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Genome-wide CRISPRa screens nominate modulators of CAR T cell survival within distinct tumor cytokine milieus bioRxiv. Immunol. Pub Date : 2024-03-18 Benjamin C Curtis, Cailyn H Spurrell, Lindsay Flint, Aalton M Lande, Marissa Leonardi, James M Rosser, Ardizon Valdez, Nat Murren, Tiffanie Chai, Michael Fitzgerald, Jasmin Martinez-Reyes, Chris P Saxby, Shannon K Oda, Michael CV Jensen
Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized the treatment of B cell malignancies and translating this success to other cancers remains an ongoing clinical objective. Next-generation T cell products in development aim to genetically modulate many facets of cell behavior, for which gene-nominating platforms provide a useful framework for prioritization. Among competing screening
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Identification and characterization of neoantigen-reactive CD8+ T cells following checkpoint blockade therapy in a pan-cancer setting bioRxiv. Immunol. Pub Date : 2024-03-17 Keith Henry Moss, Ulla Kring Hansen, Vinicius Araujo Barbosa De Lima, Annie Borch, Esteban Sanchez Marquez, Anne-mette Bjerregaard, Olga Oestrup, Amalie Kai Bentzen, Andrea Marion Marquard, Mohammed Kadivar, Inge Marie Svane, Ulrik Lassen, Sine Reker Hadrup
Background Immune checkpoint blockade (ICB) has been approved as first-line or second-line therapies for an expanding list of malignancies. T cells recognizing mutation-derived neoantigens are hypothesized to play a major role in tumor elimination. However, the dynamics and characteristics of such neoantigen-reactive T cells (NARTs) in the context of ICB are still limitedly understood. Methods To explore
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The Impact of Model Assumptions in Interpreting Cell Kinetic Studies bioRxiv. Immunol. Pub Date : 2024-03-17 Ada Yan, Ildar Sadreev, Jonas Mackerodt, Yan Zhang, Derek C Macallan, Robert Busch, Becca Asquith
Stable isotope labelling is one of the best available methods for quantifying cell dynamics in vivo, particularly in humans where the absence of toxicity makes it preferable over other techniques such as CFSE or BrdU. Interpretation of stable isotope labelling data necessitates simplifying assumptions. Here we investigate the impact of three of the most commonly used simplifying assumptions (that the
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Curcumin-mediated NRF2 induction limits inflammatory damage in preclinical models of cystic fibrosis bioRxiv. Immunol. Pub Date : 2024-03-17 Stephen A Leon-Icaza, Maxence Fretaud, Sarahdja Cornelie, Charlotte Bureau, Laure Yatime, Andres R Floto, Stephen Renshaw, Jean-Louis Herrmann, Christelle Langevin, Celine Cougoule, Audrey Bernut
Overactive inflammation is directly correlated with airway damage and early death in individuals with cystic fibrosis (CF), a genetic disorder caused by mutation in the CFTR gene. Reducing the impact of inflammatory damage is therefore a major concern in CF. Several studies indicate that a decrease in the nuclear factor erythroid 2-related factor-2 (NRF2) signaling in people with CF may hamper their
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Protective function of ex vivo expanded CD8 T cells in a mouse model of adoptive therapy for cytomegalovirus infection depends on integrin beta 1 but not CXCR3, CTLA4, or PD-1 expression bioRxiv. Immunol. Pub Date : 2024-03-17 Xiaokun Liu, Rodrigo Gutierrez Jauregui, Yvonne Lueder, Stephan Halle, Laura Ospina-Quintero, Christiane Ritter, Anja Schimrock, Stefanie Willenzon, Anika Janssen, Karen Wagner, Martin Messerle, Berislav Bosnjak, Reinhold Foerster
The adoptive transfer of virus-specific T cells (VSTs) represents a therapeutic option for viral infection treatment in immunocompromised patients. Before administration, ex vivo culture enables VST expansion. However, it is unclear how ex vivo expansion affects the circulation, homing, and intra-tissue migration of administered VSTs. We established a model of VST immunotherapy of acute cytomegalovirus
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IMMUNOPHENOTYPING AND FUNCTIONAL ANALYSIS OF NK CELL SUBSETS IN Mycobacterium tuberculosis-INFECTED INDIVIDUALS bioRxiv. Immunol. Pub Date : 2024-03-17 Carolina S Silva, Elin Folkesson, Fariba Foroogh, Maia S Gower, Linn Kleberg, Pengjun Xi, Dhifaf Sarhan, Judith Bruchfeld, Margarida Correia-Neves, Gunilla Källenius, Christopher Sundling
Infection with Mycobacterium tuberculosis remains a global health challenge, with diverse clinical outcomes ranging from latent TB (LTB) infection to active TB disease (ATB). We conducted a comprehensive analysis of NK cell subsets and function in individuals with LTB, ATB, and healthy controls to elucidate their potential association with TB pathogenesis. Peripheral blood mononuclear cells (PBMCs)
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CD39 is expressed on functional effector and tissue resident memory CD8+ T cells bioRxiv. Immunol. Pub Date : 2024-03-17 Jordan F Isaacs, Hanna N Degefu, Tiffany Chen, Sierra A Kleist, Shawn C Musial, Myles A Ford, Tyler G Searles, Chun-Chieh Lin, Alexander G.J. Skorput, Keisuke Shirai, Mary Jo Turk, George J Zanazzi, Pamela Rosato
The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on antigen-specific CD8+ short-lived effector cells (SLECs), while its co-ecto-enzyme, CD73, is found on memory
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Dendritic Cell - Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis bioRxiv. Immunol. Pub Date : 2024-03-17 Hannah Carter, Rita Medina Costa, Monica Bame, Talon Gilchrist, Claire Emch, Taylor Adams, Angela Linderholm, Justin M. Oldham, Imre Noth, Naftali Kaminski, Bethany B Moore, Stephen J Gurczynski
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that
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Optimized CART Cell Therapy for Metastatic Aggressive Thyroid Cancer bioRxiv. Immunol. Pub Date : 2024-03-17 Justyna J Gleba, Elizabeth L Siegler, Claudia Manriquez-Roman, Truc N Huynh, Long K Mai, James L Miller, Erin E Miller, Matthew L Pawlush, Aylin Alasonyalilar Demirer, Brooke L Kimball, Erin E Tapper, R Leo Sakemura, Carli M Stewart, Ismail Can, Olivia L Sirpilla, Jennifer M Feigin, Kun Yun, Omar L Gutierrez-Ruiz, Hong Xia, Mehrdad Hefazi, Kendall J Schick, Ekene J Ogbodo, Gloria Olivier, Yushi Qiu
Most thyroid cancer deaths are attributed to a subset of poorly differentiated, metastatic tumors. To improve treatment options for these aggressive thyroid cancers, we developed a novel thyroid-stimulating hormone receptor (TSHR)-targeted chimeric antigen receptor T (CART) cell therapy, which demonstrated antigen-specific activation and antitumor efficacy against TSHR-overexpressing cell lines in
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Anti-Immune Complex Antibodies are Elicited During Repeated Immunization with HIV Env Immunogens bioRxiv. Immunol. Pub Date : 2024-03-17 Sharidan Brown, Aleksandar Antanasijevic, Leigh M. Sewall, Daniel Montiel Garcia, Philip J.M. Brouwer, Rogier W. Sanders, Andrew B. Ward
Vaccination strategies against HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) using prime-boost regimens with HIV envelope (Env) immunogens. Early antibody responses to easily accessible epitopes on these antigens are directed to non-neutralizing epitopes instead of bnAb epitopes. Autologous neutralizing antibody responses appear upon boosting once immunodominant epitopes are saturated
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C1q/MASP complexes - hybrid complexes of classical and lectin pathway proteins are found in the circulation bioRxiv. Immunol. Pub Date : 2024-03-16 Anne Rosbjerg, Tereza Alica Plchov, Rafael Bayarri-Olmos, Bettina Eide Holm, Ida Sandau Pedersen, Mikkel-Ole Skjoedt, Peter Garred
Complement pathways, traditionally regarded as separate entities in vitro, are increasingly noted for cross-communication and bypass mechanisms. Among these, the MBL/Ficolin/CL associated serine protease-3 (MASP-3) - a component of lectin pathway pattern recognition receptors (PRMs) - has shown the ability to process critical substrates like pro-factor D and insulin growth factor binding protein-5
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CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2+ macrophages and CD8 T-cells bioRxiv. Immunol. Pub Date : 2024-03-16 Jesus Jimenez, Junedh Amrute, Pan Ma, Xiaoran Wang, Raymond Dai, Kory Lavine
Novel immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger
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Streptococcus agalactiae and Escherichia coli Induce Distinct Effector γδ T Cell Responses During Neonatal Sepsis and Neuroinflammation bioRxiv. Immunol. Pub Date : 2024-03-16 Lila Witt, Kara Greenfield, Kathryn Knoop
Neonates born prematurely are highly vulnerable to life-threatening conditions such as bacterial sepsis. Streptococcus agalactiae, also known as group B Streptococcus (GBS) and Escherichia coli are frequent causative pathogens of neonatal sepsis, however, it remains unclear if distinct sepsis pathogens induce differential adaptive immune responses. In the present study, we find that γδ T cells in neonatal
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Development of an engineered extracellular vesicles-based vaccine platform for combined delivery of mRNA and protein to induce functional immunity bioRxiv. Immunol. Pub Date : 2024-03-15 Xin Luo, Kathleen M. McAndrews, Kent A. Arian, Sami J. Morse, Viktoria Boeker, Shreyasee V. Kumbhar, Yingying Hu, Krishnan K. Mahadevan, Kaira A. Church, Sriram Chitta, Nicolas T. Ryujin, Janine Hensel, Jianli Dai, Dara P. Dowlatshahi, Hikaru Sugimoto, Michelle L. Kirtley, Valerie S. LeBleu, Shabnam Shalapour, Joe H. Simmons, Raghu Kalluri
mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EVX-M+P vaccine) and explore its utility in proof-of-concept immunity studies
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de Novo Sequencing of Antibodies for Identification of Neutralizing Antibodies in Human Plasma Post SARS-CoV-2 Vaccination bioRxiv. Immunol. Pub Date : 2024-03-15 Thierry Le Bihan, Teressa Nunez de Villavicencio Diaz, Chelsea Reitzel, Victoria Lange, Minyoung Park, Emma M. Beadle, Lin Wu, Marko Jovic, Rosalin M. Dubois, Amber L. Couzens, Jin Duan, Xiaobing Han, Qixin Liu, Bin Ma
We present a method for sequencing polyclonal IgG enriched from human plasma, employing a combination of de novo sequencing, proteomics, bioinformatics, protein separation, sequencing, and peptide separations. Our study analyzes a single patient's IgG antibody response triggered by the Moderna Spikevax mRNA COVID-19 vaccine. From the sequencing data of the natural polyclonal response to vaccination
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A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling bioRxiv. Immunol. Pub Date : 2024-03-15 Bodie Curren, Tufael Ahmed, Ridwan B Rashid, Ismail Sebina, Md. Al Amin Sikder, Daniel R Howard, Mariah Alorro, Md. Ashik Ullah, Alec Bissell, Muhammed Mahfuzur Rahman, Michael A Pearen, Grant A Ramm, Antiopi Varelias, Stefan Rose-John, Paraic O Cuiv, Kirsten M Spann, Paul G Dennis, Simon Phipps
Poor maternal diet during pregnancy predisposes to severe lower respiratory tract infections (sLRI) in infancy, which in turn, increases childhood asthma risk, however the underlying mechanisms remain poorly understood. Here, we show that the offspring of high fat diet (HFD)-fed mothers ('HFD-reared pups') developed a sLRI following pneumovirus inoculation in early-life and subsequent asthma in later-life
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A hemagglutinin and neuraminidase biased immunological memory shapes the dynamics of antibody responses to Influenza A virus bioRxiv. Immunol. Pub Date : 2024-03-15 Xia Lin, Jiaqi Wang, Shiman Ling, Cheng Xiao, Zaolan Liang, Cheuk Long Chow, Bingyi Yang, Biying Xiao, Benjamin J Cowling, Richard J. Webby, Mark Zanin, Sook-San Wong
Influenza A virus (IAV) infection establishes a more diverse immunological memory to different viral proteins compared to vaccination. We hypothesized that the relative abundance of pre-existing immune memory to different viral antigens could skew post-infection antibody responses. To explore this, we generated mouse models with either an IAV hemagglutinin (HA)- or neuraminidase (NA)-biased immunological
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Dynamic fibroblast-immune interactions shape wound healing after brain injury bioRxiv. Immunol. Pub Date : 2024-03-15 Nathan A. Ewing-Crystal, Nicholas M. Mroz, Anthony A. Chang, Eric Dean Merrill, Sofia E. Caryotakis, Leon Teo, Amara Larpthaveesarp, Tatsuya Tsukui, Aditya Katewa, Remy Pennington, Gabriel L. McKinsey, Sophia Nelson, Agnieszka Ciesielska, Madelene W. Dahlgren, Helena Paidassi, Saket Jain, Manish K. Aghi, James A. Bourne, Jeanne T. Paz, Fernando F. Gonzalez, Dean Sheppard, Anna V. Molofsky, Thomas D
Fibroblasts coordinate the response to tissue injury, directing organ regeneration versus scarring. In the central nervous system (CNS), fibroblasts are uncommon cells enriched at tissue borders, and their molecular, cellular, and functional interactions after brain injury are poorly understood. Here we define the fibroblast response to sterile brain damage across time and space. Early pro-fibrotic
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Divergent effects of C4a, C4adesArg, and thrombin on platelet aggregation and phosphorylation of ERK and Akt in human endothelial cells. bioRxiv. Immunol. Pub Date : 2024-03-15 Mengyao Liu, Vy K. Tran Luu, hongbin Wang
Prior studies have established C4a as an untethered ligand for protease-activated receptors (PAR)1 and PAR4, which can increase ERK phosphorylation and [Ca2+]i influx in human endothelial cells (ECs). C4adesArg is a stable metabolite produced from C4a through cleavage of an arginine at the carboxyl terminus by plasma carboxypeptidases B/N. PAR1 and PAR4 are typical receptors for thrombin and transduce
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A regulatory B cell subpopulation expressing CD301b lectin promotes breast cancer growth bioRxiv. Immunol. Pub Date : 2024-03-15 Amy V Paschall, Zahra Nawaz, Fikri Avci
Tumor-associated carbohydrate antigens (TACAs) can promote tumor growth by regulating the anti-tumor immune response. The accumulation of immune suppressor cells within the tumor in response to TACAs suggests a critical pathway to suppress immune targeting of the tumor. Employing murine breast cancer models, we isolated a regulatory B cell subpopulation in the breast tumor microenvironment that displays
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Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism bioRxiv. Immunol. Pub Date : 2024-03-15 Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi de la Palavesa, Jean-Daniel Fauny, Olivier Griso, Helene Puccio, Rebecca Fima, Thierry Huby, Emmanuel L Gautier, Anne Molitor, Raphael Carapito, Siamak Bahram, Nikolaus Romani, Bjoern E Clausen, Benjamin Voisin, Christopher George Mueller, Frederic Gros, Vincent Flacher
Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans
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Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV bioRxiv. Immunol. Pub Date : 2024-03-14 Cara W Chao, Kaitlin R Sprouse, Marcos C Miranda, Nicholas J Catanzaro, Miranda L Hubbard, Amin Addetia, Cameron Stewart, Jack T Brown, Annie Dosey, Adian Valdez, Rashmi Ravichandran, Grace G Hendricks, Maggie Ahlrichs, Craig Dobbins, Alexis Hand, Catherine Treichel, Isabelle Willoughby, Alexandra C Walls, Andrew T McGuire, Elizabeth M Leaf, Ralph S. Baric, Alexandra Schaefer, David Veesler, Neil P
Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced
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Adoptive Transfer of CD49a+ Tissue Resident memory cells reverses pulmonary fibrosis in mice. bioRxiv. Immunol. Pub Date : 2024-03-14 Samuel L Collins, Yee Chan-Li, Kevin Shenderov, Andrew M Nelson, Jeffrey M Loube, Wayne A Mitzner, Jonathan D Powell, Maureen R Horton, Astrid Gillich
Pulmonary fibrosis is a devastating disease with no effective treatments to cure, stop or reverse the unremitting, fatal fibrosis. A critical barrier to treating this disease is the lack of understanding of the pathways leading to fibrosis as well as those regulating the resolution of fibrosis. Fibrosis is the pathologic side of normal tissue repair that results when the normal wound healing programs
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The extracellular heparan sulfatase SULF2 limits myeloid IFNbeta signaling and Th17 responses in inflammatory arthritis. bioRxiv. Immunol. Pub Date : 2024-03-14 Maarten Swart, Andia Redpath, Joy Ogbechi, Ryan Cardenas, Louise Topping, Ewoud B Compeer, Michael Goddard, Anastasios Chanalaris, Richard Williams, Daniel S Brewer, Nicola Smart, Claudia Monaco, Linda Troeberg
Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated
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N-acetylcysteine counteracts immune dysfunction and autistic-related behaviors in the Shank3b mouse model of Autism Spectrum Disorders bioRxiv. Immunol. Pub Date : 2024-03-14 Luca Pangrazzi, Enrica Cerilli, Luigi Balasco, Ginevra Matilde Dall'O', Gabriele Chelini, Anna Pastore, Birgit Weinberger, Yuri Bozzi
Autism Spectrum Disorder (ASD) includes a range of neurodevelopmental disabilities characterized by social interaction deficits, communication impairments, and repetitive behaviors. Previous studies have shown that pro-inflammatory conditions play a key role in ASD. Here we reported that increased levels of molecules related to inflammation are present in the cerebellum and peripheral blood (PB) of
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Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity bioRxiv. Immunol. Pub Date : 2024-03-14 Anna Appios, James Davies, Sofia Sirvent, Stephen Henderson, Sebastien Trzebanski, Johannes Schroth, Morven L Law, Ines Boal Carvalho, Howard Yuan-Hao Kan, Shreya Lovlekar, Christina Major, Andres Vallejo, Nigel J Hall, Michael Ardern-Jones, Sian M Henson, Elaine Emmerson, Steffen Jung, Marta E Polak, Clare L Bennett
Langerhans cells (LCs) maintain tissue and immunological homeostasis at the epidermal barrier site. They are unique among phagocytes in functioning both as embryo-derived, tissue-resident macrophages that influence skin innervation and repair, and as migrating professional antigen presenting cells, a capability classically assigned to dendritic cells (DCs). Here we report the mechanisms that determine
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Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8+ T Cell Activation bioRxiv. Immunol. Pub Date : 2024-03-14 Victoria Adams, Sudeep Sarma, Carol K Hall, Arion Kennedy
MHC class I molecules play a crucial role in the immune system by presenting peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). This process is essential for immune surveillance and eliminating infected or malignant cells. In some diseases, the immune system fails to recognize and eliminate abnormal cells, leading to disease progression. Under conditions of metabolic d
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PARP14 inhibits the inflammatory response of macrophages through the NF-κB pathway bioRxiv. Immunol. Pub Date : 2024-03-14 Xuefei Guo, Yang Zhao
The poly-ADP-ribose polymerase (PARP) superfamily consists of 17 members, which regulate many biological processes in physiological or pathological conditions, such as DNA damage repair, anti-viral responses, and development of adaptive immune cells. Among them, PARP14 is the biggest member, containing two RNA recognition motifs at the N-terminal, three macro-domains, one WWE domain, and one PARP domain
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Investigating the Role and Regulation of GPNMB in Progranulin-deficient Macrophages bioRxiv. Immunol. Pub Date : 2024-03-14 Drew A Gillett, Noelle K Neighbarger, Cassandra Cole, Rebecca Wallings, Malu Gamez Tansey
Progranulin is a holoprotein that is critical for successful aging, and insufficient levels of progranulin are associated with increased risk for developing age-related neurodegenerative diseases like AD, PD, and FTD. Symptoms can vary widely, but a uniting feature among these different neurodegenerative diseases is prodromal peripheral immune cell phenotypes. However, there remains considerable gaps
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Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches bioRxiv. Immunol. Pub Date : 2024-03-14 Maria K Lagou, Dimitrios G Argyris, Stepan Vodopyanov, Leslie Gunther-Cummins, Alexandros Hardas, Theofilos Poutahidis, Christos Panorias, Sophia DesMarais, Conner Entenberg, Randall S. Carpenter, Hillary Guzik, Xheni Nishku, Joseph Churaman, Maria Maryanovich, Vera DesMarais, Frank P. Macaluso, George S. Karagiannis
The thymus, a central primary lymphoid organ of the immune system, plays a key role in T cell development. Surprisingly, the thymus is quite neglected with regards to standardized pathology approaches and practices for assessing structure and function. Most studies use multispectral flow cytometry to define the dynamic composition of the thymus at the cell population level, but they are limited by
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Type I interferon alters invasive extravillous trophoblast function. bioRxiv. Immunol. Pub Date : 2024-03-14 Michael K Simoni, Seble G Negatu, Ju Young Park, Sneha Mani, Montserrat Arreguin, Kevin Amses, Dan Dongeun Huh, Monica Mainigi, Kellie A Jurado
Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluated the consequence of elevated type I IFN exposure on implantation using a biomimetic model of human implantation in an organ-on-a-chip device. We found that type I IFN reduced extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes
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Stiffness regulates dendritic cell and macrophage subtype development and increased stiffness induces a tumor-associated macrophage phenotype in cancer co-cultures bioRxiv. Immunol. Pub Date : 2024-03-14 Carla Guenther
Mechanical properties of tissues including their stiffness change throughout our lives, during both healthy development but also during chronic diseases like cancer (1-4). How changes to stiffness, occurring during cancer progression, impact leukocytes is unknown. To address this, myeloid phenotypes resulting from mono- and cancer co-cultures of primary murine and human myeloid cells on 2D and 3D hydrogels
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Elimination of human papillomavirus 16-induced tumors by a mucosal rAd5 therapeutic vaccination in a pre-clinical study bioRxiv. Immunol. Pub Date : 2024-03-14 Molly R Braun, Jonathan D Lindbloom, Anne C Moore, Katherine A Hodgson, Emery G Dora, Sean N Tucker
Therapeutic vaccination can harness the body's cellular immune system to target and destroy cancerous cells. Several invasive treatments are currently used to eliminate cancerous lesions caused by human papillomaviruses (HPV), however therapeutic vaccination may offer and effective and minimally intrusive alternative. We have developed recombinant, non-replicating human adenovirus type 5 (rAd5) vaccines
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The β2-adrenergic receptor (ADRB2) entrains circadian gene oscillation and diurnal responses to virus infection in CD8+ T cells bioRxiv. Immunol. Pub Date : 2024-03-14 Drashya Sharma, Kira A. Kohlbach, Robert Maples, J David Farrar
Adaptive immune cells are regulated by circadian rhythms (CR) under both steady state conditions and during responses to infection. Cytolytic CD8+ T cells display variable responses to infection depending upon the time of day of exposure. However, the neuronal signals that entrain these cyclic behaviors remain unknown. Immune cells express a variety of neurotransmitter receptors including nicotinic
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Mutability and hypermutation antagonize immunoglobulin codon optimality bioRxiv. Immunol. Pub Date : 2024-03-14 Joshua JC McGrath, Juyeon Park, Chloe A Troxell, Jordan C Chervin, Lei Li, Johnathan R Kent, Siriruk Changrob, Yanbin Fu, Min Huang, Nai-Ying Zheng, G. Dewey Wilbanks, Sean A Nelson, Jiayi Sun, Giorgio Inghirami, Maria Lucia L Madariaga, George Georgiou, Patrick C Wilson
The efficacy of polyclonal antibody responses is inherently linked to paratope diversity, as generated through V(D)J recombination and somatic hypermutation (SHM). These processes arose in early jawed vertebrates; however, little is known about how immunoglobulin diversity, mutability, and hypermutation have evolved in tandem with another more ubiquitous feature of protein-coding DNA - codon optimality
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Differentiation marker-negative CD4+ T cells persist after yellow fever virus vaccination and contribute to durable memory bioRxiv. Immunol. Pub Date : 2024-03-14 Yi-Gen Pan, Laurent Bartolo, Ruozhang Xu, Bijal Patel, Veronika I Zarnitsyna, Laura F Su
Factors that contribute to durable immunological memory remain incompletely understood. In our longitudinal analyses of CD4+ T cell responses to the yellow fever virus (YFV) vaccine by peptide-MHC tetramers, we unexpectedly found naive phenotype virus-specific CD4+ T cells that persisted months to years after immunization. These Marker negative T cells (TMN) lacked CD95, CXCR3, CD11a, and CD49d surface
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Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice bioRxiv. Immunol. Pub Date : 2024-03-13 Agnes Carolin, Cameron R Bishop, Kexin Yan, Wilson Nguyen, Bing Tang, Daniel J Rawle, Andreas Suhrbier
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied
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Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes bioRxiv. Immunol. Pub Date : 2024-03-13 Matthew A. Fischer, Luo Jia, Karen L Edelblum
Intraepithelial lymphocytes (IEL) expressing the γδ T cell receptor (TCR) survey the intestinal epithelium to limit the invasion of microbial pathogens. The production of type I interferon (IFN) is a central component of an antiviral immune response, yet how these pro-inflammatory cytokines contribute to γδ IEL effector function remains unclear. Based on the unique activation status of IELs, and their
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Infiltrative classical monocyte-derived and SPP1 lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis bioRxiv. Immunol. Pub Date : 2024-03-13 Yosta Vegting, Aldo Jongejan, Annette E Neele, Nike Claessen, Gal Sela, Koen HM Prange, Jesper Kers, Joris JTH Roelofs, Joost W van der Heijden, Onno J de Boer, Ester BM Remmerswaal, Liffert Vogt, Frederike J Bemelman, Menno PJ de Winther, Perry D Moerland, Marc L Hilhorst
Background: Kidney macrophage infiltration is a histological hallmark of vasculitic lesions and is strongly linked to disease activity in anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN). The precise mechanisms by which kidney macrophages influence local inflammation and long-term damage remain largely unknown. Methods: Here, we investigate kidney macrophage diversity
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Use of Mucosally Administered Outer Membrane Vesicles Derived from Bordetella pertussis to Diminish Nasal Bacterial Colonization bioRxiv. Immunol. Pub Date : 2024-03-13 Erika Rudi, Maria Emilia Gaillard, Daniela Bottero, Daniela Hozbor
Background: We previously identified Bordetella pertussis-derived outer membrane vesicles (OMVs) as a promising immunogen for improving pertussis vaccines. In this study, we evaluated the efficacy of our vaccine prototype in immunization strategies aimed at reducing disease transmission by targeting colonization in the upper airways while maintaining protection against severe disease by reducing colonization
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eATP/P2X7R axis drives nanoparticle induced neutrophil recruitment in the pulmonary microcirculation bioRxiv. Immunol. Pub Date : 2024-03-13 Chenxi Li, Qiongliang Liu, Lianyong Han, Roland Immler, Birgit Rathkolb, Judith Secklehner, Martin Hrabe de Angelis, Ali Oender Yildirim, Annette Nicke, Leo M Carlin, Markus Sperandio, Tobias Stoeger, Markus Rehberg
Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung-specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream-suspended particles. Therefore, exact knowledge about interactions and effects of engineered NPs with
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Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross stage recognition of glutamate-rich repeats bioRxiv. Immunol. Pub Date : 2024-03-13 Axelle Amen, Randy Yoo, Amanda Fabra-Garcia, Judith Bolscher, William J.R. Stone, Isabelle Bally, Sebastian Dergan-Dylon, Iga Kucharska, Roos M de Jong, Marloes de Bruijni, Teun Bousema, C. Richter King, Randall S. MacGill, Robert W. Sauerwein, Jean-Philippe Julien, Pascal Poignard, Matthijs M. Jore
Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies (Abs) can efficiently block parasite transmission. In search for naturally acquired Ab targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed
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CRISPR/Cas9-mediated deletion of a kinetoplast-associated gene attenuates virulence in Leishmania major parasites bioRxiv. Immunol. Pub Date : 2024-03-13 Fatemeh Darzi, Ali Khamesipour, Maryam Bahrami, Mahmoud Nateghi Rostami
The CRISPR/Cas9 system has emerged as a powerful tool for precise genome editing, allowing for the deletion of genes, generation of point mutations, and addition of tags to endogenous genes. We employed an efficient CRISPR/Cas9 technique in Leishmania major to assess its efficiency in editing a kDNA-associated gene, universal minicircle sequence binding protein (UMSBP), which is involved in mitochondrial
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NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni bioRxiv. Immunol. Pub Date : 2024-03-13 Madhusoodhanan Suresh Kumar Meena Kumari, Pengyu Liu, Kaile Jump, Yoelkys Morales, Emily A Miller, Ilana Shecter, Miguel J Stadecker, Parisa Kalantari
Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types
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Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy bioRxiv. Immunol. Pub Date : 2024-03-13 Mostafa Yazdimamaghani, Oleg Kolupaev, Chaemin Lim, Duhyeong Hwang, Sonia Laurie, Charles Perou, Alexander Kabanov, Jonathan Serody
Infiltration of immunosuppressive cells into the breast tumor microenvironments (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction
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Distinct tissue-dependent composition and gene expression of human fetal innate lymphoid cells bioRxiv. Immunol. Pub Date : 2024-03-13 Inga E Rodahl, Martin A Ivarsson, Liyen Loh, Jeff E Mold, Magnus Westgren, Danielle Friberg, Jenny Mjosberg, Niklas K Bjorkstrom, Nicole Marquardt, Douglas F Nixon, Jakob Michaelsson
The human fetal immune system starts to develop in the first trimester and likely plays a crucial role in fetal development and maternal-fetal tolerance. Innate lymphoid cells (ILCs) are the earliest lymphoid cells to arise in the human fetus. ILCs consists of natural killer (NK) cells, ILC1s, ILC2s, and ILC3s that all share a common lymphoid origin. Here, we studied fetal ILC subsets, mainly NK cells
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Requirement of a Wnt5A-Microbiota Axis in the Maintenance of Gut B Cell Repertoire and Protection from Infection bioRxiv. Immunol. Pub Date : 2024-03-13 Soham Sengupta, Malini Sen
We investigated the influence of a Wnt5A-gut microbiota axis on gut B cell repertoire and protection from infection, having previously demonstrated that Wnt5A in association with gut commensals help shape gut T cell repertoire. Accordingly, Wnt5A heterozygous mice, which express less than wild type level of Wnt5A, and their isolated Peyer’s patches (PP), were studied in comparison with the wild type
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Chloride intracellular channel 4 (CLIC4) is a global regulator of type 1 interferon signaling in Systemic Sclerosis (SSc) epithelial cells bioRxiv. Immunol. Pub Date : 2024-03-12 Christopher W Wasson, Sophie L Dibb, Begona Caballero Ruiz, Eva M Clavane, Rebecca Wells, Vishal Kakkar, Enrico De Lorenzis, Rebecca L Ross, Jessica Bryon, Emma Derrett-Smith, Christopher P Denton, Paul J Meakin, Francesco Del Galdo
Objectives: Systemic sclerosis (SSc) is an autoimmune disease in which an immune-related injury induces fibrosis of the skin, progressing to affect the internal organs in the most serve cases. Type 1 interferon (IFN) signaling plays a major role in SSc disease progression. We have previously shown the chloride intracellular channel 4 (CLIC4) is upregulated in SSc skin fibroblasts and plays an important
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Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy bioRxiv. Immunol. Pub Date : 2024-03-12 Lea Paolini, Thi Tran, Stephanie Corgnac, Jean-Philippe VILLEMIN, Marie Wislez, Jennifer Arrondeau, Ludger Johannes, Jonathan Ulmer, Louis-Victorien Vieillard, Josephine Pineau, Alain Gey, Valentin Quiniou, Pierre Barennes, Hang Phuong Pham, nadege Gruel, Milena Hasan, Valentina Libri, Sebastien Mella, Sixtine de Percin, Pascaline Boudou-Rouquette, Isabelle Cremer, helene Blons, Karen Leroy, Pierre
A high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. However, in preclinical models, only some subpopulations of TRM are associated with cancer vaccine efficacy. We identified two main TRM subpopulations in tumor-infiltrating lymphocytes derived from non-small cell lung cancer (NSCLC) patients: one co-expressing CD103
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The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness bioRxiv. Immunol. Pub Date : 2024-03-12 Hu Zeng, Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens Watzlawik, Yin Maggie Chen, Ariel Raybuck, Daniel Billadeau, Virginia Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby
During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members
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Inhibition of NFAT promotes loss of tissue resident uterine natural killer cells and attendant pregnancy complications in humans bioRxiv. Immunol. Pub Date : 2024-03-12 Rebecca Asiimwe, Brittney Knott, Morgan E. Greene, Emma Wright, Markayla Bell, Daniel Epstein, Stefani D. Yates, Matthew D. Cheung, Michael V. Gonzalez, Samantha Fry, Emily Boydston, Stephanie Clevenger, Jayme E. Locke, James F. George, Richard Burney, Nitin Arora, Virginia E. Duncan, Holly E. Richter, Deidre Gunn, Aharon G. Freud, Shawn C. Little, Paige M. Porrett
Uterine natural killer cells (uNKs) are a tissue resident lymphocyte population that are critical for pregnancy success. Although mouse models have demonstrated that NK deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here we identify uterus transplant (UTx) recipients as a human population with reduced endometrial
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Epigenetic signature and key transcriptional regulators of human antigen-specific type 1 regulatory T cells bioRxiv. Immunol. Pub Date : 2024-03-12 Alma-Martina Cepika, Laura Amaya, Colin Waichler, Mansi Narula, Michelle M Mantilla, Benjamin C Thomas, Pauline P Chen, Robert A Freeborn, Mara Pavel-Dinu, Jason Nideffer, Matthew Porteus, Rosa Bacchetta, Fabian Mueller, William J Greenleaf, Howard Y Chang, Maria Grazia Roncarolo
Human adaptive immunity is orchestrated by effector and regulatory T (Treg) cells. Natural Tregs arise in the thymus where they are shaped to recognize self-antigens, while type 1 Tregs or Tr1 cells are induced from conventional peripheral CD4+ T cells in response to peripheral antigens, such as alloantigens and allergens. Tr1 cells have been developed as a potential therapy for inducing antigen-specific
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Constitutive immune surveillance of nasal mucosa by three neutrophil subsets with distinct origin, phenotype, and function bioRxiv. Immunol. Pub Date : 2024-03-12 Rodrigo J. Gonzalez, Pavel Hanc, David Alvarez, Samuel W Kazer, Marie-Angele Messou, Irina B Mazo, Colette Matysiak Match, Rohit Garg, Jennifer D. Helble, Paris Pallis, Rachel Ende, Alan Basset, Richard Malley, Isabelle Derre, Michael N. Starnbach, Ulrich H. von Andrian
The nasal mucosa (NM) has several critical functions, including as a chemosensory organ, as a filter and conditioning surface of inhaled air for the lower airways, and as a first line of defense against airborne infections. Owing to its constant exposure to ever-changing environments, the NM is arguably the most frequently infected tissue in mammals. Consequently, vertebrates harbor an intricate network
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A continuum of CD4+ T cell 'help' defines 1 Memory B cell fate bioRxiv. Immunol. Pub Date : 2024-03-11 Gretchen Harms Pritchard, Akshay T. Krishnamurty, Lauren Rodda, Courtney McDougal, Laila Shehata, Marion Pepper
Humoral immunity depends upon long-lived, antibody-secreting plasma cells and memory B cells (MBCs). MBCs exhibit significant phenotypic and functional heterogeneity. Upon homologous rechallenge, memory B cells thought to be of germinal center (GC) origin rapidly form antibody secreting plasmablasts but rarely enter a new GC, while other, less differentiated memory B cells enter secondary GCs, but
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The antigenic landscape of human influenza N2 neuraminidases from 2009 until 2017 bioRxiv. Immunol. Pub Date : 2024-03-11 Joao Paulo Catani, Anouk Smet, Tine Ysenbaert, Marnik Vuylsteke, Guy Bottu, Janick Mathys, Alexander Botzki, Guadalupe Cortes-Garcia, Tod Strudnell, Raoul Gomila, John Hamberger, John Catalan, Irina Ustyugova, Timothy Farrell, Svetlana Stegalkina, Satyajit Ray, Lauren LaRue, Xavier Saelens, Thorsten U Vogel
Human H3N2 influenza viruses are subject to rapid antigenic evolution which translates into frequent updates of the composition of seasonal influenza vaccines. Despite these updates, the effectiveness of influenza vaccines against H3N2-associated disease is suboptimal. Seasonal influenza vaccines primarily induce hemagglutinin-specific antibody responses. However, antibodies directed against influenza
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LncRNA BRE-AS1 Regulates the JAK2/STAT3-mediated Inflammatory Activation via the miR-30b-5p/SOC3 Axis in THP-1 cells bioRxiv. Immunol. Pub Date : 2024-03-11 Jae-Joon Shin, Kyoungho Suk, Won-Ha Lee
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators in numerous biological processes, including macrophage-mediated inflammatory responses, which play a critical role in the progress of diverse diseases. This study focuses on the regulatory function of lncRNA BRE-AS1 in modulating the inflammatory activation of monocytes/macrophages. Employing the THP-1 cell line as a model, we demonstrate
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T cell polarization and NFAT translocation are stiffness-dependent and are differentially regulated by Piezo1 and Orai1 bioRxiv. Immunol. Pub Date : 2024-03-11 Renping Zhao, Jingnan Zhang, Eva C. Schwarz, Aranzazu del Campo, Markus Hoth, Bin Qu
Effective T cell responses against tumor cells require diverse effector functions including polarization towards tumor cells to form immunological synapses and nuclear factor of activated T-cells (NFAT)-dependent gene transcription. While the role of tumor cell softening has been associated with malignancy, stemness, and metastasis, potentially contributing to immune evasion, its impact on cellular
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Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance bioRxiv. Immunol. Pub Date : 2024-03-10 Shivraj M Yabaji, Vadim Zhernovkov, Prasanna Babu Araveti, Suruchi Lata, Oleksii S Rukhlenko, Salam Al Abdullatif, Yuriy Alekseev, Qicheng Ma, Gargi Dayama, Nelson C. Lau, William R Bishai, Nicholas A Crossland, Joshua D Campbell, Boris N Kholodenko, Alexander A Gimelbrant, Lester Kobzik, Igor Kramnik
A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop clinical, mostly pulmonary, TB. To dissect mechanisms of susceptibility in immunocompetent individuals, we developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: development of necrotic lung lesions after infection with
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CMTM6 maintains B cell intrinsic CD40 expression to regulate anti-tumor immunity bioRxiv. Immunol. Pub Date : 2024-03-10 Yiru Long, Runqiu Chen, Wenlong Chang, Hanyue Luo, Fanglin Li, Jianhua Sun, Jing Chen, Likun Gong
Tumor cell CMTM6 is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as PD-L1 and CD58. Host CMTM6 may also play a function in the tumor microenvironment. Here, we found that CMTM6 was highly expressed in splenic B cells and tumor-infiltrating B cells. CMTM6 deficiency resulted in impaired splenic development, germinal center B cell differentiation
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Survivin in synergy with BAF/SWI complex binds bivalent chromatin regions and activates DNA damage response in CD4+ T cells bioRxiv. Immunol. Pub Date : 2024-03-10 Venkataragavan Chandrasekaran, Karin M.E. Andersson, Malin C Erlandsson, Shuxiang Li, Maria-Jose Garcia-Bonete, Eric Malmhall-Bah, Pegah Johansson, Gergely Katona, Maria I. Bokarewa
This study explores a regulatory role of oncoprotein survivin on the bivalent regions of chromatin (BvCR) characterized by concomitant deposition of trimethylated lysine of histone H3 at position 4 (H3K4me3) and 27 (H3K27me3). Intersect between BvCR and chromatin sequences bound to survivin demonstrated their co-localization on cis-regulatory elements of genes which execute DNA damage control in primary