journal
https://read.qxmd.com/read/38607370/self-regulating-car-t-cells-modulate-cytokine-release-syndrome-in-adoptive-t-cell-therapy
#1
JOURNAL ARTICLE
Meng-Yin Lin, Eunwoo Nam, Ryan M Shih, Amanda Shafer, Amber Bouren, Melanie Ayala Ceja, Caitlin Harris, Mobina Khericha, Kenny H Vo, Minsoo Kim, Chi-Hong Tseng, Yvonne Y Chen
Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration...
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38597954/interstitial-macrophages-are-a-focus-of-viral-takeover-and-inflammation-in-covid-19-initiation-in-human-lung
#2
JOURNAL ARTICLE
Timothy Ting-Hsuan Wu, Kyle J Travaglini, Arjun Rustagi, Duo Xu, Yue Zhang, Leonid Andronov, SoRi Jang, Astrid Gillich, Roozbeh Dehghannasiri, Giovanny J Martínez-Colón, Aimee Beck, Daniel Dan Liu, Aaron J Wilk, Maurizio Morri, Winston L Trope, Rob Bierman, Irving L Weissman, Joseph B Shrager, Stephen R Quake, Christin S Kuo, Julia Salzman, W E Moerner, Peter S Kim, Catherine A Blish, Mark A Krasnow
Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture...
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38597953/sounding-the-alarm-in-the-lung-with-tl1a
#3
JOURNAL ARTICLE
Silvia Pires, Randy S Longman
Environmental airborne antigens are central to the development of allergic asthma, but the cellular processes that trigger disease remain incompletely understood. In this report, Schmitt et al. (https://doi.org/10.1084/jem.20231236) identify TNF-like protein 1A (TL1A) as an epithelial alarmin constitutively expressed by a subset of lung epithelial cells, which is released in response to airborne microbial challenge and synergizes with IL-33 to drive allergic disease.
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38597952/tl1a-is-an-epithelial-alarmin-that-cooperates-with-il-33-for-initiation-of-allergic-airway-inflammation
#4
JOURNAL ARTICLE
Pauline Schmitt, Anais Duval, Mylène Camus, Emma Lefrançais, Stéphane Roga, Cécile Dedieu, Nathalie Ortega, Elisabeth Bellard, Emilie Mirey, Emmanuelle Mouton-Barbosa, Odile Burlet-Schiltz, Anne Gonzalez-de-Peredo, Corinne Cayrol, Jean-Philippe Girard
Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low "ILC9" phenotype and produce prodigious amounts of IL-9...
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38563820/individuals-with-jak1-variants-are-affected-by-syndromic-features-encompassing-autoimmunity-atopy-colitis-and-dermatitis
#5
JOURNAL ARTICLE
Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic
Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1...
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38563819/nf-%C3%AE%C2%BAb-subunits-rela-and-c-rel-selectively-control-cd4-t-cell-function-in-multiple-sclerosis-and-cancer
#6
JOURNAL ARTICLE
Guilhem Lalle, Raphaëlle Lautraite, Khaled Bouherrou, Maud Plaschka, Aurora Pignata, Allison Voisin, Julie Twardowski, Marlène Perrin-Niquet, Pierre Stéphan, Sarah Durget, Laurie Tonon, Maude Ardin, Cyril Degletagne, Alain Viari, Laurence Belgarbi Dutron, Nathalie Davoust, Thomas S Postler, Jingyao Zhao, Christophe Caux, Julie Caramel, Stéphane Dalle, Philippe A Cassier, Ulf Klein, Marc Schmidt-Supprian, Roland Liblau, Sankar Ghosh, Yenkel Grinberg-Bleyer
The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro...
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38563818/divergent-local-and-systemic-antitumor-response-in-primary-uveal-melanomas
#7
JOURNAL ARTICLE
Francesca Lucibello, Ana I Lalanne, Anne-Laure Le Gac, Abdoulaye Soumare, Setareh Aflaki, Joana Cyrta, Lea Dubreuil, Martin Mestdagh, Marion Salou, Alexandre Houy, Christina Ekwegbara, Camille Jamet, Sophie Gardrat, Anais Le Ven, Karine Bernardeau, Nathalie Cassoux, Alexandre Matet, Denis Malaise, Gaelle Pierron, Sophie Piperno-Neumann, Marc-Henri Stern, Manuel Rodrigues, Olivier Lantz
Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors...
June 3, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38607420/immune-drivers-of-physiological-and-pathological-pain
#8
JOURNAL ARTICLE
Aakanksha Jain, Sara Hakim, Clifford J Woolf
Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38597926/hormonal-basis-of-brain-fog-in-cancer-treatment
#9
JOURNAL ARTICLE
Yuan Pan, Jian Hu
The cognitive side effects of cancer treatment are common, but no targeted therapy exists yet to treat or prevent such neurological sequelae. We explore the role of hormones as mediators between cancer therapy and cognitive impairment, discussing potential future directions.
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38587494/cd19-directed-t-cell-engaging-antibodies-for-the-treatment-of-autoimmune-disease
#10
JOURNAL ARTICLE
Jennifer S Michaelson, Patrick A Baeuerle
Jennifer S. Michaelson, Chief Scientific Officer at Cullinan Oncology, and Patrick A. Baeuerle, scientific advisor to Cullinan Oncology and honorary professor in immunology at Ludwig Maximilians University Munich, discuss the use of CD19-specific T cell-engaging antibody therapies (TCEs) as therapeutics for autoimmune diseases.
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38557723/helper-t-cell-immunity-in-humans-with-inherited-cd4-deficiency
#11
JOURNAL ARTICLE
Antoine Guérin, Marcela Moncada-Vélez, Katherine Jackson, Masato Ogishi, Jérémie Rosain, Mathieu Mancini, David Langlais, Andrea Nunez, Samantha Webster, Jesse Goyette, Taushif Khan, Nico Marr, Danielle T Avery, Geetha Rao, Tim Waterboer, Birgitta Michels, Esmeralda Neves, Cátia Iracema Morais, Jonathan London, Stéphanie Mestrallet, Pierre Quartier Dit Maire, Bénédicte Neven, Franck Rapaport, Yoann Seeleuthner, Atar Lev, Amos J Simon, Jorge Montoya, Ortal Barel, Julio Gómez-Rodríguez, Julio C Orrego, Anne-Sophie L'Honneur, Camille Soudée, Jessica Rojas, Alejandra C Velez, Irini Sereti, Benjamin Terrier, Nancy Marin, Luis F García, Laurent Abel, Stéphanie Boisson-Dupuis, Joel Reis, Antonio Marinho, Andrea Lisco, Emilia Faria, Christopher C Goodnow, Julia Vasconcelos, Vivien Béziat, Cindy S Ma, Raz Somech, Jean-Laurent Casanova, Jacinta Bustamante, Jose Luis Franco, Stuart G Tangye
CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38557722/neutrophil-il-26-fuels-autoinflammation
#12
JOURNAL ARTICLE
Krisztina Futosi, Attila Mócsai
Pustular psoriasis is an inflammatory skin disease with features of neutrophil-mediated sterile autoinflammation. In this issue of JEM, Baldo et al. (https://doi.org/10.1084/jem.20231464) show that this autoinflammation is driven by a vicious cycle through neutrophil-derived IL-26.
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38536100/cracking-the-nlrp3-code-pioneering-precision-medicine-for-inflammation
#13
JOURNAL ARTICLE
Alexander N R Weber, Maria Mateo Tortola, Jasmin B Kuemmerle-Deschner
Precisely diagnosing and effectively treating cryopyrin-associated periodic syndrome (CAPS), an inflammatory condition linked to gain-of-function NLRP3 inflammasome mutations, poses challenges. A novel classification approach may help inform therapeutic decisions and offer valuable insights into broader inflammatory conditions (Cosson et al. J. Exp. Med. 2024. https://doi.org/10.1084/jem.20231200).
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38530241/functional-diversity-of-nlrp3-gain-of-function-mutants-associated-with-caps-autoinflammation
#14
JOURNAL ARTICLE
Camille Cosson, Romane Riou, Danish Patoli, Tingting Niu, Amaury Rey, Marine Groslambert, Charlotte De Rosny, Elodie Chatre, Omran Allatif, Thomas Henry, Fabienne Venet, Florian Milhavet, Guilaine Boursier, Alexandre Belot, Yvan Jamilloux, Etienne Merlin, Agnès Duquesne, Gilles Grateau, Léa Savey, Alexandre Thibault Jacques Maria, Anne Pagnier, Solène Poutrel, Olivier Lambotte, Coralie Mallebranche, Samuel Ardois, Olivier Richer, Irène Lemelle, Frédéric Rieux-Laucat, Brigitte Bader-Meunier, Zahir Amoura, Isabelle Melki, Laurence Cuisset, Isabelle Touitou, Matthias Geyer, Sophie Georgin-Lavialle, Bénédicte F Py
NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38530240/induction-of-immortal-like-and-functional-car-t-cells-by-defined-factors
#15
JOURNAL ARTICLE
Lixia Wang, Gang Jin, Qiuping Zhou, Yanyan Liu, Xiaocui Zhao, Zhuoyang Li, Na Yin, Min Peng
Long-term antitumor efficacy of chimeric antigen receptor (CAR) T cells depends on their functional persistence in vivo. T cells with stem-like properties show better persistence, but factors conferring bona fide stemness to T cells remain to be determined. Here, we demonstrate the induction of CAR T cells into an immortal-like and functional state, termed TIF. The induction of CARTIF cells depends on the repression of two factors, BCOR and ZC3H12A, and requires antigen or CAR tonic signaling. Reprogrammed CARTIF cells possess almost infinite stemness, similar to induced pluripotent stem cells while retaining the functionality of mature T cells, resulting in superior antitumor effects...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38530239/piezo1-channels-restrain-ilc2s-and-regulate-the-development-of-airway-hyperreactivity
#16
JOURNAL ARTICLE
Benjamin P Hurrell, Stephen Shen, Xin Li, Yoshihiro Sakano, Mohammad Hossein Kazemi, Christine Quach, Pedram Shafiei-Jahani, Kei Sakano, Homayon Ghiasi, Omid Akbari
Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here, we report that Piezo1 channels repress group 2 innate lymphoid cell (ILC2)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we found that Piezo1 engagement reduces ILC2 oxidative metabolism...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38517332/a-tbk1-variant-causes-autophagolysosomal-and-motoneuron-pathology-without-neuroinflammation-in-mice
#17
JOURNAL ARTICLE
David Brenner, Kirsten Sieverding, Jahnavi Srinidhi, Susanne Zellner, Christopher Secker, Rüstem Yilmaz, Julia Dyckow, Shady Amr, Anna Ponomarenko, Esra Tunaboylu, Yasmin Douahem, Joana S Schlag, Lucía Rodríguez Martínez, Georg Kislinger, Cornelia Niemann, Karsten Nalbach, Wolfgang P Ruf, Jonathan Uhl, Johanna Hollenbeck, Lucas Schirmer, Alberto Catanese, Christian S Lobsiger, Karin M Danzer, Deniz Yilmazer-Hanke, Christian Münch, Philipp Koch, Axel Freischmidt, Martina Fetting, Christian Behrends, Rosanna Parlato, Jochen H Weishaupt
Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38512136/antigen-independent-autonomous-b-cell-receptor-signaling-drives-activated-b-cell-dlbcl
#18
JOURNAL ARTICLE
Janneke A Eken, Marvyn T Koning, Kristyna Kupcova, Julieta H Sepúlveda Yáñez, Ruben A L de Groen, Edwin Quinten, Jurriaan Janssen, Cornelis A M van Bergen, Joost S P Vermaat, Arjen Cleven, Marcelo A Navarrete, Bauke Ylstra, Daphne de Jong, Ondrej Havranek, Hassan Jumaa, Hendrik Veelken
Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38506708/dietary-fiber-is-a-critical-determinant-of-pathologic-ilc2-responses-and-intestinal-inflammation
#19
JOURNAL ARTICLE
Mohammad Arifuzzaman, Tae Hyung Won, Hiroshi Yano, Jazib Uddin, Elizabeth R Emanuel, Elin Hu, Wen Zhang, Ting-Ting Li, Wen-Bing Jin, Alex Grier, Sanchita Kashyap, Chun-Jun Guo, Frank C Schroeder, David Artis
Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38502057/distinct-molecular-profiles-drive-multifaceted-characteristics-of-colorectal-cancer-metastatic-seeds
#20
JOURNAL ARTICLE
Yuanyuan Zhao, Bing Zhang, Yiming Ma, Mengmeng Guo, Fuqiang Zhao, Jianan Chen, Bingzhi Wang, Hua Jin, Fulai Zhou, Jiawei Guan, Qian Zhao, Qian Liu, Hongying Wang, Fangqing Zhao, Xia Wang
Metastasis of primary tumors remains a challenge for early diagnosis and prevention. The cellular properties and molecular drivers of metastatically competent clones within primary tumors remain unclear. Here, we generated 10-16 single cell-derived lines from each of three colorectal cancer (CRC) tumors to identify and characterize metastatic seeds. We found that intrinsic factors conferred clones with distinct metastatic potential and cellular communication capabilities, determining organ-specific metastasis...
May 6, 2024: Journal of Experimental Medicine
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