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Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling on intestinal epithelial cells bioRxiv. Immunol. Pub Date : 2021-01-26 darine w El-Naccache; fei chen; mark palma; alexander lemenze; wenhui Wu; pankaj mishra; holger eltzshig; simon c robson; francesco Di Virgilio; Gyorgy Hasko; william gause
Multicellular intestinal nematode parasites can cross the epithelial barrier potentially causing tissue damage and release of danger associated molecular patterns (DAMPs) that may promote type 2 responses and host protective immunity. We investigated whether adenosine specifically binding the A2B adenosine receptor (A2BAR) on epithelial cells played an important role in driving intestinal immunity
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Induction of a colitogenic phenotype in Th1 cells depends on IL-23R signaling bioRxiv. Immunol. Pub Date : 2021-01-26 Mathias Pawlak; David DeTomaso; Gerd Meyer zu Horste; Youjin Lee; Jackson Nyman; Danielle Dionne; Chao Wang; Antonia Wallrapp; Patrick R Burkett; Samantha J Riesenfeld; Ana C Anderson; Aviv Regev; Ramnik J Xavier; Nir Yosef; Vijay K Kuchroo
The cytokine receptor IL-23R plays a fundamental role in inflammation and autoimmunity. However, several observations have been difficult to reconcile under the assumption that only Th17 cells critically depend on IL-23 to acquire a pathogenic phenotype. Here, we report that Th1 cells differentiated in vitro with IL-12 + IL-21 show similar levels of IL-23R expression as in pathogenic Th17 cells. We
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CCR1 regulatory variants linked to pulmonary macrophage recruitment in severe COVID-19 bioRxiv. Immunol. Pub Date : 2021-01-26 Bernard Stikker; Gregoire Stik; Rudi W. Hendriks; Ralph Stadhouders
Genome-wide association studies have identified 3p21.31 as the main risk locus for severe symptoms and hospitalization in COVID-19 patients. To elucidate the mechanistic basis of this genetic association, we performed a comprehensive epigenomic dissection of the 3p21.31 locus. Our analyses pinpoint activating variants in regulatory regions of the chemokine receptor-encoding CCR1 gene as potentially
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Adhatoda Vasica ameliorates cellular hypoxia dependent mitochondrial dysfunction in acute and severe asthmatic mice. bioRxiv. Immunol. Pub Date : 2021-01-26 Atish Prabhakar Gheware; Lipsa Panda; Kritika Khanna; Naveen Kumar Bhatraju; Vaibhav Jain; Shakti Sagar; Manish Kumar; Vijay Pal Singh; S Kannan; V Subramanian; Mitali Mukerji; Anurag Agrawal; Bhavana Prasher
Severe asthma is a chronic airway disease that exhibits poor response to conventional asthma therapies. Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patients and in model systems. In this study, we elucidate the therapeutic effects and mechanistic basis of Adhatoda Vasica (AV) aqueous extract on mouse models of acute allergic as well as severe
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Combining an alarmin HMGN1 peptide with PD-L1 blockade facilitates stem-like CD8+ T cell expansion and results in robust antitumor effects bioRxiv. Immunol. Pub Date : 2021-01-25 Chang-Yu Chen; Satoshi Ueha; Yoshiro Ishiwata; Shigeyuki Shichino; Shoji Yokochi; De Yang; Joost J Oppenheim; Haru Ogiwara; Shungo Deshimaru; Yuzuka Kanno; Tatsuro Ogawa; Shiro Shibayama; Kouji Matsushima
Background: The expansion of intratumoral stem-like CD8+ T (Tstem) cells provides a potential approach to improving the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, here we demonstrate a strategy to facilitate Tstem cell expansion by combining an alarmin high-mobility group nucleosome binding domain 1 (HMGN1) peptide with programmed death-ligand 1 (PD-L1) blockade. Methods: The antitumor
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Hemagglutination Inhibition (HAI) Antibody Landscapes after Vaccination with diverse H7 hemagglutinin (HA) proteins bioRxiv. Immunol. Pub Date : 2021-01-25 Hyesun Jang; Ted M Ross
Background A systemic evaluation of the antigenic differences of the H7 influenza hemagglutinin (HA) proteins, especially for the viruses isolated after 2016, are limited. The purpose of this study was to investigate the antigenic differences of major H7 strains with an ultimate aim to discover H7 HA proteins that can elicit protective receptor-blocking antibodies against co-circulating H7 influenza
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The CXCR6/CXCL16 axis links inflamm-aging to disease severity in COVID-19 patients bioRxiv. Immunol. Pub Date : 2021-01-25 Daniel J Payne; Surita Dalal; Richard Leach; Richard Parker; Stephen Griffin; Clive S McKimmie; Graham P Cook; Stephen J Richards; Peter Hillmen; Tal Munir; Louise Arnold; Kathryn Riley; Claire McKinley; Sandra Place; Richard L Baretto; Darren J Newton
Advancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+ T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated
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Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint. bioRxiv. Immunol. Pub Date : 2021-01-25 Stephen Chenard; Chelsea Jackson; Thiago Vidotto; Lina Chen; Celine Hardy; Tamara Jamaspishvilli; David M Berman; David Robert Siemens; Madhuri Koti
Non-muscle invasive bladder cancer (NMIBC) is significantly more common in men than women. However, female patients with NMIBC often present with more aggressive disease and do not respond as well to immunotherapy treatments. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients. To test this hypothesis
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mRNA-1273 efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after challenge bioRxiv. Immunol. Pub Date : 2021-01-25 Michelle Meyer; Yuan Wang; Darin Edwards; Gregory R Smith; Aliza B Rubenstein; Palaniappan Ramanathan; Chad E Mire; Colette Pietzsch; Xi Chen; Yongchao Ge; Wan Sze Cheng; Carole Henry; Angela Woods; LingZhi Ma; Guillaume B. E. Stewart-Jones; Kevin W Bock; Minai Mahnaz; Bianca M Nagata; Sivakumar Periasamy; Pei-Yong Shi; Barney S Graham; Ian N Moore; Irene Ramos; Olga G. Troyanskaya; Elena Zaslavsky;
The mRNA-1273 vaccine was recently determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit more severe SARS-CoV-2 disease
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Ubiquitin ligase RIPLET mediates polyubiquitination of RIG-I and LGP2 and regulates the innate immune responses to SARS-CoV-2 infection bioRxiv. Immunol. Pub Date : 2021-01-25 Takahisa Kouwaki; Tasuku Nishimura; Guanming Wang; Reiko Nakagawa; Hiroyuki Oshiumi
RIG-I, a cytoplasmic viral RNA sensor, is crucial for innate antiviral immune responses; however, there are controversies about the regulatory mechanism of RIG-I by several ubiquitin ligases and LGP2. This study revealed that the RIPLET ubiquitin ligase is a general activating factor for RIG-I signaling. In contrast, another ubiquitin ligase, TRIM25, activated RIG-I in a cell-type-specific manner.
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A multiscale model suggests that a moderately weak inhibition of SARS-CoV-2 replication by type I IFN could accelerate the clearance of the virus bioRxiv. Immunol. Pub Date : 2021-01-25 Anass Bouchnita; Alexey Tokarev; Vitaly Volpert
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that emerged in China at the end of 2019 and caused a large global outbreak. The interaction between SARS-CoV-2 and the immune response is complex because it is regulated by various processes taking part at the intracellular, tissue, and host levels. To gain a better understanding of the pathogenesis and
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Next generation vaccine platform: polymersomes as stable nanocarriers for a highly immunogenic and durable SARS-CoV-2 spike protein subunit vaccine bioRxiv. Immunol. Pub Date : 2021-01-25 Jian Hang Lam; Amit Kumar Khan; Thomas Andrew Cornell; Regine Josefine Dress; Teck Wan Chia; Wen Wang William Yeow; Nur Khairiah Mohd-Ismail; Shrinivas Venkatraman; Kim Tien Ng; Yee-Joo Tan; Danielle E. Anderson; Florent Ginhoux; Madhavan Nallani
Multiple successful vaccines against SARS-CoV-2 are urgently needed to address the ongoing Covid-19 pandemic. In the present work, we describe a subunit vaccine based on the SARS-CoV-2 spike protein co-administered with CpG adjuvant. To enhance the immunogenicity of our formulation, both antigen and adjuvant were encapsulated with our proprietary artificial cell membrane (ACM) polymersome technology
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mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants bioRxiv. Immunol. Pub Date : 2021-01-25 Kai Wu; Anne P. Werner; Juan I. Moliva; Matthew Koch; Angela Choi; Guillaume B.E. Stewart-Jones; Hamilton Bennett; Seyhan Boyoglu-Barnum; Wei Shi; Barney S Graham; Andrea Carfi; Kizzmekia S. Corbett; Robert A. Seder; Darin K. Edwards
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative infection of a global pandemic that has led to more than 2 million deaths worldwide. The Moderna mRNA-1273 vaccine has demonstrated ~94% efficacy in a Phase 3 study and has been approved under Emergency Use Authorization. The emergence of SARS-CoV-2 variants with mutations in the spike protein, most recently circulating isolates
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Is Vaccination a Viable Method to Control Johne's Disease Caused by Mycobacterium avium subsp. paratuberculosis? Data from 12 Million Ovine Vaccinations and 7.6 Million Carcass Examinations in New South Wales, Australia from 1999-2009 bioRxiv. Immunol. Pub Date : 2021-01-24 Ian Joseph Links; Laurence J. Denholm; Marilyn Evers; Lloyd J. Kingham; Robert J. Greenstein
Background: Mycobacterium avium subsp. paratuberculosis (MAP) causes Johne's disease (or paratuberculosis), a chronic wasting disease of ruminants and other animals resulting from granulomatous enteritis. There are increasing concerns that MAP is zoonotic. The prevalence of Johne's disease is increasing worldwide. In an attempt to control an epidemic of ovine Johne's disease (OJD) in New South Wales
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An Autoantigen Atlas from Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19 bioRxiv. Immunol. Pub Date : 2021-01-24 Julia Y. Wang; Wei Zhang; Michael W. Roehrl; Victor B. Roehrl; Michael H. Roehrl
COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. Using DS affinity, we identified an autoantigenome of 408 proteins from
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CD8+ T cell epitope variations suggest a potential antigen presentation deficiency for spike protein of SARS-CoV-2 bioRxiv. Immunol. Pub Date : 2021-01-24 Congling Qiu; Chanchan Xiao; Zhigang Wang; Guodong Zhu; Xiongfei Chen; Lijuan Gao; Jieping Den; Jun Su; Huanxin Su; Evandro Fei Fang; ZhangJing Zhang; Jikai Zhang; Oscar Junhong Luo; Pengchen Wang; Guobing Chen
COVID-19 is caused by a newly identified coronavirus, SARS-CoV-2, and has become a pandemic around the world. The illustration of the immune responses against SARS-CoV-2 is urgently needed for understanding the pathogenesis of the disease and its vaccine development. CD8+ T cells are critical for virus clearance and induce long lasting protection in the host. Here we identified specific HLA-A2 restricted
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Moderately pathogenic maternal influenza A virus infection disrupts placental integrity but spares the fetal brain bioRxiv. Immunol. Pub Date : 2021-01-23 Adrienne M Antonson; Adam D Kenney; Helen J Chen; Kara N Corps; Jacob S Yount; Tamar L Gur
Maternal infection during pregnancy is a known risk factor for offspring mental health disorders. Animal models of maternal immune activation (MIA) have implicated specific cellular and molecular etiologies of psychiatric illness, but most rely on pathogen mimetics. Here, we developed a mouse model of live H3N2 influenza A virus (IAV) infection during pregnancy that induces a robust inflammatory response
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Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination bioRxiv. Immunol. Pub Date : 2021-01-23 Veronika I Zarnitsyna; Rama S Akondy; Hasan Ahmed; Don J McGuire; Vladimir G Zarnitsyn; Mia Moore; Philip L F Johnson; Rafi Ahmed; Kelvin Li; Marc Hellerstein; Rustom Antia
Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models
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The magnitude of airway remodelling is not altered by distinct allergic inflammatory responses in BALB/c vs C57BL/6 mice but matrix composition differs bioRxiv. Immunol. Pub Date : 2021-01-23 James E Parkinson; Stella Pearson; Dominik Ruckerl; Judith E Allen; Tara E Sutherland
Allergic airway inflammation is heterogenous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodelling in asthma, but clinical data suggests that neutralising type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilised C57BL/6 and BALB/c mice to investigate the development of allergic
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Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model bioRxiv. Immunol. Pub Date : 2021-01-23 Shivkumar Biradar; Yash Agarwal; Antu Das; Sherry T Shu; Jasmine Samal; Sara Ho; Cole Beatty; Isabella Castronova; Robbie B. Mailliard; Thomas E Smithgall; Moses Turkle Bility
Loss of function mutations in the human immunodeficiency virus (HIV) negative factor (Nef) gene are associated with reduced viremia, robust T cell immune responses, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. In vitro studies have shown that mutations in the Nef dimerization interface significantly attenuate viral replication and impair host defense. However, in vivo
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γδ intraepithelial lymphocytes facilitate pathological epithelial cell shedding via CD103-mediated granzyme release. bioRxiv. Immunol. Pub Date : 2021-01-22 Madeleine D. Hu; Natasha B. Golovchenko; Thomas J. Kelly; Jonathan Agos; Matthew R. Zeglinski; Edward M. Bonder; Inga Sandrock; Immo Prinz; David J. Granville; Alastair J.M. Watson; Karen L Edelblum
Excessive shedding of enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. However, the mechanisms underlying this phenomenon remain unclear. Intraepithelial lymphocytes (IEL) expressing the γδ T-cell receptor (TCR) provide surveillance of the intestinal mucosa at steady-state, which is regulated, in part, by CD103. Intravital microscopy
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Structured decomposition improves systems serology prediction and interpretation bioRxiv. Immunol. Pub Date : 2021-01-22 Madeleine Murphy; Scott D Taylor; Aaron Samuel Meyer
Systems serology measurements provide a comprehensive view of humoral immunity by profiling both the antigen-binding and Fc properties of antibodies. Identifying patterns in these measurements will help to guide vaccine and therapeutic antibody development, and improve our understanding of disorders. Furthermore, consistent patterns across diseases may reflect conserved regulatory mechanisms; recognizing
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Systemic administration of anti-CD20 indirectly reduces B cells in the inflamed meninges in a chronic model of central nervous system autoimmunity bioRxiv. Immunol. Pub Date : 2021-01-22 Yodit Tesfagiorgis; Heather C Craig; Kate A Parham; Steven M Kerfoot
Anti-CD20 B cell depleting therapies have demonstrated that these cells are important drivers of disease progress in Multiple Sclerosis, although the pathogenic mechanisms are not well understood. A population of B cells accumulates in the inflamed meninges in MS and also some chronic animal models of disease, typically adjacent to demyelinating lesions. The role of these meningeal B cells in disease
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Bispecific antibody prevents SARS-CoV-2 escape and protects mice from disease bioRxiv. Immunol. Pub Date : 2021-01-22 Raoul De Gasparo; Mattia Pedotti; Luca Simonelli; Petr Nickl; Frauke Muecksch; Julio C. C. Lorenzi; Federica Mazzola; Davide Magrì; Tereza Michalcikova; Jan Haviernik; Vaclav Honig; Irene Cassaniti; Elena Percivalle; Blanka Mrazkova; Natalie Polakova; Andrea Fortova; Jolana Tureckova; Veronika Iatsiuk; Salvatore Di Girolamo; Martin Palus; Dagmar Zudova; Petr Bednar; Ivana Bukova; Filippo Bianchini;
Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19). We developed a bispecific, IgG1-like molecule based on two antibodies derived from COVID-19 convalescent donors, C121 and C135. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies
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Tristetraprolin prevents gastric metaplasia in mice by suppressing pathogenic inflammation bioRxiv. Immunol. Pub Date : 2021-01-21 Jonathan T Busada; Stuti Kadka; Kylie N Peterson; Deborah J Stumpo; Lecong Zhou; John A Cidlowski; Perry J Blackshear
Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin
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Low adenovirus vaccine doses administered to skin using microneedle patches induce better functional antibody immunogenicity as compared to systemic injection. bioRxiv. Immunol. Pub Date : 2021-01-21 Olivia Flynn; Kate Dillane; Juliane Sousa Lanza; Jennife M Marshall; Jing Jin; Sarah E Silk; Simon J Draper; Anne C Moore
Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases including COVID-19. However the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralising immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using
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Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation bioRxiv. Immunol. Pub Date : 2021-01-21 Madeline J Price; Christopher D Scharer; Anna K Kania; Troy Randall; Jeremy Boss
Memory B cells (MBCs) have enhanced capabilities to differentiate to plasma cells and generate a rapid burst of antibodies upon secondary stimulation. To determine if MBCs harbor an epigenetic landscape that contributes to increased differentiation potential, we derived the chromatin accessibility and transcriptomes of influenza-specific IgM and IgG MBCs compared to naive cells. MBCs possessed an accessible
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Analysis of HIV Reservoirs in Cellular Conjugates from Peripheral Blood bioRxiv. Immunol. Pub Date : 2021-01-21 Eli Boritz; Liliana Pérez; Daniel Crespo-Vélez; Max Lee; Saami Zakaria; April Poole; Jennifer Bell; Stephen Migueles; Tae-Wook Chun; Susan Moir; Frank Maldarelli
Defining distinctive attributes of HIV-infected cells will inform development of HIV cure-directed therapies. Prior ex vivo studies of blood and tissue have suggested that some HIV-infected CD4 T cells are found in conjugates with other cell types. Here, we analyzed levels and sequences of HIV nucleic acids in sorted cellular conjugates from PBMC. Compared to single CD4 T cells, conjugates containing
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Systemic inflammation recruits fast-acting anti-inflammatory innate myeloid progenitors from BM into lymphatics bioRxiv. Immunol. Pub Date : 2021-01-21 Juana Serrano-Lopez; Shailaja Hegde; Sachin Kumar; Josefina Serrano; Jing Fang; Ashley Wellendorf; Paul Roche; Yamileth Rangel; Leolene J Carrington; Hartmut Geiger; Lee Grimes; Sanjiv Luther; Ivan Maillard; Joaquin Sanchez-Garcia; Daniel Starczynowski; Jose Cancelas
Innate immune cellular effectors are actively consumed during systemic inflammation but the systemic traffic and the mechanisms that support their replenishment remain unknown. Here we demonstrate that acute systemic inflammation induces the emergent activation of a previously unrecognized system of rapid migration of granulocyte-macrophage progenitors and committed macrophage-dendritic progenitors
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Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis bioRxiv. Immunol. Pub Date : 2021-01-21 Edd Ricker; Michela Manni; Danny Flores-Castro; Daniel Jenkins; Sanjay Gupta; Juan Rivera-Correa; Wenzhao Meng; Aaron M Rosenfeld; Tania Pannellini; Yurii Chinenov; Peter K Sculco; Rolf Jessberger; Eline T Luning Prak; Alessandra B Pernis
Sex differences characterize immune responses to viruses and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that
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Itaconate and derivatives reduce interferon responses and inflammation in influenza A infection bioRxiv. Immunol. Pub Date : 2021-01-20 Aaqib Sohail; Azeem Iqbal; Nishika Sahini; Mohamed Tantawy; Moritz Winterhoff; Robert Geffers; Thomas Ebensen; Klaus Schughart; Marina Pils; Fangfang Chen; Carlos Alberto Guzman; Matthias Preusse; Stephan Pleschka; Ahmed Mostafa; Christine Falk; Alessandro Michelucci; Frank Pessler
Itaconate has recently emerged as a metabolite with immunomodulatory properties. We evaluated effects of endogenous itaconate and exogenous itaconate, dimethyl-, and 4-octyl-itaconate on host responses to influenza A virus infection. Infection induced ACOD1 (the enzyme that catalyzes itaconate synthesis) mRNA in monocytes and macrophages, which correlated with viral replication and was abrogated by
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RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signalling bioRxiv. Immunol. Pub Date : 2021-01-20 Kaiwen Chen; Benjamin Demarco; Rosalie Heilig; Saray Ramos; James Grayczyk; Charles-Antoine Assenmacher; Enrico Radaelli; Leonel Joannas; Jorge Henao-Mejia; Igor Brodsky; Petr Broz
Injection of effector proteins to block host innate immune signalling is a common strategy used by many pathogenic organisms to establish an infection. Pathogenic Yersinia species for example inject the acetyltransferase YopJ into target cells to inhibit NF-kB and MAPK signalling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing
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Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein bioRxiv. Immunol. Pub Date : 2021-01-20 Naveenchandra Suryadevara; Swathi Shrihari; Pavlo Gilchuk; Laura VanBlargan; Elad Binshtein; Seth Zost; Rachel Nargi; Rachel Sutton; Emma S Winkler; Elaine C Chen; Mallorie E. Fouch; Edgar Davidson; Benjamin Doranz; Robert H Carnahan; Larissa Thackray; Michael D Diamond; James E. Crowe
Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing
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NF-kB c-Rel is dispensable for the development but is required for the cytotoxic function of NK cells bioRxiv. Immunol. Pub Date : 2021-01-20 Yorleny Vicioso; Keman Zhang; Parameswaran Ramakrishnan; Reshmi Parameswaran
Natural Killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. We found that germ-line deficiency of NF-kB c-Rel results in a marked decrease in cytotoxic function of NK cells, both in vitro and in vivo, with no significant differences in the stages of NK cell development. We found that c-Rel binds to the promoters of perforin and granzyme B, two key proteins required for
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SARS-CoV-2 infection of circulating immune cells is not responsible for virus dissemination in severe COVID-19 patients bioRxiv. Immunol. Pub Date : 2021-01-19 Nicole L Rosin; Arzina Jaffer; Sarthak Sinha; Rory P Mulloy; Carolyn Robinson; Elodie Labit; Luiz G Almeida; Antoine Dufour; Jennifer A Corcoran; Bryan Yipp; Jeff Biernaskie
In late 2019 a novel coronavirus (SARS-CoV-2) emerged, and has since caused a global pandemic. Understanding the pathogenesis of COVID-19 disease is necessary to inform development of therapeutics, and management of infected patients. Using scRNAseq of blood drawn from SARS-CoV-2 patients, we asked whether SARS-CoV-2 may exploit immune cells as a 'Trojan Horse' to disseminate and access multiple organ
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Hinge Influences in Murine IgG Binding to Cryptococcus neoformans Capsule bioRxiv. Immunol. Pub Date : 2021-01-19 Diane Sthefany Lima de Oliveira; Verenice Paredes; Adrielle Veloso Caixeta; Nicole Moreira Henriques; Maggie P. Wear; Patrícia Albuquerque; Maria Sueli Soares Felipe; Arturo Casadevall; André Moraes Nicola
Decades of studies on antibody structure led to the tenet that the V region binds antigens while the C region interacts with immune effectors. In some antibodies, however, the C region affects affinity and/or specificity for the antigen. One such case is that of the 3E5 antibodies, a family of monoclonal murine IgGs in which the mIgG3 isotype has different fine specificity to the Cryptococcus neoformans
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Metabolic control of type 2 innate lymphoid cells plasticity toward protective type 1-like cells during Mycobacterium tuberculosis infection bioRxiv. Immunol. Pub Date : 2021-01-19 Denis Hudrisier; Dan Corral; Alison Charton; Maria Z Krauss; Eve Blanquart; Florence Levillain; Emma Lefrancais; Jean-Philippe Girard; Gerard Eberl; Yannick Poquet; Jean-Charles Guery; Rafael J Arguello; Matthew R Hepworth; Olivier Neyrolles
Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis and protect against pathogens at mucosal surfaces and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues in their tissue of residence remains to be fully understood. Here we show that Mycobacterium tuberculosis infection alters the biology of lung
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Mitochondrial oxidative stress drives IL-12/IL-18-induced IFN-gamma production by CD4+ T cells and is controlled by Fas bioRxiv. Immunol. Pub Date : 2021-01-19 Gorjana Rackov; Parinaz Tavakoli Zaniani; Sara Colomo del Pino; Rahman Shokri; Melchor Alvarez Mon; Carlos Martinez-A; Dimitrios Balomenos
Mitochondrial activation and mROS production are crucial for CD4+ T cell responses and have a role in naive cell signaling after TCR activation. However, little is known about their role in recall responses driven by cytokine signaling. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-gamma, an essential cytokine in inflammatory and autoimmune disease development
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The impact of Spike mutations on SARS-CoV-2 neutralization bioRxiv. Immunol. Pub Date : 2021-01-19 Chloe Rees-Spear; Luke Muir; Sarah A Griffith; Judith Heaney; Yoann Aldon; Jonne Snitselaar; Peter Thomas; Carl Graham; Jeffrey Seow; Nayung Lee; Annachiara Rosa; Chloe Roustan; Catherine F Houlihan; Rogier W Sanders; Ravindra K Gupta; Peter Cherepanov; Hans Stauss; Eleni Nastouli; Katie J Doores; Marit J van Gils; Laura E McCoy
Multiple SARS-CoV-2 vaccines have shown protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, Spike. Antibodies from SARS-CoV-2 infection neutralize the virus by focused targeting of Spike and there is limited serum cross-neutralization of the closely-related SARS-CoV. As new SARS-CoV-2 variants are rapidly emerging, exemplified by the B
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Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera bioRxiv. Immunol. Pub Date : 2021-01-19 Alexander Muik; Ann-Kathrin Wallisch; Bianca Saenger; Kena A Swanson; Julia Muehl; Wei Chen; Hui Cai; Ritu Sarkar; Oezlem Tuereci; Philip R Dormitzer; Ugur Sahin
Recently, a new SARS-CoV-2 lineage called B.1.1.7 has emerged in the United Kingdom that was reported to spread more efficiently than other strains. This variant has an unusually large number of mutations with 10 amino acid changes in the spike protein, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we investigated SARS-CoV-2-S pseudoviruses bearing either the
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mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants bioRxiv. Immunol. Pub Date : 2021-01-19 Zijun Wang; Fabian Schmidt; Yiska Weisblum; Frauke Muecksch; Christopher O Barnes; Shlomo Finkin; Dennis Schaefer-Babajew; Melissa Cipolla; Christian Gaebler; Jenna A Lieberman; Zhi Yang; Morgan E Abernathy; Kathryn E Huey-Tubman; Arlene Hurley; Martina Turroja; Kamille A West; Kristie Gordon; Katrina G Millard; Victor Ramos; Justin Da Silva; Jianliang Xu; Robert A Colbert; Roshni Patel; Juan P Dizon;
To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected nearly 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease-2019 (COVID-19) including two novel mRNA-based vaccines. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies
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FcγR responses to soluble immune complexes are governed by solubility and size bioRxiv. Immunol. Pub Date : 2021-01-19 Haizhang Chen; Andrea Maul-Pavicic; Martin Holzer; Ulrich Salzer; Nina Chevalier; Reinhard Edmund Voll; Hartmut Hengel; Philipp Kolb
Fcγ-receptor (FcγR) activation by antibody derived soluble immune complexes (sICs) is a major contributor to inflammation in autoimmune diseases such as systemic lupus erythematosus (SLE). A robust and scalable test system allowing for the detection and quantification of sICs with regard to receptor activation is missing. We developed a comprehensive cell-based reporter system capable of measuring
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SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma bioRxiv. Immunol. Pub Date : 2021-01-19 Constantinos Kurt Wibmer; Frances Ayres; Tandile Hermanus; Mashudu Madzivhandila; Prudence Kgagudi; Bronwen E Lambson; Marion Vermeulen; Karin van den Berg; Theresa Rossouw; Michael Boswell; Veronica Ueckermann; Susan Meiring; Anne von Gottberg; Cheryl Cohen; Lynn Morris; Jinal N Bhiman; Penny L Moore
SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein. Here we show that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma
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Dermatan Sulfate Is a Potential Master Regulator of IgH via Interactions with Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts bioRxiv. Immunol. Pub Date : 2021-01-19 Jongmin Lee; Jung-hyun Rho; Michael H. Roehrl; Julia Y. Wang
Dermatan sulfate (DS) and autoantigen (autoAg) complexes are capable of stimulating autoreactive CD5+ B-1 cells. We examined the activity of DS on CD5+ pre-B lymphoblast NFS-25 cells. CD19, CD5, CD72, PI3K, and Fas possess varying degrees of DS affinity. The three pre-BCR components, Ig heavy chain mu (IgH), VpreB, and lambda 5, display differential DS affinities, with IgH having the strongest affinity
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Inflammatory Cytokines Regulate T-cell Development from Blood Progenitor Cells in a Stage and Dose-Specific Manner bioRxiv. Immunol. Pub Date : 2021-01-19 John M Edgar; Peter W Zandstra
T-cell development from hematopoietic stem and progenitor cells (HSPCs) is tightly regulated through Notch pathway activation by the Notch ligands Delta-like (DL) 1 and 4 and Jagged-2. Other molecules, such as stem cell factor (SCF), FMS-like tyrosine kinase 3 ligand (Flt3L) and interleukin (IL)-7, play a supportive role in regulating the survival, differentiation, and proliferation of developing progenitor
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Simultaneous Control of Infection and Inflammation by Keratin-Derived Antimicrobial Peptides (KAMPs) Targeting TLRs and Co-receptors bioRxiv. Immunol. Pub Date : 2021-01-19 Yan Sun; Jonathan Chan; Karthikeyan Bose; Connie Tam
The use and the timing of initiation of steroids for controlling unwanted infectious inflammation are major clinical dilemmas due to their possible adverse effects including delayed microbial clearance and wound healing. Compounding this difficulty is the continued emergence of drug-resistant bacteria; yet anti-infective strategies aiming at augmenting inflammatory responses to facilitate bacterial
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Potent but transient immunosuppression of T-cells is a general feature of erythroid progenitor cells bioRxiv. Immunol. Pub Date : 2021-01-19 Tomasz M Grzywa; Anna Sosnowska; Zuzanna Rydzynska; Michal Lazniewski; Dariusz Plewczynski; Klaudia Klicka; Milena Malecka; Anna Rodziewicz-Lurzynska; Olga Ciepiela; Magdalena Justyniarska; Paulina Pomper; Marcin M Grzybowski; Roman Blaszczyk; Michal Wegrzynowicz; Agnieszka Tomaszewska; Grzegorz Basak; Jakub Golab; Dominika Nowis
Erythroid progenitor cells (EPCs) have been recently recognized as potent immunoregulatory cells with defined roles in fetomaternal tolerance and immune response to infectious agents in neonates and cancer patients. Here, we show that early-stage EPCs are enriched in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). EPCs expansion in anemic mice leads to the L-arginine
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Loss of C3aR induces immune infiltration and inflammatory microbiota in a novel spontaneous model of colon cancer bioRxiv. Immunol. Pub Date : 2021-01-19 Carsten Krieg; Sara Carloni; Lukas M Weber; Bruno Fosso; Gary Hardiman; Erika Mileti; Sahar El Aidy; Marinella Marzano; Graziano Pesole; Francesco Asnicar; Nicola Segata; Mark D Robinson; Silvia Guglietta
Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of colorectal cancer (CRC) and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune response. Emerging evidence suggests that complement anaphylatoxin C3a produced
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Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mice and non-human primates bioRxiv. Immunol. Pub Date : 2021-01-19 Nerea Zabaleta; Wenlong Dai; Urja Bhatt; Jessica A. Chichester; Julio Sanmiguel; Reynette Estelien; Kristofer T. Michalson; Cheikh Diop; Dawid Maciorowski; Wenbin Qi; Elissa Hudspeth; Allison Cucalon; Cecilia D. Dyer; M. Betina Pampena; James J. Knox; Regina C. LaRocque; Richelle C. Charles; Dan Li; Maya Kim; Abigail Sheridan; Nadia Storm; Rebecca I. Johnson; Jared Feldman; Blake M. Hauser; Eric Zinn;
The SARS-CoV-2 pandemic has affected more than 70 million people worldwide and resulted in over 1.5 million deaths. A broad deployment of effective immunization campaigns to achieve population immunity at global scale will depend on the biological and logistical attributes of the vaccine. Here, two adeno-associated viral (AAV)-based vaccine candidates demonstrate potent immunogenicity in mouse and
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Common anti-hemostatic medications increase the severity of uropathogenic Escherichia coli sepsis bioRxiv. Immunol. Pub Date : 2021-01-18 Vi Tran; Elinor Hortle; Warwick J Britton; Stefan H Oehlers
Uropathogenic Escherichia coli (UPEC) causes urinary tract infections that can result in sepsis. Hemostasis is protective in the pyelonephritis stage of ascending UPEC infection, the role of hemostasis but has not been investigated during sepsis. Here we utilize a zebrafish-UPEC sepsis model to visualize infection-induced coagulation and examine the effects of commonly prescribed anti-hemostatic medications
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Selenium-dependent metabolic reprogramming during inflammation and resolution bioRxiv. Immunol. Pub Date : 2021-01-18 Arvind M. Korwar; Ayaan Hossain; Tai-Jung Lee; Ashley E Shay; Venkatesha Basrur; Kevin P Conlon; Philip B Smith; Bradley A Carlson; Howard M Salis; Andrew D. Patterson; K. Sandeep Prabhu
Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine (Sec), into selenoproteins through tRNA[Ser]Sec. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin
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Allosteric activation of T-cell antigen receptor signalling by quaternary structure relaxation bioRxiv. Immunol. Pub Date : 2021-01-18 Anna-Lisa Lanz; Giulia Masi; Nicla Porciello; Andre Cohnen; Deborah Cipria; Dheeraj Prakaash; Stefan Balint; Roberto Raggiaschi; Donatella Galgano; David Cole; Marco Lepore; Omer Dushek; Michael Dustin; Mark Sansom; Antreas C Kalli; Oreste Acuto
The mechanism of T cell antigen receptor (TCR-CD3) signalling remains elusive. Here, we identified mutations in the transmembrane region of TCRβ or CD3ζ that augmented pMHC-induced signalling, not explicable by enhanced ligand binding, lateral diffusion, clustering or co-receptor function. Using a novel biochemical assay and molecular dynamics simulation, we demonstrated that the gain-of-function mutations
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Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity bioRxiv. Immunol. Pub Date : 2021-01-17 Avery J Lam; David T. S. Lin; Jana K Gillies; Prakruti Uday; Anne M Pesenacker; Michael S Kobor; Megan K Levings
Treg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we
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Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites bioRxiv. Immunol. Pub Date : 2021-01-17 Lakmali Munasinghage Silva; Andrew D Doyle; Collin L Tran; Teresa Greenwell-Wild; Nicolas Dutzan; Andrew G Lum; Cary S Agler; Megan Sibree; Priyam Jani; Daniel Martin; Vardit Kram; Francis J Castellino; Matthew J Flick; Kimon Divaris; Thomas H Bugge; Niki M Moutsopoulos
Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we document that the clotting factor fibrin is a critical regulator of neutrophil function at mucosal barriers. We demonstrate that fibrin engages neutrophils through the aMb2 integrin receptor and activates effector functions, including the production of reactive oxygen species and NET formation. These immune-protective neutrophil
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Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes bioRxiv. Immunol. Pub Date : 2021-01-17 Matias Gutierrez-Gonzalez; Ahmed S Fahad; Matt Ardito; Padma Nanaware; Liying Lu; Erica Normandin; Bharat Madan; Jacob Tivin; Emily Coates; Amy R Henry; Farida Laboune; Barney S Graham; Daniel C Douek; Julie E Ledgerwood; John R Mascola; William D Martin; Lawrence Stern; Annie S De Groot; Brandon J DeKosky
Human antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody development in vivo. Large-scale antibody sequence
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Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5 bioRxiv. Immunol. Pub Date : 2021-01-17 Hiroshi Ichise; Shoko Tsukamoto; Tsuyoshi Hirashima; Yoshinobu Konishi; Choji Oki; Shinya Tsukiji; Satoshi Iwano; Atsushi Miyawaki; Kenta Sumiyama; Kenta Terai; Michiyuki Matsuda
Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is not known. Here we have combined ultra-sensitive bioluminescence whole body imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated
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Discovery of 10,828 new putative human immunoglobulin heavy chain IGHV variants bioRxiv. Immunol. Pub Date : 2021-01-17 Fabio R Martins; Lucas Alves de Melo Pontes; Tiago Antonio de Oliveira Mendes; Liza F Felicori
The correct identification of immunoglobulin alleles in genome sequences is a challenge. Nevertheless, it can assist in the study of several human diseases associated with the antibody repertoire and in the development of new therapies using antibody engineering techniques. The advent of next-generation sequencing of human genomes and antibody repertoires enabled the development of several tools for
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Locally confined IFNγ production by CD4+ T cells provides niches for murine cytomegalovirus replication in the salivary gland bioRxiv. Immunol. Pub Date : 2021-01-16 Josua Oderbolz; Nathan Zangger; Lea Zimmermann; Ioana Sandu; Joern Starruss; Frederik Graw; Annette Oxenius
Cytomegalovirus (CMV) has evolved a unique virus-host relationship in the salivary glands (SGs) to sustain prolonged viral replication and hence chances for horizontal transmission. Previous reports have established a decisive role for IFNγ producing CD4+ T cells to control murine CMV (MCMV) infection in the SGs; however, micro-anatomical information regarding their mode of action is largely missing