bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of iNKT cells: influence of Y-chromosome genes (153.44)
Authors: Toussaint Leon , Case Laure , Terrizzi Stephanie , Ericson Jeffrey , Benoist Christophe , Teuscher Cory , Brossay Laurent 
Published: January 2023

Abstract
In previous studies, we identified a mouse strain, B6.Ynkt, in which only males were deficient in iNKT cells and demonstrated that the deficiency was linked to Y-chromosome factors. We reasoned that the deficiency could be due to either a consomic effect of the Y-chromosome or due to a spontaneous germ line mutation on the Y- chromosome that occurred during the backcross to B6 background. To test the consomic hypothesis, we examined the iNKT cell frequency and number, in 16 different Y consomic strains. Although there is variation between the different strains tested none of them have a drastic decrease in iNKT cell number and frequency. To test the second hypothesis, we performed µarray on residual iNKT cells and conventional CD4+ T cells from the B6.Ynkt strain. The gene expression profile from these cells was compared to B6 iNKT cells and CD4+ T cells. We found that 4 contiguous genes on the Y-chromosome, were not expressed in the B6.Ynkt iNKT cells but were expressed in wild-type B6 iNKT cells. Importantly, these genes were expressed similarly in conventional CD4+ T cells from both wild-type B6 and B6.Ynkt mice suggesting the phenotype observed was not due to a deletion in this area. Genomic analysis confirmed that these 4 genes are present in both strains of mice. Taken together, our results argue against a consomic effect. Rather the data revealed a possible genetic expression repression of specific genes found contiguously on the Y-chromosome.
A simple and fast method for the enrichment of lymphoid progenitors from mouse bone marrow (153.9)
Authors: Tabatabaei-Zavareh Nooshin , Thomas Terry , Fairhurst Maureen 
Published: January 2023

Abstract
The expression of IL-7Rα in the common lymphoid progenitor (CLP) population marks initiation and/or commitment to the lymphoid lineage. CLPs hold potential for only B, T and NK cell lymphoid lineages and are defined as Lin−IL-7Rα+c-KitloSca-1lo. Study of lymphocyte development largely relies on access to CLPs or other IL-7Rα+ lymphoid progenitors. Fluorescence-activated cell sorting (FACS) commonly used to isolate lymphoid progenitors is costly, time-consuming and possibly detrimental to cell viability. We describe a fast and efficient method for the isolation of lymphoid progenitors from mouse bone marrow (BM). This method is based on immunomagnetic, column-free cell separation technology (EasySepTM). Using this method, lineage positive cells are first depleted by cross-linking them to magnetic particles using biotinylated antibodies. Next, IL-7Rα+ cells are positively selected from the Lin−/lo population. After enrichment, average purity of Lin−IL-7Rα+ lymphoid progenitors as assessed by flow cytometry is 32 ± 10% (n=18). Lin−IL-7Rα+c-KitloSca-1lo cells are enriched 60-fold from 0.08 ± 0.05% in start BM to 4.6 ± 2.5%. Limiting dilution analysis of enriched cells shows increased frequencies of B cell (1:73, n=12), T cell (1:16, n=5) and NK cell (1:65, n=6) progenitors as compared to non-depleted control BM. This system introduces an easy method for the enrichment of lymphoid progenitors with good viability that will enable study of developmental immunology.
TLR-9 agonist protects human monocytic cells against HIV-Vpr-induced apoptosis: a critical role for Calmodulin-dependent protein kinase-II, c-JUN N terminal kinase and anti-apoptotic c-IAP-2 gene (154.11)
Authors: Saxena Mansi , Busca Aurelia , Pandey Sunita , Kumar Ashok 
Published: January 2023

Abstract
Monocytic cells unlike CD4+ T cells survive HIV induced apoptosis and serve as key viral reservoirs. Mechanisms underlying the development of resistance to HIV-induced cytopathic effects are poorly understood. In chronic HIV infections, microbial products translocate from the gut and may activate lymphocytes conferring anti-apoptotic signals. By using Vpr52-96 peptide, an accessory protein of HIV known to cause apoptosis in various cell types, as a model for apoptosis-inducing protein, we demonstrate that Vpr52-96 induced apoptosis in primary monocytes and undifferentiated THP-1 cells. However, monocyte-derived macrophages and PMA-differentiated THP-1 cells exhibited profound resistance to Vpr-induced apoptosis. Interestingly, prior treatment of primary monocytes and undifferentiated THP-1 cells with TLR-9 agonist, CpG, induced resistance to Vpr-mediated apoptosis. This resistance was found to be mediated by extracellular calcium influx, activation of c-Jun N terminal kinase via Calmodulin-dependent kinase II and induction of anti apoptotic cIAP2 gene. Our results also revealed a novel pathway by which Vpr may dysregulate TLR signaling in monocytes by targeting MyD88. Interestingly, CpG protected these cells by blocking the Vpr-induced inhibition of MyD88. Overall, our results suggest that anti-apoptotic cIAP2 gene and calcium activated JNK signaling play a crucial role in conferring resistance induced by CpG against Vpr-mediated apoptosis in monocytic cells.
Basic mechanisms of Friend virus-induced immunomodulation and tumorigenesis (154.34)
Authors: Shen Limei , Balkow Sandra , Bros Matthias , Grabbe Stephan 
Published: January 2023

Abstract
Friend murine leukemia Virus (FV) infection of immunocompetent mice is a well established model to acquire further knowledge about retrovirus-associated mechanisms, enabling the development of preventive and therapeutic treatments against retrovirus-induced diseases. Our own studies show that formation of the immunological synapse between FV-infected DCs and T cells is altered. Those DCs induced a regulatory phenotype and suppressive function in cocultured CD4+ T cells (Treg). In order to identify key molecules that contribute to this Treg induction, expression patterns of cytoplasmatic proteins in uninfected and FV-infected DCs were comparatively analyzed by Protein-mass fingerprinting. By that approach about 600 differentially expressed proteins were identified. Interestingly, many of these are cytoskeletal proteins, and some are known to be involved in DC-T cell interactions (e.g. Myosins1F, 9, and 14). Notably, several MHCII antigens are downregulated in FV-infected DCs as compared with uninfected DCs. Recent studies show that the endocytic capacity of FV-infected DCs was significantly enhanced as compared with control DCs. Our current work is focussed on elucidating the function of signalling proteins which are differentially expressed in FV-infected vs. uninfected DCs. Taken together, our work is aimed to understand how retroviral infection of DCs alters DC-T cell interactions, and at which extent these effects contribute to retrovirus-induced immunosuppression.
Human herpesvirus 6 suppresses T cell proliferation through the induction of infected cell cycle arrest in G2/M phase (154.38)
Authors: Yao Kun , Li Lingyun , Zhou Feng , Chi Jing , Wang Fang , Peng Guangyong , Gu Bin , Xie Fangyi , Qing Jian , Feng Dongju , Lu Shiqiang 
Published: January 2023

Abstract
Human herpesvirus 6 is an important immunosuppressive and immunomodulatory virus which infects immune cells and strongly suppresses the proliferation of infected cells. However, the mechanisms responsible for the regulation and suppression mediated by HHV-6 are still unknown. In this study, we examined the ability of HHV-6A to manipulate cell cycle progression in the infected cells and explored the potential molecular mechanisms. We demonstrated that infection with HHV-6A imposed a growth-inhibitory effect on HSB-2 cells by inducing cell cycle arrest at G2/M phase. We then showed that the activity of Cdc2-cyclinB1 complex was significantly decreased in HHV-6A infected HSB-2 cells. Furthermore, we found that inactivation of Cdc2-cyclinB1 in infected cells was through the inhibitory Tyr15 phosphorylation resulting from the elevated Wee1 expression and inactivated Cdc25C; Meanwhile, the reduction of Cdc2-cyclinB1 activity in infected cells was also partly due to the increased expression of cell cycle regulatory molecule p21 in a p53-dependent manner. In addition, HHV-6A infection activated the DNA damage checkpoint kinases, Chk2 and Chk1. Our data suggest that HHV-6A infection induces G2/M arrest in infected T cells via various regulatory mechanisms. These results demonstrate potential mechanisms involved in immune suppression and modulation mediated by HHV-6 infection, and provide new insights relevant to the development of novel vaccines and immunotherapeutic approaches.
Ectromelia NF-κβ inhibitor 002 is essential for virus pathogenesis (154.4)
Authors: Rubio Daniel , Alcami Antonio , Sigal Luis 
Published: January 2023

Abstract
Ectromelia virus is an orthopoxvirus and the causative agent of mousepox in mice. The virus codifies several proteins to control the host response. One of them is the NF-κβ inhibitor, ECTV 002 which has orthologs in other poxviruses including cowpox, monkeypox and variola viruses. We generated an ectromelia virus that lacks this gene (ECTV Δ002) and its correspondent revertant virus. Both viruses grew normally in vitro; however, when used to infected BALB/C mice in the footpad, only the WT and revertant viruses killed the mice. When using different doses, the LD50s were lower than 1pfu for the WT and revertant viruses but higher than 105 for the ECTV Δ002 indicating an attenuation of at least 5 orders of magnitude. We then analyzed the virus spread by measuring virus titers in different organs. The virus load in the draining lymph node was lower in mice infected with the ECTV Δ002 than with the revertant virus and consequently, the virus titer in peripheral organs like spleen or liver was lower as well. When we compared the immune responses in the draining lymph nodes by flow cytometry, we did not find significant differences between ECTV Δ002 and WT viruses. However, 7 dpi, the mice infected with ECTV Δ002 had elevated numbers of NK, CD8 and CD4 cells in their spleens as compared to mice infected with revertant virus. Altogether our results show that ECTV 002 is essential for ECTV pathogenesis and that the control of the infection occurs early in the draining lymph node.
A cationic lipid/DNA complexes (JVRS-100) combined with influenza A H5N1 vaccine induce long-term antibody responses and protection against H5N1 virus in BALB/c mice (155.31)
Authors: Liu Feng , Hancock Kathy , Katz Jacqueline , Fairman Jeffery , Lu Xiuhua 
Published: January 2023

Abstract
Highly pathogenic avian influenza A H5N1 viruses pose a pandemic threat. An adjuvant is needed due to poor immunogenicity of pre-pandemic H5N1 vaccine in humans. JVRS-100 is a novel adjuvant, composed of cationic liposomes and plasmid DNA. Here, we investigated the long-term immunogenicity and protective efficacy of JVRS-100-adjuvanted H5N1 vaccine in mice. One year after immunization with one dose of vaccine with or without JVRS-100 adjuvant, significantly higher levels of hemagglutination-inhibition antibody and IgG antibody could be detected in serum of mice immunized with adjuvanted vaccine compared to that of mice receiving vaccine only. No or limited waning of antibody response was observed up to one year after immunization. IgG2a clearly predominated in serum of mice that received adjuvanted vaccine, suggesting that JVRS-100 preferentially stimulates a Th1 response. Mice were challenged with a high lethal dose of H5N1 virus 14 months after immunization. Co-administration of JVRS-100 with H5N1 vaccine significantly reduced virus titers in the lungs and brains and completely protected mice from severe disease and death. Our results indicate that the addition of JVRS-100 to H5N1 vaccine enhanced long-term antibody responses and protection against H5N1 virus lethal disease in mice. Therefore, JVRS-100 warrants further investigation as a potential adjuvant for use in human vaccination against avian influenza viruses with pandemic potential.
IRX-2, a novel immunotherapeutic, enhances NK cell function and protects NK cells from TGFβ-mediated inhibition. (156.14)
Authors: Schilling Bastian , Schuler Patrick , Harasymczuk Malgorzata , Egan James , Whiteside Theresa 
Published: January 2023

Abstract
Background: IRX-2 is a primary biologic which has been used for therapy of head and neck cancer with promising clinical results. Since NK cell function is compromised in head and neck cancer (HNC) patients, we tested the effects of IRX-2 on human NK cells in vitro. Methods: PBMC were isolated 10 HNC patients and 10 healthy donors (HD). NK cell phenotype and function were compared before and after culture ± IRX-2 or 50 IU/ml IL-2. NK cell phenotype, signaling, cytotoxicity and cytokine production were studied by flow cytometry. Results: Cytotoxicity was impaired in HNC patients (614 LU20 vs. 2760 LU20, p&lt;0.01). Mean expression of NKG2D, NKp30 and NKp46 was significantly lower in HNC patients than in HD (p&lt;0.05). Patients’ NK cells treated with IRX-2 expressed higher levels of these receptors than those treated with IL-2 (p&lt;0.05) and showed higher cytotoxicity (3000 LU20 vs. 1300 LU20, p&lt;0.01). In the presence of TGF-β, IL-2 did not increase the expression of activating NK cell receptors while IRX-2 still upregulated NKG2D and NKp30 (p&lt;0.05). More importantly, IRX-2 protected NK cells from TGF-β- mediated impairment of cytotoxicity (p&lt;0.05), while IL-2 did not. Conclusions: IRX-2 is more effective in enhancing and protecting NK cell function of HNC patients in vitro than IL-2 alone. Our data suggest that clinical responses previously observed in HNC patients treated with IRX-2 could be, at least in part, attributed to restored NK cell function.
Cytomegalovirus-based cancer vaccines expressing TRP2 induce potent antitumor effect against melanoma in mice (156.20)
Authors: Xu Guangwu , Smith Tameka , Hill Ann 
Published: January 2023

Abstract
Cytomegalovirus (CMV) induces strong and long-lasting immune responses, which make it an attractive candidate for a cancer vaccine vector. In this study, we tested whether a tumor antigen expressed in CMV can induce an anti-tumor effect. We expressed the melanoma tumor antigen, tyrosinase-related protein 2 (TRP2), in murine cytomegalovirus (MCMV). A single prophylactic dose of MCMV-TRP2 induced complete rejection of B16 melanoma cells. In a therapeutic setting, MCMV-TRP2 significantly inhibited the growth of melanoma. In addition, the growth of B16 cells inoculated five months after a single vaccination with MCMV-TRP2 was still inhibited, which indicates the vaccine induced a long-term protection. MCMV-TRP2 induced the production of both TRP2-specific CD8 T cells and antibodies. Depletion of CD4 and CD8 T cells did not compromise the antitumor effect, but MCMV-TRP2-vaccinated B cell deficient (µMT) mice did not reject B16 cells. This indicated that antibody rather than T cells was the main mediator of the antitumor effect induced by MCMV-TRP2. We also made a spread-deficient MCMV-TRP2 vaccine, which showed a similar antitumor effect. In conclusion, our study indicates that TRP2 expressed in MCMV induces a strong and long-lasting anti-melanoma effect through an antibody dependent mechanism. Our findings demonstrated for the first time that CMV is a promising vector for cancer vaccines.
Sequential administration of chemotherapy and tumor lysate pulsed autologous dendritic cells induce stronger anti-tumor activity in treatment of metastatic colorectal cancer: immunologic results and the underlying mechanisms from a phase II trial. (156.3)
Authors: Wu Yanfeng , Wan Tao , Cao Xuetao 
Published: January 2023

Abstract
We conducted a randomized phase II trial to determine whether sequential administration of chemoherapy plus DC vaccine is superior to chemotherapy alone. Our studies indicated that appropriate doses of oxaliplatin(OXA) and/or 5-Fu could enhance HLA-A2 and Fas expression, depressed FasL expression on SW480 cell surface and stimulate higher counts of IFN-γ secretion antigen-specific T cells, decrease the productions of immunosuppression cytokines such as IL-10, TGF-β, and VEGF in supernatants of treated SW480 cells, in peripheral blood of patients with metastatic colorectal cancer(MCRC) and CT26 liver metastasis mice models. The proportions of CD4+CD25+ Treg were observed to reduce in PBMCs from MCRC patients or in splenocytes from CT26 liver metastasis mice, as well as CD11b+Gr-1+ MSCs after the chemotherapy. Sequential antigen-pulsed DC administration could stabilize above-mentioned results afterwards. We also found that the production of Hsp70, a new Th1 polarization adjuvant which is a chaperone important to the DCs’ cross-presentation, significant increased in peripheral blood of MCRC patients after OXA and 5-Fu chemotherapy. The survival time of CT26 liver metastasis mice had been significant prolonged and specific anti-tumor immune response induced by receiving sequential immuno-chemotherapy. We hope that these results may provide new strategies and methods in clinical trials revolving immunotherapy.
Carcinoembryonic antigen-related cell adhesion molecule 1 down regulates Syk coupled neutrophil NLRP3 inflammasome activation through ITIM and the recruitment of SHP-1 (157.12)
Authors: Lu Rongze , Pan Hao , Shively John 
Published: January 2023

Abstract
IL-1β is a critical pro-inflammatory cytokine produced by innate immune cells, and is regulated by the inflammasome. Recently thioredoxin -interacting protein (TXNIP) has been shown to associate with and activate the Nod-like receptor protein 3(NLRP3) inflammosome in a ROS-sensitive manner. We have found LPS induced the NLRP3 inflammasome activation in neutrophils was dependent on ROS production and lysosomal damage, both of which were regulated by spleen tyrosine kinase (Syk).We have demonstrated LPS induced phosphorylation of Syk and formation of a complex platform including Toll -like receptor 4(TLR4), TXNIP and p-Syk, to facilitate ROS production the inflammosome activation. We also found that carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1) associated with TLR4 ,TXNIP and p-Syk complex in response to LPS. IL-1β, pro-caspase-1, ROS and lysosomal destabilization are enhanced in neutrophils from ceacam1-/- mice. CEACAM negatively regulates phosphorylation of Syk and the inflammosome activation by recruiting phosphatase SHP-1 through CEACAM1’s (immunoreceptor tyrosine-based inhibition motif) ITIMs. Pharmaceutical inhibition of Syk activation or knock down of Syk attenuated Syk phosphorylation and the inflammosome activation in ceacam1-/- neutrophils. Reconstitution of CEACAM1 restores inflammasome activation to normal level. Therefore, we identify CEACAM1 as a negative regulator of the Syk coupled NLRP3 inflammasome activation.
Cytosolic DNA sensing by AIM2 inflammasome is integral to anti-microbial defense (157.5)
Authors: Rathinam Vijay , Waggoner Stephen , Jiang Zhaozhao , Sharma Shruti , Monks Brian , Waggoner Lisa , Fitzgerald Katherine 
Published: January 2023

Abstract
Cytosolic DNA of microbial and eukaryotic origins elicits strong inflammatory responses characterized by the production of type I interferons and IL-1β/IL-18. The maturation of proforms of IL-1β and IL-18 into bioactive forms is mediated by a multiprotein complex in the cytosol called inflammasomes. Recently, AIM2 (absent in melanoma 2) protein was shown to recognize cytosolic DNA and form an inflammasome complex. To understand the role of AIM2 in innate immunity, we generated AIM2 deficient mice. Using the AIM2-deficient mice, we demonstrate that AIM2 inflammasome is an essential and non-redundant mechanism mediating IL-1β and IL-18 responses to cytosolic DNA from bacterial and viral infections. In contrast, cytosolic DNA-induced activation of NF-κB and IRF-3 are normal in AIM2-/- cells indicating that AIM2 is least likely to play a role in type I interferon production elicited by cytosolic DNA. Importantly, AIM2 deficient mice infected with vaccinia virus (VV) or mouse cytomegalovirus (mCMV) demonstrated a marked reduction in serum IL-18 levels and in number of IFN-γ producing splenic NK cells, which are critical events in the early control of VV and mCMV infection. Correspondingly, AIM2 deficiency hampered the control of virus replication in the infected mice. Overall, we demonstrate that AIM2 inflammasome is an integral component of cytosolic DNA sensing in microbial infections.
NLRC4 inflammasomes in dendritic cells evoke non-cognate effector function by memory CD8 T cells that improve immunity to Salmonella typhimurium (158.1)
Authors: Bedoui Sammy , Andreas Kupz , Guarda Greta , Gebhardt Thomas , Sander Leif , Curtis Roy , Tschopp Jurg , Strugnell Richard 
Published: January 2023

Abstract
Salmonella enterica is the causative agent of typhoid fever, a condition with considerable global human morbidity and mortality. Although it is well established that interferon-γ (IFN-γ) is critical for the control of Salmonella infections, the cellular source of this protective cytokine and its regulation during Salmonella infection remain unclear. CD4 T cells have been suggested as prime producers of IFN-γ during Salmonella infection. However, in contrast to non-lethal Salmonellosis ensuing in CD4 T cell deficient hosts, mice lacking IFN-γ rapidly succumb to the infection, suggesting that cells other than CD4 T cells contribute to IFN-γ-mediated protection against Salmonella infection. Here, we identify a novel mechanism by which Salmonella Typhimurium-derived flagellin triggers IFN-γ secretion by CD62Lhi memory CD8 T cells in an antigen-independent fashion. Our findings not only resolve that this phenomenon depends on the release of IL-18 by dendritic cells (DC) upon flagellin recognition through NLRC4 inflammasomes in vivo, but also demonstrate that non-cognate memory CD8 T cells improve survival following Salmonella Typhimurium infection. Thus, these findings uncover a novel, innate role for memory CD8 T cells in protection against Salmonella and establish a functional link between inflammasome activation in DC and CD8 T cell function in vivo.
Macrophage migration inhibitory factor increases MHC II and CD86 on dendritic cells and favors proinflammatory cytokine production mediated by ERK1/2 phosphorylation in Trypanosoma cruzi infection (158.14)
Authors: Rodríguez-Sosa Miriam , Terrazas César A , Huitron Erick , Vazquez Alicia , Juárez Imelda , Camacho Griselda , Elsa A. Calleja 
Published: January 2023

Abstract
Macrophage migration inhibitory factor (MIF) has been found to be involved in host resistance to several parasitic infections. To determine the mechanisms of MIF-dependent responses to Trypanosoma cruzi (Queretaro strain), we investigated host resistance in MIF-/- mice (BALB/c background) during an intraperitoneal (i.p.) infection. We focused on the potential involvement of MIF on Dendritic Cell (DC) maturation and cytokine production. Following i.p. T. cruzi infection, wild type (WT) mice developed a strong IL-12 response with an adequate maturation of their DC in draining mesenteric lymph node (MLNDC), these mice were resistant to a challenge with 5x103 parasites. In contrast, similarly infected MIF-/- mice mounted a weak IL-12 response, displayed immature MLNDCs in the early phases of infection and rapidly succumbed to a similar challenge. Lack of maturation and IL-12 production of DCs in response to total or soluble T. cruzi antigens was confirmed by in vitro studies, such effects were reversed following treatment with recombinant MIF. Interestingly, whereas DC from WT mice exposed to total T. cruzi antigens had ERK1/2 MAPK phosphorylation, MIF-/- DC did not. These findings demonstrate that MIF-induced early DC maturation and IL-12 production mediate resistance to T. cruzi infection, probably by activation of ERK1/2 MAPK pathway.