe E. Oftedal, Eirik Bratland, Martina M. Erichsen, Amund Berger, Ayelet Avin, Shir Nevo, Uku Haljasorg, Yael Kuperman, Adi Ulman, Rebecca Haffner-Krausz, Ziv Porat, Ulus Atasoy, Dena Leshkowitz, Eystein S. Husebye, Jakub Abramson

    The autoimmune regulator (AIRE) is essential for the establishment of central tolerance and prevention of autoimmunity. Interestingly, different AIRE mutations cause autoimmunity in either recessive or dominant-negative manners. Using engineered mouse models, we establish that some monoallelic mutants, including C311Y and C446G, cause breakdown of central tolerance. By using RNAseq, ATACseq, ChIPseq

  •   A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-02
    Julie C.F. Rappe, Katja Finsterbusch, Stefania Crotta, Matthias Mack, Simon L. Priestnall, Andreas Wack

    Cytokine-mediated immune-cell recruitment and inflammation contribute to protection in respiratory virus infection. However, uncontrolled inflammation and the “cytokine storm” are hallmarks of immunopathology in severe infection. Cytokine storm is a broad term for a phenomenon with diverse characteristics and drivers, depending on host genetics, age, and other factors. Taking advantage of the differential

  •   Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-02
    Juan Li, Wei-Te Lei, Peng Zhang, Franck Rapaport, Yoann Seeleuthner, Bingnan Lyu, Takaki Asano, Jérémie Rosain, Boualem Hammadi, Yu Zhang, Simon J. Pelham, András N. Spaan, Mélanie Migaud, David Hum, Benedetta Bigio, Maya Chrabieh, Vivien Béziat, Jacinta Bustamante, Shen-Ying Zhang, Emmanuelle Jouanguy, Stephanie Boisson-Dupuis, Jamila El Baghdadi, Vishukumar Aimanianda, Katharina Thoma, Manfred Fliegauf

    Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking

  •   Arkadia-SKI/SnoN signaling differentially regulates TGF-β–induced iTreg and Th17 cell differentiation
    J. Exp. Med. (IF 14.307) Pub Date : 2021-09-02
    Hao Xu, Lin Wu, Henry H. Nguyen, Kailin R. Mesa, Varsha Raghavan, Vasso Episkopou, Dan R. Littman

    TGF-β signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-β

  •   Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-30
    Giovanni Cova, Chiara Taroni, Marie-Céline Deau, Qi Cai, Vincent Mittelheisser, Muriel Philipps, Matthieu Jung, Marie Cerciat, Stéphanie Le Gras, Christelle Thibault-Carpentier, Bernard Jost, Leif Carlsson, Angela M. Thornton, Ethan M. Shevach, Peggy Kirstetter, Philippe Kastner, Susan Chan

    Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte

  •   Imatinib augments standard malaria combination therapy without added toxicity
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-26
    Huynh Dinh Chien, Antonella Pantaleo, Kristina R. Kesely, Panae Noomuna, Karson S. Putt, Tran Anh Tuan, Philip S. Low, Francesco M. Turrini

    To egress from its erythrocyte host, the malaria parasite, Plasmodium falciparum, must destabilize the erythrocyte membrane by activating an erythrocyte tyrosine kinase. Because imatinib inhibits erythrocyte tyrosine kinases and because imatinib has a good safety profile, we elected to determine whether coadministration of imatinib with standard of care (SOC) might be both well tolerated and therapeutically

  •   Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-25
    Julia Gschwend, Samantha P.M. Sherman, Frederike Ridder, Xiaogang Feng, Hong-Erh Liang, Richard M. Locksley, Burkhard Becher, Christoph Schneider

    Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected

  •   JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-24
    Joseph M. McGraw, Flavian Thelen, Eric N. Hampton, Nelson E. Bruno, Travis S. Young, Wendy L. Havran, Deborah A. Witherden

    T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions

  •   TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-23
    Garyfallia Gouna, Christian Klose, Mar Bosch-Queralt, Lu Liu, Ozgun Gokce, Martina Schifferer, Ludovico Cantuti-Castelvetri, Mikael Simons

    Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification

  •   The early interferon catches the SARS-CoV-2
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-23
    Thomas Decker

    Interferons establish innate antiviral immunity. Two recent papers in JEM by Lopez et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211211) and Cheemarla et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210583) show that an appropriate supply of antiviral interferon enables epithelial cells of the nasopharyngeal mucosa to inhibit SARS-CoV-2 growth and that interferon-induced mucosal genes

  •   Characterization of human FDCs reveals regulation of T cells and antigen presentation to B cells
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-23
    Balthasar A. Heesters, Kyah van Megesen, Ilhan Tomris, Robert P. de Vries, Giuliana Magri, Hergen Spits

    Stromal-derived follicular dendritic cells (FDCs) are essential for germinal centers (GCs), the site where B cells maturate their antibodies. FDCs present native antigen to B cells and maintain a CXCL13 gradient to form the B cell follicle. Yet despite their essential role, the transcriptome of human FDCs remains undefined. Using single-cell RNA sequencing and microarray, we provided the transcriptome

  •   Correction: Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-20
    Jonathan Lopez, Marine Mommert, William Mouton, Andrés Pizzorno, Karen Brengel-Pesce, Mehdi Mezidi, Marine Villard, Bruno Lina, Jean-Christophe Richard, Jean-Baptiste Fassier, Valérie Cheynet, Blandine Padey, Victoria Duliere, Thomas Julien, Stéphane Paul, Paul Bastard, Alexandre Belot, Antonin Bal, Jean-Laurent Casanova, Manuel Rosa-Calatrava, Florence Morfin, Thierry Walzer, Sophie Trouillet-Assant

    Vol. 218, No. 10 | 10.1084/jem.20211211 | August 6, 2021

  •   MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-20
    Robin S. Lindsay, Jennifer C. Whitesell, Kristen E. Dew, Erika Rodriguez, Adam M. Sandor, Dayna Tracy, Seth F. Yannacone, Brittany N. Basta, Jordan Jacobelli, Rachel S. Friedman

    Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate

  •   Single-cell imaging of T cell immunotherapy responses in vivo
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-20
    Chuan Yan, Qiqi Yang, Songfa Zhang, David G. Millar, Eric J. Alpert, Daniel Do, Alexandra Veloso, Dalton C. Brunson, Benjamin J. Drapkin, Marcello Stanzione, Irene Scarfò, John C. Moore, Sowmya Iyer, Qian Qin, Yun Wei, Karin M. McCarthy, John F. Rawls, Nick J. Dyson, Mark Cobbold, Marcela V. Maus, David M. Langenau

    T cell immunotherapies have revolutionized treatment for a subset of cancers. Yet, a major hurdle has been the lack of facile and predicative preclinical animal models that permit dynamic visualization of T cell immune responses at single-cell resolution in vivo. Here, optically clear immunocompromised zebrafish were engrafted with fluorescent-labeled human cancers along with chimeric antigen receptor

  •   The microbial one-hit wonder
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-19
    Brigida A. Rusconi, Rodney D. Newberry

    Intestinal inflammation, in the absence of infection, occurs from contributions by genetics and environment. Chen et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210324) challenge this concept by demonstrating that a dominant transmissible dysbiotic microbial community predisposes to intestinal inflammation in absence of genetic alterations.

  •   Surmounting structural barriers to tackle endemic infectious diseases
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-19
    Felix Calderón, Alan H. Fairlamb, Mike Strange, Pauline Williams, Carl F. Nathan

    A unique experiment in bringing academic and industrial scientists together to tackle endemic infectious diseases has proved a success. The Tres Cantos Open Lab Foundation, guided and advised by independent experts, funds extended stays of academics at the campus of a pharmaceutical company, where they access the firm’s resources in partnership with company scientists. Progress in tackling tuberculosis

  •   CD4 + T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-19
    Sarah A. Greaves, Avinash Ravindran, Radleigh G. Santos, Lan Chen, Michael T. Falta, Yang Wang, Angela M. Mitchell, Shaikh M. Atif, Douglas G. Mack, Alex N. Tinega, Lisa A. Maier, Shaodong Dai, Clemencia Pinilla, Johan Grunewald, Andrew P. Fontenot

    Löfgren’s syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated

  •   Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-18
    Sarah C. Huen, Andrew Wang, Kyle Feola, Reina Desrouleaux, Harding H. Luan, Richard Hogg, Cuiling Zhang, Qing-Jun Zhang, Zhi-Ping Liu, Ruslan Medzhitov

    Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast

  •   Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-18
    Tim Pieters, Sara T’Sas, Stijn Vanhee, André Almeida, Yasmine Driege, Juliette Roels, Wouter Van Loocke, Willem Daneels, Mathijs Baens, Arnaud Marchand, Maaike Van Trimpont, Filip Matthijssens, Julie Morscio, Kelly Lemeire, Béatrice Lintermans, Lindy Reunes, Patrick Chaltin, Fritz Offner, Jo Van Dorpe, Tino Hochepied, Geert Berx, Rudi Beyaert, Jens Staal, Pieter Van Vlierberghe, Steven Goossens

    Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that

  •   A SHHecret target of relapsed medulloblastoma: Astrocytes
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-16
    Zulekha A. Qadeer, William A. Weiss

    In this issue of JEM, Guo et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202350) examine the importance of tumor-derived astrocytes in SHH-medulloblastoma recurrence. They show that tumor cells transdifferentiate to tumor-derived astrocytes via bone morphogenetic proteins and Sox9, which excitingly can be targeted by BMP inhibitors.

  •   Persistent RNA virus infection is short-lived at the single-cell level but leaves transcriptomic footprints
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-16
    Peter Reuther, Katrin Martin, Mario Kreutzfeldt, Matias Ciancaglini, Florian Geier, Diego Calabrese, Doron Merkler, Daniel D. Pinschewer

    Several RNA viruses can establish life-long persistent infection in mammalian hosts, but the fate of individual virus-infected cells remains undefined. Here we used Cre recombinase–encoding lymphocytic choriomeningitis virus to establish persistent infection in fluorescent cell fate reporter mice. Virus-infected hepatocytes underwent spontaneous noncytolytic viral clearance independently of type I

  •   The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-17
    Amalie C Grenov,Lihee Moss,Sarit Edelheit,Ross Cordiner,Dominik Schmiedel,Adi Biram,Jacob H Hanna,Torben Heick Jensen,Schraga Schwartz,Ziv Shulman

    Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required

  •   The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination.
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-17
    Helen A Beilinson,Rebecca A Glynn,Anurupa Devi Yadavalli,Jianxiong Xiao,Elizabeth Corbett,Huseyin Saribasak,Rahul Arya,Charline Miot,Anamika Bhattacharyya,Jessica M Jones,Jagan M R Pongubala,Craig H Bassing,David G Schatz

    Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1-383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination

  •   Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-13
    Alice Lepelley, Erika Della Mina, Erika Van Nieuwenhove, Lise Waumans, Sylvie Fraitag, Gillian I. Rice, Ashish Dhir, Marie-Louise Frémond, Mathieu P. Rodero, Luis Seabra, Edwin Carter, Christine Bodemer, Daniela Buhas, Bert Callewaert, Pascale de Lonlay, Lien De Somer, David A. Dyment, Fran Faes, Lucy Grove, Simon Holden, Marie Hully, Manju A. Kurian, Hugh J. McMillan, Kristin Suetens, Henna Tyynismaa

    Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated

  •   T2B or not to B: Calming neutrophils offshore
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-10
    Hafsa Munir, Theresa T. Lu

    In this issue of JEM, Podstawka et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210409) show that B cells can limit neutrophil responses within the lung microvasculature by marginating and acting on marginated neutrophils. This study provides a new view of B cells and reveals a novel mechanism of cell-mediated intravascular regulation.

  •   Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-06
    Jonathan Lopez, Marine Mommert, William Mouton, Andrés Pizzorno, Karen Brengel-Pesce, Mehdi Mezidi, Marine Villard, Bruno Lina, Jean-Christophe Richard, Jean-Baptiste Fassier, Valérie Cheynet, Blandine Padey, Victoria Duliere, Thomas Julien, Stéphane Paul, Paul Bastard, Alexandre Belot, Antonin Bal, Jean-Laurent Casanova, Manuel Rosa-Calatrava, Florence Morfin, Thierry Walzer, Sophie Trouillet-Assant

    IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3–dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature

  •   Eosinophils are part of the granulocyte response in tuberculosis and promote host resistance in mice
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-04
    Andrea C. Bohrer, Ehydel Castro, Zhidong Hu, Artur T.L. Queiroz, Claire E. Tocheny, Maike Assmann, Shunsuke Sakai, Christine Nelson, Paul J. Baker, Hui Ma, Lin Wang, Wen Zilu, Elsa du Bruyn, Catherine Riou, Keith D. Kauffman, Tuberculosis Imaging Program, Ian N. Moore, Franca Del Nonno, Linda Petrone, Delia Goletti, Adrian R. Martineau, David M. Lowe, Mark R. Cronan, Robert J. Wilkinson, Clifton E

    Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions

  •   A newly characterized malaria antigen on erythrocyte and merozoite surfaces induces parasite inhibitory antibodies
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-03
    Ian C. Michelow, Sangshin Park, Shu-Whei Tsai, Bonnie Rayta, Charisse Flerida A. Pasaje, Sara Nelson, Angela M. Early, Anne P. Frosch, George Ayodo, Dipak K. Raj, Christina E. Nixon, Christian P. Nixon, Sunthorn Pond-Tor, Jennifer F. Friedman, Michal Fried, Patrick E. Duffy, Karine G. Le Roch, Jacquin C. Niles, Jonathan D. Kurtis

    We previously identified a Plasmodium falciparum (Pf) protein of unknown function encoded by a single-copy gene, PF3D7_1134300, as a target of antibodies in plasma of Tanzanian children in a whole-proteome differential screen. Here we characterize this protein as a blood-stage antigen that localizes to the surface membranes of both parasitized erythrocytes and merozoites, hence its designation as Pf

  •   ASC deglutathionylation is a checkpoint for NLRP3 inflammasome activation
    J. Exp. Med. (IF 14.307) Pub Date : 2021-08-03
    Shuhang Li, Linlin Wang, Zhihao Xu, Yuanyuan Huang, Rufeng Xue, Ting Yue, Linfeng Xu, Fanwu Gong, Shiyu Bai, Qielan Wu, Jiwei Liu, Bolong Lin, Huimin Zhang, Yanhong Xue, Pingyong Xu, Junjie Hou, Xiaofei Yang, Tengchuan Jin, Rongbin Zhou, Jizhong Lou, Tao Xu, Li Bai

    Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits

  •   Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-29
    Matthew DeBerge, Connor Lantz, Shirley Dehn, David P. Sullivan, Anja M. van der Laan, Hans W.M. Niessen, Margaret E. Flanagan, Daniel J. Brat, Matthew J. Feinstein, Sunjay Kaushal, Lisa D. Wilsbacher, Edward B. Thorp

    Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the

  •   AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-29
    Keitaro Fukuda, Ken Okamura, Rebecca L. Riding, Xueli Fan, Khashayar Afshari, Nazgol-Sadat Haddadi, Sean M. McCauley, Mehmet H. Guney, Jeremy Luban, Takeru Funakoshi, Tomonori Yaguchi, Yutaka Kawakami, Anastasia Khvorova, Katherine A. Fitzgerald, John E. Harris

    The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient

  •   A dark side to NS1 antibodies?
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-28
    Davide F. Robbiani, Daniel Růžek

    The NS1 protein of flaviviruses is taking center stage. Recent work has made it an attractive target for development of vaccines and immunotherapeutics. Cavazzoni and colleagues (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210580) now reveal a dark side to NS1, linking it to the development of self-reactive antibodies.

  •   Marginating transitional B cells modulate neutrophils in the lung during inflammation and pneumonia
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-27
    John Podstawka, Sarthak Sinha, Carlos H. Hiroki, Nicole Sarden, Elise Granton, Elodie Labit, Jung Hwan Kim, Graciela Andonegui, Yuefei Lou, Brendan D. Snarr, Donald C. Sheppard, Nicole L. Rosin, Jeff Biernaskie, Bryan G. Yipp

    Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation

  •   Translation from bats to humans beyond infectious diseases
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-27
    Matae Ahn, Lin-Fa Wang

    Bats are attracting the greatest attention recently as a putative reservoir of SARS-CoV-2 responsible for the COVID-19 pandemic. However, less known to the public, bats also have several unique traits of high value to human health. The lessons we learn from bats can potentially help us fight many human diseases, including infection, aging, and cancer.

  •   Epigenetic and transcriptional control of interferon-β
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-23
    Andrew W. Daman, Steven Z. Josefowicz

    The three classes of interferons (IFNs) share the ability to inhibit viral replication, activating cell transcriptional programs that regulate both innate and adaptive responses to viral and intracellular bacterial challenge. Due to their unique potency in regulating viral replication, and their association with numerous autoimmune diseases, the tightly orchestrated transcriptional regulation of IFNs

  •   Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN–driven CCL5 and CXCL10
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-23
    Courtney Mowat, Shayla R. Mosley, Afshin Namdar, Daniel Schiller, Kristi Baker

    Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that

  •   ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-23
    Anna-Maria Herzner, Zia Khan, Eric L. Van Nostrand, Sara Chan, Trinna Cuellar, Ronald Chen, Ximo Pechuan-Jorge, Laszlo Komuves, Margaret Solon, Zora Modrusan, Benjamin Haley, Gene W. Yeo, Timothy W. Behrens, Matthew L. Albert

    Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC

  •   Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-22
    Yun Chen, Marco Colonna

    Alzheimer’s disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated

  •   Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-22
    Davide Pisu, Lu Huang, Vipin Narang, Monique Theriault, Gabrielle Lê-Bury, Bernett Lee, Agnes E. Lakudzala, David T. Mzinza, David V. Mhango, Steven C. Mitini-Nkhoma, Kondwani C. Jambo, Amit Singhal, Henry C. Mwandumba, David G. Russell

    In this study, we detail a novel approach that combines bacterial fitness fluorescent reporter strains with scRNA-seq to simultaneously acquire the host transcriptome, surface marker expression, and bacterial phenotype for each infected cell. This approach facilitates the dissection of the functional heterogeneity of M. tuberculosis–infected alveolar (AMs) and interstitial macrophages (IMs) in vivo

  •   The immunodominant antibody response to Zika virus NS1 protein is characterized by cross-reactivity to self
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-22
    Cecilia B. Cavazzoni, Vicente B.T. Bozza, Tostes C.V. Lucas, Luciana Conde, Bruno Maia, Luka Mesin, Ariën Schiepers, Jonatan Ersching, Romulo L.S. Neris, Jonas N. Conde, Diego R. Coelho, Tulio M. Lima, Renata G.F. Alvim, Leda R. Castilho, Heitor A. de Paula Neto, Ronaldo Mohana-Borges, Iranaia Assunção-Miranda, Alberto Nobrega, Gabriel D. Victora, Andre M. Vale

    Besides antigen-specific responses to viral antigens, humoral immune response in virus infection can generate polyreactive and autoreactive antibodies. Dengue and Zika virus infections have been linked to antibody-mediated autoimmune disorders, including Guillain-Barré syndrome. A unique feature of flaviviruses is the secretion of nonstructural protein 1 (NS1) by infected cells. NS1 is highly immunogenic

  •   Functional immune cell–astrocyte interactions
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-22
    Liliana M. Sanmarco, Carolina M. Polonio, Michael A. Wheeler, Francisco J. Quintana

    Astrocytes are abundant glial cells in the central nervous system (CNS) that control multiple aspects of health and disease. Through their interactions with components of the blood–brain barrier (BBB), astrocytes not only regulate BBB function, they also sense molecules produced by peripheral immune cells, including cytokines. Here, we review the interactions between immune cells and astrocytes and

  •   Reversal of emphysema by restoration of pulmonary endothelial cells
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-21
    Shu Hisata, Alexandra C. Racanelli, Pouneh Kermani, Ryan Schreiner, Sean Houghton, Brisa Palikuqi, Balvir Kunar, Aiyuan Zhou, Keith McConn, Allyson Capili, David Redmond, Daniel J. Nolan, Michael Ginsberg, Bi-Sen Ding, Fernando J. Martinez, Joseph M. Scandura, Suzanne M. Cloonan, Shahin Rafii, Augustine M.K. Choi

    Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here

  •   Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-21
    Zuojia Chen, Jialie Luo, Jian Li, Girak Kim, Eric S. Chen, Sheng Xiao, Scott B. Snapper, Bin Bao, Dingding An, Richard S. Blumberg, Cheng-hui Lin, Sui Wang, Jiaxin Zhong, Kuai Liu, Qiyuan Li, Chuan Wu, Vijay K. Kuchroo

    Mucus produced by goblet cells in the gastrointestinal tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been well studied. Here, we identify that Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines

  •   Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-21
    Roberto Vendramin, Vicky Katopodi, Sonia Cinque, Angelina Konnova, Zorica Knezevic, Sara Adnane, Yvessa Verheyden, Panagiotis Karras, Ewout Demesmaeker, Francesca M. Bosisio, Lukas Kucera, Jan Rozman, Ivan Gladwyn-Ng, Lara Rizzotto, Erik Dassi, Stefania Millevoi, Oliver Bechter, Jean-Christophe Marine, Eleonora Leucci

    The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using

  •   Macrophage-adipocyte communication and cardiac remodeling
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-20
    Gautham Yepuri, Syed Nurul Hasan, Ann Marie Schmidt, Ravichandran Ramasamy

    In obesity complicated by hypertension, multicellular processes integrate to orchestrate cardiac fibrosis; the underlying mechanisms, however, remain elusive. In this issue of JEM, Cheng et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210252) describe adipocyte–macrophage collaboration to foster cardiac fibrosis through the actions of angiotensin II in obesity.

  •   PGD 2 and CRTH2 counteract Type 2 cytokine–elicited intestinal epithelial responses during helminth infection
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-20
    Oyebola O. Oyesola, Michael T. Shanahan, Matt Kanke, Bridget M. Mooney, Lauren M. Webb, Shuchi Smita, Macy K. Matheson, Pamela Campioli, Duc Pham, Simon P. Früh, John W. McGinty, Madeline J. Churchill, Jordan L. Cahoon, Pavithra Sundaravaradan, Becca A. Flitter, Karthik Mouli, Marija S. Nadjsombati, Elena Kamynina, Seth A. Peng, Rebecca L. Cubitt, Karsten Gronert, James D. Lord, Isabella Rauch, Jakob

    Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D2 (PGD2) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced

  •   Single-cell analysis of human skin identifies CD14 + type 3 dendritic cells co-producing IL1B and IL23A in psoriasis
    J. Exp. Med. (IF 14.307) Pub Date : 2021-07-19
    Satoshi Nakamizo, Charles-Antoine Dutertre, Ahad Khalilnezhad, Xiao Meng Zhang, Shawn Lim, Josephine Lum, Geraldine Koh, Charlene Foong, Pearly Jean Ai Yong, Kahbing Jasmine Tan, Reiko Sato, Kaori Tomari, Laurent Yvan-Charvet, Helen He, Emma Guttman-Yassky, Benoit Malleret, Rintaro Shibuya, Masashi Iwata, Baptiste Janela, Tsuyoshi Goto, Tan Siyun Lucinda, Mark B.Y. Tang, Colin Theng, Valerie Julia

    Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD

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