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NADPH oxidase exerts a B cell–intrinsic contribution to lupus risk by modulating endosomal TLR signals J. Exp. Med. (IF 15.3) Pub Date : 2024-03-05 Shuozhi Liu, Jonathan Lagos, Natali M. Shumlak, Andrea D. Largent, Sebastien T.E. Lewis, Ursula Holder, Samuel W. Du, Yifan Liu, Baidong Hou, Mridu Acharya, Shaun W. Jackson
Genome-wide association studies in systemic lupus erythematosus (SLE) have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to disease pathogenesis. The prevailing model holds that reduced NOX2 activity promotes SLE via defective efferocytosis, the immunologically silent clearance of apoptotic cells. Here, we describe a parallel B cell–intrinsic
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Meningeal lymphatics can influence stroke outcome J. Exp. Med. (IF 15.3) Pub Date : 2024-03-05 Gou Young Koh, Donald M. McDonald
Meningeal lymphatics are conduits for cerebrospinal fluid drainage to lymphatics and lymph nodes in the neck. In this issue of JEM, Boisserand et al. (https://doi.org/10.1084/jem.20221983) provide evidence that expansion of meningeal lymphatics protects against ischemic stroke.
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Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity J. Exp. Med. (IF 15.3) Pub Date : 2024-02-28 Yaoyuan Zhang, Rhiannon Morris, Grant J. Brown, Ayla May D. Lorenzo, Xiangpeng Meng, Nadia J. Kershaw, Pamudika Kiridena, Gaétan Burgio, Simon Gross, Jean Y. Cappello, Qian Shen, Hao Wang, Cynthia Turnbull, Tom Lea-Henry, Maurice Stanley, Zhijia Yu, Fiona D. Ballard, Aaron Chuah, James C. Lee, Ann-Maree Hatch, Anselm Enders, Seth L. Masters, Alexander P. Headley, Peter Trnka, Dominic Mallon, Jeffery
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3—a negative regulator of cytokine and growth factor receptor signaling—harbors rare coding variants in over 5% of SLE patients. Here, we show
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E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming J. Exp. Med. (IF 15.3) Pub Date : 2024-02-27 Gengyi Zou, Yuanjian Huang, Shengzhe Zhang, Kyung-Pil Ko, Bongjun Kim, Jie Zhang, Vishwa Venkatesan, Melissa P. Pizzi, Yibo Fan, Sohee Jun, Na Niu, Huamin Wang, Shumei Song, Jaffer A. Ajani, Jae-Il Park
Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC
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Framework for in vivo T cell screens J. Exp. Med. (IF 15.3) Pub Date : 2024-02-27 Lauren E. Milling, Samuel C. Markson, Qin Tjokrosurjo, Nicole M. Derosia, Ivy S.L. Streeter, Grant H. Hickok, Ashlyn M. Lemmen, Thao H. Nguyen, Priyamvada Prathima, William Fithian, Marc A. Schwartz, Nir Hacohen, John G. Doench, Martin W. LaFleur, Arlene H. Sharpe
In vivo T cell screens are a powerful tool for elucidating complex mechanisms of immunity, yet there is a lack of consensus on the screen design parameters required for robust in vivo screens: gene library size, cell transfer quantity, and number of mice. Here, we describe the Framework for In vivo T cell Screens (FITS) to provide experimental and analytical guidelines to determine optimal parameters
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Regenerating murine CD8 + lung tissue resident memory T cells after targeted radiation exposure J. Exp. Med. (IF 15.3) Pub Date : 2024-02-16 Mariah Hassert, Lecia L. Pewe, Rui He, Mohammad Heidarian, Pornpoj Phruttiwanichakun, Stephanie van de Wall, Madison R. Mix, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
Radiation exposure occurs during medical procedures, nuclear accidents, or spaceflight, making effective medical countermeasures a public health priority. Naïve T cells are highly sensitive to radiation-induced depletion, although their numbers recover with time. Circulating memory CD8+ T cells are also depleted by radiation; however, their numbers do not recover. Critically, the impact of radiation
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Ion channel TRPV2 is critical in enhancing B cell activation and function J. Exp. Med. (IF 15.3) Pub Date : 2024-02-14 Cuifeng Li, Meng Zhao, Xiaohang Liu, Yuxin Li, Bihua Xu, Lina Zhou, Xiaolin Sun, Wenbo Sun, Na Kang, Zhenglin Ji, Tong Li, Haoran An, Fei Wang, Chuan Wu, Jing-Ying Ye, Jing-Ren Zhang, Qingwen Wang, Xiaodong Zhao, Zhanguo Li, Wanli Liu
The function of transient receptor potential vanilloid (TRPV) cation channels governing B cell activation remains to be explored. We present evidence that TRPV2 is highly expressed in B cells and plays a crucial role in the formation of the B cell immunological synapse and B cell activation. Physiologically, TRPV2 expression level is positively correlated to influenza-specific antibody production and
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Proliferation of HIV-1 reservoir cells: The delusion of infinite growth J. Exp. Med. (IF 15.3) Pub Date : 2024-02-12 Melanie Lancien, Mathias Lichterfeld
Proliferation of HIV-1–infected cells contributes to viral persistence despite antiretroviral therapy. A new study by Kufera et al. (https://doi.org/10.1084/jem.20231511) demonstrates that proliferative growth of cells infected with genome-intact HIV-1 is not limitless; rather, these cells seem to be at least partially refractory to TCR stimulation, restricting their ability to proliferate in response
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INPP4B ensures that ILC1s and NK cells set up a productive home office J. Exp. Med. (IF 15.3) Pub Date : 2024-02-08 Zi Yan Chen, Arthur Mortha
In this issue of JEM, Peng et al. (https://doi.org/10.1084/jem.20230124) identify inositol polyphosphate 4-phosphatase type II (encoded by Inpp4b) as an important enzyme for tissue-resident ILC1 and NK cell survival, signal transduction, and anti-tumor immunity.
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TCR signaling induces STAT3 phosphorylation to promote T H 17 cell differentiation J. Exp. Med. (IF 15.3) Pub Date : 2024-02-07 Zhen Qin, Ruining Wang, Ping Hou, Yuanyuan Zhang, Qianmu Yuan, Ying Wang, Yuedong Yang, Tao Xu
TH17 differentiation is critically controlled by “signal 3” of cytokines (IL-6/IL-23) through STAT3. However, cytokines alone induced only a moderate level of STAT3 phosphorylation. Surprisingly, TCR stimulation alone induced STAT3 phosphorylation through Lck/Fyn, and synergistically with IL-6/IL-23 induced robust and optimal STAT3 phosphorylation at Y705. Inhibition of Lck/Fyn kinase activity by Srci1
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Addendum: Resolvins suppress tumor growth and enhance cancer therapy J. Exp. Med. (IF 15.3) Pub Date : 2024-01-31 Megan L. Sulciner, Charles N. Serhan, Molly M. Gilligan, Dayna K. Mudge, Jaimie Chang, Allison Gartung, Kristen A. Lehner, Diane R. Bielenberg, Birgitta Schmidt, Jesmond Dalli, Emily R. Greene, Yael Gus-Brautbar, Julia Piwowarski, Tadanori Mammoto, David Zurakowski, Mauro Perretti, Vikas P. Sukhatme, Arja Kaipainen, Mark W. Kieran, Sui Huang, Dipak Panigrahy
Vol. 215, No. 1 | https://doi.org/10.1084/jem.20170681 | November 30, 2017
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Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2 J. Exp. Med. (IF 15.3) Pub Date : 2024-01-30 Chen Yu, Eleonora M. Lad, Rose Mathew, Nobuhiko Shiraki, Sejiro Littleton, Yun Chen, Jinchao Hou, Kai Schlepckow, Simone Degan, Lindsey Chew, Joshua Amason, Joan Kalnitsky, Catherine Bowes Rickman, Alan D. Proia, Marco Colonna, Christian Haass, Daniel R. Saban
Outer retinal degenerations, including age-related macular degeneration (AMD), are characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. In these blinding diseases, macrophages accumulate at atrophic sites, but their ontogeny and niche specialization remain poorly understood, especially in humans. We uncovered a unique profile of microglia, marked by galectin-3 upregulation,
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Unraveling the Tcrb interactome J. Exp. Med. (IF 15.3) Pub Date : 2024-01-29 Noah Ollikainen, Ranjan Sen
In this issue of JEM, Allyn et al. (https://doi.org/10.1084/jem.20230985) provide mechanistic insights into the nuclear organization of the Tcrb locus that permits long-range genomic rearrangements.
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Dural mural cells paint an anti-inflammatory picture J. Exp. Med. (IF 15.3) Pub Date : 2024-01-25 Nicole C. Lummis, Benjamin D. Gastfriend, Richard Daneman
Mural cells directly contact macrophages in the dural layer of the meninges to suppress pro-inflammatory phenotypes, including antigen presentation and lymphocyte differentiation. These mechanisms represent new targets for modulating CNS immune surveillance and pathological inflammation (Min et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20230326).
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Correction: Landscape of mast cell populations across organs in mice and humans J. Exp. Med. (IF 15.3) Pub Date : 2024-01-24 Marie Tauber, Lilian Basso, Jeremy Martin, Luciana Bostan, Marlene Magalhaes Pinto, Guilhem R. Thierry, Raïssa Houmadi, Nadine Serhan, Alexia Loste, Camille Blériot, Jasper B.J. Kamphuis, Mirjana Grujic, Lena Kjellén, Gunnar Pejler, Carle Paul, Xinzhong Dong, Stephen J. Galli, Laurent L. Reber, Florent Ginhoux, Marc Bajenoff, Rebecca Gentek, Nicolas Gaudenzio
Vol. 220, No. 10 | https://doi.org/10.1084/jem.20230570 | July 18, 2023
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Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway J. Exp. Med. (IF 15.3) Pub Date : 2024-01-10 Vincent Peng, Tihana Trsan, Raki Sudan, Bishan Bhattarai, Victor S. Cortez, Martina Molgora, Jean Vacher, Marco Colonna
Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase
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Yukiko Gotoh: I am fascinated by the beauty of science J. Exp. Med. (IF 15.3) Pub Date : 2024-01-10 Lucie Van Emmenis
Yukiko Gotoh is a professor in the Department of Pharmaceutical Sciences at the University of Tokyo. Her lab studies the mechanisms that underlie the regulation of neural stem/progenitor cell fate during brain development and homeostasis. They are particularly interested in the underlying genetic and epigenetic mechanisms that control cell fate and neuronal maturation, as well as the relevance of neural
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Mural cells interact with macrophages in the dura mater to regulate CNS immune surveillance J. Exp. Med. (IF 15.3) Pub Date : 2024-01-09 Hyunjung Min, Shane M. O’Neil, Li Xu, E. Ashley Moseman, Joanne Kurtzberg, Anthony J. Filiano
The central nervous system (CNS) tightly regulates access of circulating immune cells. Immunosurveillance is therefore managed in the meninges at the borders of the CNS. Here, we demonstrated that mural cells, which include pericytes and smooth muscle cells, decreased coverage around blood vessels in the dura, the outermost layer of the meninges, and upregulated gene pathways involved in leukocyte
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Eomes-dependent mitochondrial regulation promotes survival of pathogenic CD4+ T cells during inflammation J. Exp. Med. (IF 15.3) Pub Date : 2024-01-08 Emeline Joulia, Michaël F. Michieletto, Arantxa Agesta, Cindy Peillex, Virginie Girault, Anne-Louise Le Dorze, Romain Peroceschi, Florence Bucciarelli, Marion Szelechowski, Adeline Chaubet, Nawad Hakim, Rémi Marrocco, Emeline Lhuillier, Manuel Lebeurrier, Rafael J. Argüello, Abdelhadi Saoudi, Hicham El Costa, Veronique Adoue, Thierry Walzer, Jean-Emmanuel Sarry, Anne S. Dejean
The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells
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Locus folding mechanisms determine modes of antigen receptor gene assembly J. Exp. Med. (IF 15.3) Pub Date : 2024-01-08 Brittney M. Allyn, Katharina E. Hayer, Clement Oyeniran, Vincent Nganga, Kyutae Lee, Bikash Mishra, Ahmet Sacan, Eugene M. Oltz, Craig H. Bassing
The dynamic folding of genomes regulates numerous biological processes, including antigen receptor (AgR) gene assembly. We show that, unlike other AgR loci, homotypic chromatin interactions and bidirectional chromosome looping both contribute to structuring Tcrb for efficient long-range V(D)J recombination. Inactivation of the CTCF binding element (CBE) or promoter at the most 5′Vβ segment (Trbv1)
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IL-23 to see: Gut DCs shine bright in inductive sites J. Exp. Med. (IF 15.3) Pub Date : 2024-01-05 Isabel Ulmert, Katharina Lahl
The cytokine IL-23 plays important roles in intestinal barrier protection and integrity, but is also linked to chronic inflammation. In this issue of JEM, Ohara et al. (https://doi.org/10.1084/jem.20230923) provide clarity on the much-debated question of which cells produce IL-23.
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Notch2 with retinoic acid license IL-23 expression by intestinal EpCAM+ DCIR2+ cDC2s in mice J. Exp. Med. (IF 15.3) Pub Date : 2024-01-05 Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Yoonha Lee, Hiroki Mukoyama, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota
Despite the importance of IL-23 in mucosal host defense and disease pathogenesis, the mechanisms regulating the development of IL-23–producing mononuclear phagocytes remain poorly understood. Here, we employed an Il23aVenus reporter strain to investigate the developmental identity and functional regulation of IL-23–producing cells. We showed that flagellin stimulation or Citrobacter rodentium infection
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Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children J. Exp. Med. (IF 15.3) Pub Date : 2024-01-04 Paul Bastard, Adrian Gervais, Maki Taniguchi, Liisa Saare, Karita Särekannu, Tom Le Voyer, Quentin Philippot, Jérémie Rosain, Lucy Bizien, Takaki Asano, Marina Garcia-Prat, Alba Parra-Martínez, Mélanie Migaud, Miyuki Tsumura, Francesca Conti, Alexandre Belot, Jacques G. Rivière, Tomohiro Morio, Junko Tanaka, Etienne Javouhey, Filomeen Haerynck, Sotirija Duvlis, Tayfun Ozcelik, Sevgi Keles, Yacine Tandjaoui-Lambiotte
We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing
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CD163+ macrophages monitor enhanced permeability at the blood–dorsal root ganglion barrier J. Exp. Med. (IF 15.3) Pub Date : 2023-12-20 Harald Lund, Matthew A. Hunt, Zerina Kurtović, Katalin Sandor, Paul B. Kägy, Noah Fereydouni, Anais Julien, Christian Göritz, Elisa Vazquez-Liebanas, Maarja Andaloussi Mäe, Alexandra Jurczak, Jinming Han, Keying Zhu, Robert A. Harris, Jon Lampa, Jonas Heilskov Graversen, Anders Etzerodt, Lisbet Haglund, Tony L. Yaksh, Camilla I. Svensson
In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural
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A conserved transcriptional program for MAIT cells across mammalian evolution J. Exp. Med. (IF 15.3) Pub Date : 2023-12-20 Hélène Bugaut, Yara El Morr, Martin Mestdagh, Aurélie Darbois, Rafael A. Paiva, Marion Salou, Laetitia Perrin, Mariela Fürstenheim, Anastasia du Halgouet, Linda Bilonda-Mutala, Anne-Laure Le Gac, Manon Arnaud, Ahmed El Marjou, Coralie Guerin, Atitheb Chaiyasitdhi, Julie Piquet, David M. Smadja, Agata Cieslak, Bernhard Ryffel, Valdone Maciulyte, James M.A. Turner, Karine Bernardeau, Xavier Montagutelli
Mucosal-associated invariant T (MAIT) cells harbor evolutionarily conserved TCRs, suggesting important functions. As human and mouse MAIT functional programs appear distinct, the evolutionarily conserved MAIT functional features remain unidentified. Using species-specific tetramers coupled to single-cell RNA sequencing, we characterized MAIT cell development in six species spanning 110 million years
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Nucleotide modifications enable rational design of TLR7-selective ligands by blocking RNase cleavage J. Exp. Med. (IF 15.3) Pub Date : 2023-12-14 Ann-Jay Tong, Rebecca Leylek, Anna-Maria Herzner, Diamanda Rigas, Sara Wichner, Craig Blanchette, Siri Tahtinen, Christopher C. Kemball, Ira Mellman, Benjamin Haley, Emily C. Freund, Lélia Delamarre
Toll-like receptors 7 (TLR7) and 8 (TLR8) each sense single-stranded RNA (ssRNA), but their activation results in different immune activation profiles. Attempts to selectively target either TLR7 or TLR8 have been hindered by their high degree of homology. However, recent studies revealed that TLR7 and TLR8 bind different ligands resulting from the processing of ssRNA by endolysosomal RNases. We demonstrate
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Plasticity of intragraft alloreactive T cell clones in human gut correlates with transplant outcomes J. Exp. Med. (IF 15.3) Pub Date : 2023-12-13 Jianing Fu, Zicheng Wang, Mercedes Martinez, Aleksandar Obradovic, Wenyu Jiao, Kristjana Frangaj, Rebecca Jones, Xinzheng V. Guo, Ya Zhang, Wan-I Kuo, Huaibin M. Ko, Alina Iuga, Constanza Bay Muntnich, Adriana Prada Rey, Kortney Rogers, Julien Zuber, Wenji Ma, Michelle Miron, Donna L. Farber, Joshua Weiner, Tomoaki Kato, Yufeng Shen, Megan Sykes
The site of transition between tissue-resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity, and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single-cell level after human intestinal transplantation. Host-versus-graft (HvG)–reactive T cells were mainly distributed to TRM, effector T (Teff)/TRM
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Beyond antiviral: Interferon induced by bacteria maintains tolerance in the gut J. Exp. Med. (IF 15.3) Pub Date : 2023-12-13 Yi Yang, Ken Cadwell
Type I interferons are best known for their antiviral role. Here, Ayala et al. (https://doi.org/10.1084/jem.20230063) reveal that commensal bacteria elicit tonic type I interferons to prime dendritic cells and induce regulatory T cells that maintain a tolerogenic intestinal milieu.
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Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice J. Exp. Med. (IF 15.3) Pub Date : 2023-12-12 Adriana Vasquez Ayala, Chia-Yun Hsu, Renee E. Oles, Kazuhiko Matsuo, Luke R. Loomis, Ekaterina Buzun, Marvic Carrillo Terrazas, Romana R. Gerner, Hsueh-Han Lu, Sohee Kim, Ziyue Zhang, Jong Hwee Park, Paul Rivaud, Matt Thomson, Li-Fan Lu, Booki Min, Hiutung Chu
Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral
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Mechanisms and functions of intestinal vascular specialization J. Exp. Med. (IF 15.3) Pub Date : 2023-12-05 Jeremiah Bernier-Latmani, Alejandra González-Loyola, Tatiana V. Petrova
The intestinal vasculature has been studied for the last 100 years, and its essential role in absorbing and distributing ingested nutrients is well known. Recently, fascinating new insights into the organization, molecular mechanisms, and functions of intestinal vessels have emerged. These include maintenance of intestinal epithelial cell function, coping with microbiota-induced inflammatory pressure
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A novel memory-like Tfh cell subset is precursor to effector Tfh cells in recall immune responses J. Exp. Med. (IF 15.3) Pub Date : 2023-12-04 Han Feng, Zixuan Zhao, Xiaohong Zhao, Xue Bai, Weiwei Fu, Liangtao Zheng, Boxi Kang, Xiaohu Wang, Zemin Zhang, Chen Dong
T follicular helper (Tfh) cells, essential for germinal center reactions, are not identical, with different phenotypes reported. Whether, when, and how they generate memory cells is still poorly understood. Here, through single-cell RNA-sequencing analysis of CXCR5+Bcl6+ Tfh cells generated under different conditions, we discovered, in addition to PD-1hi effector Tfh cells, a CD62L+PD1low subpopulation
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Protective fibroblastic niches in secondary lymphoid organs J. Exp. Med. (IF 15.3) Pub Date : 2023-12-01 Angelina De Martin, Yves Stanossek, Natalia Barbara Pikor, Burkhard Ludewig
Fibroblastic reticular cells (FRCs) are specialized fibroblasts of secondary lymphoid organs that provide the structural foundation of the tissue. Moreover, FRCs guide immune cells to dedicated microenvironmental niches where they provide lymphocytes and myeloid cells with homeostatic growth and differentiation factors. Inflammatory processes, including infection with pathogens, induce rapid morphological
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Scaling up robust immunopeptidomics technologies for a global T cell surveillance digital network J. Exp. Med. (IF 15.3) Pub Date : 2023-11-30 Saketh Kapoor, Loïze Maréchal, Isabelle Sirois, Étienne Caron
The human immunopeptidome plays a central role in disease susceptibility and resistance. In our opinion, the development of immunopeptidomics and other peptide sequencing technologies should be prioritized during the next decade, particularly within the framework of the Human Immunopeptidome Project initiative. In this context, we present bold ideas, fresh arguments, and call upon industrial partners
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Expression of Concern: ACKR4 restrains antitumor immunity by regulating CCL21 J. Exp. Med. (IF 15.3) Pub Date : 2023-11-28
Based on external and internal investigations conducted by QIMR Berghofer Medical Research Institute in response to concerns around data fabrication and falsification by Professor Mark Smyth, JEM is issuing this Expression of Concern regarding Figures 4 A, 4 I, 5 A, 5 B, S2 D, and S2 F from Whyte et al. (2020) J. Exp. Med. 217 (6): e20190634.
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Women in STEM becoming independent: Science thrives on diverse perspectives J. Exp. Med. (IF 15.3) Pub Date : 2023-11-17 Lucie Van Emmenis
In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher. As well as being able to celebrate the positives of becoming an independent researcher, we would also like to use this platform to discuss the unique challenges they face as women scientists in their respective scientific
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A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation J. Exp. Med. (IF 15.3) Pub Date : 2023-11-14 Victor G. Lui, Manfred Hoenig, Berenice Cabrera-Martinez, Ryan M. Baxter, Josselyn E. Garcia-Perez, Olivia Bailey, Atanu Acharya, Karl Lundquist, Jesusa Capera, Paul Matusewicz, Frederike A. Hartl, Marco D’Abramo, Josephine Alba, Eva-Maria Jacobsen, Doris Niewolik, Myriam Lorenz, Ulrich Pannicke, Ansgar S. Schulz, Klaus-Michael Debatin, Wolfgang W. Schamel, Susana Minguet, James C. Gumbart, Michael
Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)–mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients’ T cells show residual TCR signal
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Role of affinity in plasma cell development in the germinal center light zone J. Exp. Med. (IF 15.3) Pub Date : 2023-11-08 Mohamed A. ElTanbouly, Victor Ramos, Andrew J. MacLean, Spencer T. Chen, Maximilian Loewe, Sandra Steinbach, Tarek Ben Tanfous, Brianna Johnson, Melissa Cipolla, Anna Gazumyan, Thiago Y. Oliveira, Michel C. Nussenzweig
Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined
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ARL6IP1 gene delivery reduces neuroinflammation and neurodegenerative pathology in hereditary spastic paraplegia model J. Exp. Med. (IF 15.3) Pub Date : 2023-11-07 Jung Hwa Lim, Hyun Mi Kang, Dae Hun Kim, Bohyeon Jeong, Da Yong Lee, Jae-Ran Lee, Jeong Yeob Baek, Hyun-Soo Cho, Mi-Young Son, Dae Soo Kim, Nam-Soon Kim, Cho-Rok Jung
ARL6IP1 is implicated in hereditary spastic paraplegia (HSP), but the specific pathogenic mechanism leading to neurodegeneration has not been elucidated. Here, we clarified the molecular mechanism of ARL6IP1 in HSP using in vitro and in vivo models. The Arl6ip1 knockout (KO) mouse model was generated to represent the clinically involved frameshift mutations and mimicked the HSP phenotypes. Notably
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Stem cell–like reprogramming is required for leukemia-initiating activity in B-ALL J. Exp. Med. (IF 15.3) Pub Date : 2023-11-06 Vincent Fregona, Manon Bayet, Mathieu Bouttier, Laetitia Largeaud, Camille Hamelle, Laura A. Jamrog, Naïs Prade, Stéphanie Lagarde, Sylvie Hebrard, Isabelle Luquet, Véronique Mansat-De Mas, Marie Nolla, Marlène Pasquet, Christine Didier, Ahmed Amine Khamlichi, Cyril Broccardo, Éric Delabesse, Stéphane J.C. Mancini, Bastien Gerby
B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell–like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation
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Early innate role for CD8αα+ cells in tuberculosis J. Exp. Med. (IF 15.3) Pub Date : 2023-11-02 Daniel L. Barber
Cell types that mediate early control of Mycobacterium tuberculosis (Mtb) infection are not well understood. Winchell and Nyquist et al. (https://doi.org/10.1084/jem.20230707) show that CD8αα+ lymphocytes have a major role in the innate suppression of Mtb growth in the lungs of macaques.
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First-in-human therapy with Treg produced from thymic tissue (thyTreg) in a heart transplant infant J. Exp. Med. (IF 15.3) Pub Date : 2023-10-31 Esther Bernaldo-de-Quirós, Manuela Camino, Marta Martínez-Bonet, Juan Miguel Gil-Jaurena, Nuria Gil, Diana Hernández-Flórez, Maria Eugenia Fernández-Santos, Laura Butragueño, I. Esmé Dijke, Megan K. Levings, Lori J. West, Marjorie Pion, Rafael Correa-Rocha
Due to their suppressive capacity, regulatory T cells (Tregs) have attracted growing interest as an adoptive cellular therapy for the prevention of allograft rejection, but limited Treg recovery and lower quality of adult-derived Tregs could represent an obstacle to success. To address this challenge, we developed a new approach that provides large quantities of Tregs with high purity and excellent
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STIM-mediated calcium influx regulates maintenance and selection of germinal center B cells J. Exp. Med. (IF 15.3) Pub Date : 2023-10-30 Yutaro Yada, Masanori Matsumoto, Takeshi Inoue, Akemi Baba, Ryota Higuchi, Chie Kawai, Masashi Yanagisawa, Daisuke Kitamura, Shouichi Ohga, Tomohiro Kurosaki, Yoshihiro Baba
Positive selection of high-affinity germinal center (GC) B cells is driven by antigen internalization through their B cell receptor (BCR) and presentation to follicular helper T cells. However, the requirements of BCR signaling in GC B cells remain poorly understood. Store-operated Ca2+ entry, mediated by stromal interacting molecule 1 (STIM1) and STIM2, is the main Ca2+ influx pathway triggered by
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Segmented filamentous bacteria–induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover J. Exp. Med. (IF 15.3) Pub Date : 2023-10-30 Tomáš Brabec, Martin Schwarzer, Katarína Kováčová, Martina Dobešová, Dagmar Schierová, Jiří Březina, Iva Pacáková, Dagmar Šrůtková, Osher Ben-Nun, Yael Goldfarb, Iva Šplíchalová, Michal Kolář, Jakub Abramson, Dominik Filipp, Jan Dobeš
Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII–mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that
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BATF represses BIM to sustain tolerant T cells in the periphery J. Exp. Med. (IF 15.3) Pub Date : 2023-10-20 Philip J. Titcombe, Milagros Silva Morales, Na Zhang, Daniel L. Mueller
T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed
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Host factor TIMP1 sustains long-lasting myeloid-biased hematopoiesis after severe infection J. Exp. Med. (IF 15.3) Pub Date : 2023-10-18 Tengfei Song, Yonghong Yao, Julien Papoin, Barbara Sherry, Betty Diamond, Hua Gu, Lionel Blanc, Yong-Rui Zou
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection
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CD8+ lymphocytes are critical for early control of tuberculosis in macaques J. Exp. Med. (IF 15.3) Pub Date : 2023-10-16 Caylin G. Winchell, Sarah K. Nyquist, Michael C. Chao, Pauline Maiello, Amy J. Myers, Forrest Hopkins, Michael Chase, Hannah P. Gideon, Kush V. Patel, Joshua D. Bromley, Andrew W. Simonson, Roisin Floyd-O’Sullivan, Marc Wadsworth, Jacob M. Rosenberg, Rockib Uddin, Travis Hughes, Ryan J. Kelly, Josephine Griffo, Jaime Tomko, Edwin Klein, Bonnie Berger, Charles A. Scanga, Joshua Mattila, Sarah M. Fortune
The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss of all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden. Analysis of barcoded Mtb from
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The CD4+ T cell repertoire specific for citrullinated peptides shows evidence of immune tolerance J. Exp. Med. (IF 15.3) Pub Date : 2023-10-13 Matthew K. McElwee, Thamotharampillai Dileepan, Shawn A. Mahmud, Marc K. Jenkins
Rheumatoid arthritis occurs most often in people who express HLA-DR molecules containing a five aa “shared epitope” in the β chain. These MHCII molecules preferentially bind citrullinated peptides formed by posttranslational modification of arginine. Citrullinated peptide:HLA-DR complexes may act as arthritis-initiating neo-antigens for CD4+ T cells. Here, we used fluorophore-conjugated HLA-DR tetramers
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Tregs tame skin bacteria and IFN-γ–associated pathology J. Exp. Med. (IF 15.3) Pub Date : 2023-10-10 Michail S. Lionakis
Mibrobial dysbiosis worsens cutaneous leishmaniasis. In this issue of JEM, Singh et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230558) show that Rorγt+ regulatory T cells suppress pathogenic IFN-γ responses to control Staphylococcus aureus growth and limit S. aureus– and Leishmamia braziliensis–associated immunopathology at the skin barrier.
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B cell–intrinsic Myd88 regulates disease progression in murine lupus J. Exp. Med. (IF 15.3) Pub Date : 2023-10-03 Jeremy S. Tilstra, Minjung Kim, Rachael A. Gordon, Claire Leibler, Haylee A. Cosgrove, Sheldon Bastacky, Kevin M. Nickerson, Mark J. Shlomchik
Nucleic acid–specific Toll-like receptors (TLRs) have been implicated in promoting disease pathogenesis in systemic lupus erythematosus (SLE). Whether such TLRs mediate disease onset, progression, or both remains undefined; yet the answer to this question has important therapeutic implications. MyD88 is an essential adaptor that acts downstream of IL-1 family receptors and most TLRs. Both global and
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Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites J. Exp. Med. (IF 15.3) Pub Date : 2023-09-29 Nikhat Shaikh, Alex Waterhölter, Ann-Christin Gnirck, Martina Becker, Virginia Adamiak, Lena Henneken, Malte Wunderlich, Wiebke Hartmann, Lara Linnemann, Tobias B. Huber, Christian F. Krebs, Ulf Panzer, Richard M. Locksley, Christoph Wilhelm, Minka Breloer, Jan-Eric Turner
Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed
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Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy J. Exp. Med. (IF 15.3) Pub Date : 2023-09-29 Romina Marone, Emmanuelle Landmann, Anna Devaux, Rosalba Lepore, Denis Seyres, Jessica Zuin, Thomas Burgold, Corinne Engdahl, Giuseppina Capoferri, Alessandro Dell’Aglio, Clément Larrue, Federico Simonetta, Julia Rositzka, Manuel Rhiel, Geoffroy Andrieux, Danielle N. Gallagher, Markus S. Schröder, Amélie Wiederkehr, Alessandro Sinopoli, Valentin Do Sacramento, Anna Haydn, Laura Garcia-Prat, Christopher
Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody–drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3
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TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance J. Exp. Med. (IF 15.3) Pub Date : 2023-09-29 Elif Çakan, Marie Dominique Ah Kioon, Yolanda Garcia-Carmona, Salomé Glauzy, David Oliver, Natsuko Yamakawa, Andrea Vega Loza, Yong Du, Jean-Nicolas Schickel, Joshua M. Boeckers, Chao Yang, Alessia Baldo, Lionel B. Ivashkiv, Ryan M. Young, Louis M. Staudt, Krishna L. Moody, Kerstin Nündel, Ann Marshak-Rothstein, Caspar I. van der Made, Alexander Hoischen, Anthony Hayward, Marzia Rossato, Timothy R
Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis
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A twist in the tail: Of T cell subsets and disease J. Exp. Med. (IF 15.3) Pub Date : 2023-09-27 Shiv Pillai
In this issue of JEM, the work of Joachim et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20231028) on knockin mice with a specific tail mutation in LAT provides valuable insights about cytotoxic CD4+ T cells and human inflammatory diseases.
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Maternal diet during early gestation influences postnatal taste activity–dependent pruning by microglia J. Exp. Med. (IF 15.3) Pub Date : 2023-09-21 Chengsan Sun, Shuqiu Zheng, Justin S.A. Perry, Geoffrey T. Norris, Mei Cheng, Fanzhen Kong, Rolf Skyberg, Jianhua Cang, Alev Erisir, Jonathan Kipnis, David L. Hill
A key process in central sensory circuit development involves activity-dependent pruning of exuberant terminals. Here, we studied gustatory terminal field maturation in the postnatal mouse nucleus of the solitary tract (NST) during normal development and in mice where their mothers were fed a low NaCl diet for a limited period soon after conception. Pruning of terminal fields of gustatory nerves in
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Women in STEM becoming independent: Great mentors make all the difference J. Exp. Med. (IF 15.3) Pub Date : 2023-09-20 Lucie Van Emmenis
In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher. As well as being able to celebrate the positives of becoming an independent researcher, we would also like to use this platform to discuss the unique challenges they face as women scientists in their respective scientific
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Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells J. Exp. Med. (IF 15.3) Pub Date : 2023-09-20 Farhad Farjood, Justine D. Manos, Yue Wang, Anne L. Williams, Cuiping Zhao, Susan Borden, Nazia Alam, Glen Prusky, Sally Temple, Jeffrey H. Stern, Nathan C. Boles
Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell–derived (RPESC-RPE) cell
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Essential role of the Pax5 C-terminal domain in controlling B cell commitment and development J. Exp. Med. (IF 15.3) Pub Date : 2023-09-19 Sarah Gruenbacher, Markus Jaritz, Louisa Hill, Markus Schäfer, Meinrad Busslinger
The B cell regulator Pax5 consists of multiple domains whose function we analyzed in vivo by deletion in Pax5. While B lymphopoiesis was minimally affected in mice with homozygous deletion of the octapeptide or partial homeodomain, both sequences were required for optimal B cell development. Deletion of the C-terminal regulatory domain 1 (CRD1) interfered with B cell development, while elimination
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The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling J. Exp. Med. (IF 15.3) Pub Date : 2023-09-13 Lisa Sandner, Marlis Alteneder, Ramona Rica, Barbara Woller, Eleonora Sala, Tobias Frey, Anela Tosevska, Ci Zhu, Moritz Madern, Matarr Khan, Pol Hoffmann, Alexandra Schebesta, Ichiro Taniuchi, Michael Bonelli, Klaus Schmetterer, Matteo Iannacone, Mirela Kuka, Wilfried Ellmeier, Shinya Sakaguchi, Ruth Herbst, Nicole Boucheron
T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice,
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Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis J. Exp. Med. (IF 15.3) Pub Date : 2023-08-29 Kim Samirah Robinson, Gee Ann Toh, Muhammad Jasrie Firdaus, Khek Chian Tham, Pritisha Rozario, Chrissie K. Lim, Ying Xiu Toh, Zhi Heng Lau, Sophie Charlotte Binder, Jacob Mayer, Carine Bonnard, Florian I. Schmidt, John E.A. Common, Franklin L. Zhong
The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors. One such toxin, diphtheria toxin (DT), the causative agent for human diphtheria, triggers
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MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer J. Exp. Med. (IF 15.3) Pub Date : 2023-08-29 Jinhyuk Bhin, Julia Yemelyanenko, Xue Chao, Sjoerd Klarenbeek, Mark Opdam, Yuval Malka, Liesbeth Hoekman, Dinja Kruger, Onno Bleijerveld, Chiara S. Brambillasca, Justin Sprengers, Bjørn Siteur, Stefano Annunziato, Matthijs J. van Haren, Nathaniel I. Martin, Marieke van de Ven, Dennis Peters, Reuven Agami, Sabine C. Linn, Epie Boven, Maarten Altelaar, Jos Jonkers, Daniel Zingg, Lodewyk F.A. Wessels
Targeting the PI3K–AKT–mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K–AKT–mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent