bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of cytotoxic anti-tumor antibodies against N Glycolyl containing gangliosides through idiotypic vaccination: clinical data (P2022)
Authors: Hernandez Anita 
Published: January 2023

Abstract
N glycolylated (NeuGc) gangliosides are not normal components of the cytoplasmic membrane in humans, but their expression has been demonstrated in several human malignant tumors. We demonstrated in healthy donors the existence of naturally occurring antibodies that bind NeuGc containing gangliosides and are able to kill NeuGcGM3 expressing tumor cells. Both the levels and frequency of these anti NeuGcGM3 antibodies decreased with age. Interestingly, this reactivity was almost absent in the sera of non-small cell lung cancer patients. 1E10 is an anti-idiotype mAb specific for an antibody which reacts to NeuGc gangliosides. A phase 2 multicenter, controlled, randomized, double blind clinical trial was conducted to evaluate the effect of aluminum hydroxide precipitated 1E10 vaccine in the overall survival of patients with advanced NSCLC who have completed onco specific treatment. The clinical results of this study showed a significant increase in the overall survival, according to both the intent to treat and the per protocol analysis, as well as in the long term survival rates, for the 1E10 treated patients in comparison with the placebo group. The immunological studies performed showed that the patients that elicited anti NeuGcGM3 antibodies with cytotoxic capacity had a statistically significant increase in the survival times.
IL-2 produced by CD8+ immune T cells can augment their IFN-γ production independently from their proliferation in the secondary response to an intracellular pathogen (P3336)
Authors: Sa Qila , Woodward Jerold , Suzuki Yasuhiro 
Published: January 2023

Abstract
Chronic infection with Toxoplasma gondii induces a potent resistance to re-infection, and IFN-γ production by CD8+ T cells is crucial for the resistance. Here we examined the role of IL-2 in IFN-γ production by CD8+ immune T cells in their secondary responses using T. gondii-specific CD8+ T cell hybridomas and splenic CD8+ immune T cells from chronically infected mice. The majority of CD8+ T cell hybridomas produced large amounts of IFN-γ only when a low amount (0.5 ng/ml) of exogenous IL-2 was provided in combination with T. gondii antigens. Inhibition of cell proliferation by mitomycin C (MMC) did not affect the enhancing effect of IL-2 on the IFN-γ production, and significant increases in transcription factor T-bet expression were associated with the IL-2-mediated IFN-γ amplification. Splenic CD8+ immune T cells produced similar low levels of IL-2 in the secondary response to T. gondii, and a blocking of IL-2 signaling by anti-IL-2Rα antibody or inhibitors of JAK1 and JAK3 significantly reduced IFN-γ production of the T cells. This IL-2-mediated upregulation of IFN-γ production was observed in MMC-treated CD8+ immune T cells, thus independent from their cell division. Therefore, endogenous IL-2 produced by CD8+ immune T cells can play an important autocrine enhancing role on their IFN-γ production in the secondary responses to T. gondii, suggesting an importance of induction of CD8+ immune T cells with an appropriate IL-2 production for vaccine development.
Genetically-determined cytokine programs of human NK cells uncover a novel mechanism of NK cells and Killer cell IgG-like Receptor genes in Crohn’s Disease susceptibility (P3262)
Authors: Lin Lin , Ma Chao , Wei Bo , Rajalingam Raja , Yusung Susy , Trachtenberg Elizabeth , Targan Stephan , McGovern Dermot , Braun Jonathan 
Published: January 2023

Abstract
Mucosal innate lymphocyte subsets have emerged as an important new factor in CD pathogenesis, but the role of NK cells is poorly understood. A recent genetic study identified the KIR gene KIR2DL2/3 as a risk factor for CD in the genetic context of its ligand HLA-C1. However, the biologic mechanism of this genetic contribution is unknown. NK cells are mainly known for their cytolytic function, but recent work indicates that strong KIR/HLA interactions that induce NK “licensing” augment NK cytotoxicity but also IFN-γ production. We therefore tested the hypothesis that human NK licensing by KIR2DL2/3 and HLA-C1 induces a broader cytokine program that modifies the threshold of pro-inflammatory T cell activation. Single cell multiplex functional proteomics revealed that licensed and unlicensed NK cells had strikingly distinct cytokine programs. Licensed NK cells were distinguished by high-output, proinflammatory, poly-cytokine expression. Select cytokine among this output fully accounted for their unique capacity, unlike unlicensed NK cells, to efficiently augment antigenic CD4+ T cell proliferation and induce CD4+ T cell IL-17A production. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel cytokine program of NK cells that activates and induces pro-inflammatory CD4+ T cells, and therefore provides a predisposing biologic mechanism for this KIR-associated susceptibility to CD and other chronic inflammatory syndromes.
Innate lymphoid cells promote airway epithelial repair through the amphiregulin-EGFR pathway (P3250)
Authors: Monticelli Laurel , Sonnenberg Gregory , Abt Michael , Osborne Lisa , Tait Wojno Elia , Alenghat Theresa , Ziegler Carly , Wherry E. , Artis David 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) are a recently described group of immune cells that regulate immunity and inflammation at barrier surfaces. While recent studies have implicated Group 2 ILCs as initiators of pathologic Type 2 airway inflammation, the tissue-protective roles of ILCs in the respiratory tract remain poorly understood. Using genome-wide transcriptional profiling, we identify that naïve lung-resident group 2 ILCs express multiple genes associated with tissue repair pathways, including the epidermal growth factor family member amphiregulin. Amphiregulin was increased in a model of influenza virus-induced lung injury and ILC depletion during infection resulted in decreased amphiregulin expression, reduced lung function and impaired airway remodeling. IL-33 promoted expression of amphiregulin in lung ILCs and administration of amphiregulin effectively restored airway tissue remodeling in ILC-depleted mice, suggesting that ILC-intrinsic amphiregulin is a central mediator of epithelial repair. Supporting this, chemical or genetic inhibition of the EGFR-amphiregulin pathway resulted in severely impaired lung function and a failure to restore airway tissue homeostasis, leading to increased host mortality. Taken together, these data indicate a critical role for group 2 ILCs in mediating lung tissue homeostasis though an IL-33-amphiregulin-EGFR axis and suggest that ILCs serve as a key link between the signaling pathways of Type 2 inflammation and tissue repair.
Dermal γδ T cells and their role in contact hypersensitivity (P3252)
Authors: Jiang Xiaodong , Geddes Jenna , Gaide Olivier , Yoo Min Jae , Kupper Thomas 
Published: January 2023

Abstract
Recent studies have shown that γδ T cells not only exist in murine epidermis (Dendritic Epidermal T cells, DETC) but also populate in the dermis. DETC have been well-studied for decades. However, little is known about the homeostasis of dermal γδ T cells and their roles in skin immune responses such as in contact hypersensitivity (CHS). In this study, phenotype analysis showed that dermal γδ T cells have heterogeneous γδ TCR repertoires (30% TCR Vγ2+), but have a memory phenotype (CD62L-CD44hi) and express high levels of CD69, CD103, and E- and P-selectin ligands. Upon activation, dermal γδ T cells can produce large amounts of IL-17 and IL-22. Parabiosis experiment further showed that dermal γδ T cells are constantly circulating, whereas DETC are non-recirculating. To explore their roles in CHS, we first sensitized and challenged TCRδ-/- mice with 2, 4-dinitrofluorobenzene (DNFB). A remarkable reduction of CHS responses in these pan-γδ T cell-deficient mice was observed, suggesting γδ T cells play a pivotal role in CHS responses. We next generated dermal γδ T cell-deficient chimeric mice and found CHS responses in these mice were significantly lower than that of wild type mice, demonstrating dermal γδ T cells do participate in CHS responses. Finally, depletion of IL-17-producing Vγ2+ dermal γδ T cells also resulted in a significant reduction of CHS responses. Therefore, our data suggest that γδ T cells in dermis play an important role in establishing CHS responses.
Viral antigen induces differentiation of Foxp3+ natural regulatory T cells in influenza virus-infected mice (P1043)
Authors: Bedoya Felipe , Cheng Guang-Shing , Leibow Abigail , Zakhary Nardine , Weissler Katherine , Garcia Victoria , Kropf Elizabeth , Aitken Malinda , Garlick David , Wherry E. , Erikson Jan , Caton Andrew 
Published: January 2023

Abstract
We have examined the formation, participation and functional specialization of virus-reactive Foxp3+ regulatory T cells (Tregs) in a mouse model of influenza virus infection. “Natural” Tregs generated intra-thymically based on interactions with a self-peptide proliferated in response to a homologous viral antigen in the lungs, and to a lesser extent in the lung-draining mediastinal LN (medLN), of virus-infected mice. By contrast, conventional CD4+ T cells with identical TCR specificity underwent little or no conversion to become “adaptive” Tregs. The virus-reactive Tregs in the medLN and the lungs of infected mice upregulated a variety of molecules associated with Treg activation, and also acquired expression of molecules (T-bet, Blimp-1 and IL-10) that confer functional specialization to Tregs. Notably, however, the phenotypes of the T-bet+ Tregs obtained from these sites were distinct, since Tregs isolated from the lungs expressed significantly higher levels of T-bet, Blimp-1 and IL-10 than did Tregs from the medLN. Adoptive transfer of antigen-reactive Tregs led to decreased proliferation of anti-viral CD4+ and CD8+ effector T cells in the lungs of infected hosts, while depletion of Tregs had a reciprocal effect. These studies demonstrate that thymically-generated Tregs can become activated by a pathogen-derived peptide and acquire discrete T-bet+ Treg phenotypes while participating in and modulating an antiviral immune response.
Efficient in vivo delivery of immunomodulating biomolecules and enhanced antitumor immunity using multifunctional hybrid nanoconjugates (P4275)
Authors: Lim Yong Taik , Noh Young-Woock , Heo Min Beom 
Published: January 2023

Abstract
Immunotherapy is regarded as a method of attractive treatment for cancer. Especially, dendritic cells (DCs) represent important targets for cell-mediated immunotherapy in cancer because they can capture tumor antigens that are released from tumor cells and migrate to the tumor-draining lymph nodes, where they present the antigens to T cells and secrete the pro-inflammatory cytokines that enhance T cell activation. However, immunosuppressive factors, such as signal transducer and activator of transcription-3 (STAT3), represent a major limitation for DCs-based cancer therapies. In this study, we have designed and synthesized an immunomodulatory hybrid nanoconjugates (HNC) system based on polymer nanocomposites containing quantum dots (QDs; as imaging tracers) that are decorated with CpG ODNs (as a TLR9 ligand) and STAT3 siRNAs (as an immunosuppressive gene silencer) for the efficient immunotherapeutic cancer therapy. These HNC efficiently targeted immune cells, induced TLR activation, and silenced immunosuppressive genes. Simultaneous in vivo delivery of STAT3 siRNA and CpG ODN to DCs in the tumor microenvironment induced both the inhibition of STAT3 and activation of DCs by CpG ODNs, and synergistically elicited anti-tumor effects. By using NIR-emitting QDs, the migration of in vivo DCs to lymph nodes was also tracked by real-time NIR fluorescence imaging. In the future, these studies are expected to facilitate the development of immune cell-based cancer therapy.
Natural killer T cell adjuvanted inactivated swine influenza virus vaccine enhanced the viral load and suppressed the host immune response to pandemic 2009 H1N1 virus in pigs (P6093)
Authors: Gourapura Renukaradhya , Manickam Cordelia , Dwivedi Varun , Ouyang Kang , Binjawadagi Basavaraj , Henn Kara , Crittenden Patrick , Hiremath Jagadish , Khatri Mahesh 
Published: January 2023

Abstract
Swine influenza virus (SIV) causes an acute respiratory disease in pigs, and pigs are infectable by both avian and mammalian influenza viruses. Activation of NKT cell induces heterologous protection against influenza viruses in rodent studies. We discovered CD1d-restricted NKT cell in pigs. Aim of this study was to determine the efficacy of UV-inactivated bivalent SIV vaccine, comprising of triple reassortant zoonotic H1N1 (Sw/OH/24366/07) and H3N2 (Sw/OH/04) viruses; coadministered intranasally with NKT cell adjuvants, phosphatidylinositolmannosides-2 (PIM2) and α-Galctosylceramide (α-GalCer). In vaccinated homologous H1N1 virus challenged pigs, reduced viral load in the lungs associated with increased IFN-γ+ lymphocytes in the lungs and tracheobronchial lymph nodes by ELISPOT, and an increase in IFN-γ+CD8+ and IFN-γ+ γδ T cells was observed. Further, increased virus specific IgA response in the BAL fluid and enhanced lung NK cell-cytotoxicity was detected. However, in vaccinated pandemic 2009 H1N1 virus challenged pigs, enhanced nasal viral shedding and lung viral load was detected. Immunologically, reduced frequency of total lymphocytes and CD8+ T cells, and reduced frequency of total IFN-γ+ T cells was detected in the lungs. In conclusion, NKT cell adjuvanted inactivated SIV vaccine in pigs enhanced the pandemic 2009 H1N1 replication and dampened the anti-viral immune response.
Inflammatory and regulatory T cells contribute to a unique immune microenvironment in tumor tissue of colorectal cancer patients (P2145)
Authors: Kemp Roslyn , Taylor Edward , Girardin Adam , Munro Fran , Black Mik , McCall John 
Published: January 2023

Abstract
Colorectal cancer (CRC) is a leading causes of cancer mortality. T cells play a crucial role in the elimination of cancer. Despite their importance little in known about the composition of the T cell subsets in CRC and how the cancer cells can affect these subsets. Using a novel analytical flow cytometric approach, we have analysed T cell subsets in CRC tumor tissue and matched non-transformed bowel tissue. We discovered that the tumor has a lower frequency of effector T cells, but a higher frequency of both regulatory and inflammatory T cells, compared with associated non-transformed bowel tissue. To study the functional interactions of these cell subsets, methods have been established to isolate live, unmanipulated T cell subsets from tumor tissue and non-transformed bowel tissue. Effector T cells (IFNγ +), regulatory T cells (CD25hi, FoxP3+) and inflammatory T cells (IL-17+) have been isolated from CRC tumor tissue or non-transformed bowel tissue. Ex vivo studies have shown that effector T cells from the tumor tissue proliferate less, and are unable to produce IL-2 upon stimulation, than effector T cells from non-transformed bowel tissue. In addition, regulatory T cells isolated from non-transformed bowel tissue actively inhibit proliferation of T cells from the same tissue. These data describe an immune microenvironment in colorectal cancer unique, in both phenotype and function, to the tumor tissue and distinct from the surrounding non-transformed bowel tissue.
Usurpation of a lymphocyte costimulatory molecule as a novel melanoma cell survival pathway (P2187)
Authors: Haymaker Cara , Chen Jie Qing , Bernatchez Chantale , Kale Charuta , Torres-Cabala Carlos , Radvanyi Laszlo 
Published: January 2023

Abstract
BTLA (B- and T- lymphocyte attenuator), binds to the TNF-R family member HVEM (herpes virus entry mediator). HVEM through its interaction with BTLA in trans or in cis has been shown to act as a pro-survival signal through activation of NF-κB. In contrast, signaling through BTLA following HVEM engagement has been found to induce a negative signaling pathway by activating SHP1/2 phosphatases. During an initial immunohistochemistry screen for the expression of BTLA in melanoma tumor sections, we unexpectedly found that a many tumor cells also exhibited a uniform and strong positive intracellular expression of BTLA. BTLA was expressed in both primary and metastatic melanoma cells with low to negative expression in benign nevi. PCR analysis also revealed that although most tumor lines expressed isoform 1 of BTLA, some lines expressed both isoform 1 and 2 suggesting BTLA by be secreted. Moreover, we also found that melanoma cells express both surface and intracellular HVEM. Intriguingly, significant pools of BTLA were found to be co-localized with intracellular HVEM in the melanoma cells. This co-localization suggests that tumor cells may use HVEM activation as a mechanism of cell survival. Blockade of BTLA or inhibition of BTLA or HVEM expression on melanoma cells may therefore be a novel approach to inhibit tumor cell survival as well as prevent negative signaling through BTLA in immune cells.
PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1/PD-L1 in airway epithelium (P3199)
Authors: Matsumoto Koichiro , Kan-o Keiko , Asai Yukari , Fukuyama Satoru , Hamano Saaka , Seki Nanae , Yanagi Shigehisa , Suzuki Akira , Nakanishi Yoichi , Inoue Hiromasa 
Published: January 2023

Abstract
B7-H1/PD-L1 is implicated in the escape of viruses from the host defense systems, leading to persistence of infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. We previously reported that stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic-polycytidylic acid (poly IC), upregulated the expression of B7-H1 via activation of NF-κB. The mechanism of upregulation was further investigated with regard to involvement of phosphatidylinositol 3-kinases. Poly IC-induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by a chemical inhibitor or a small interfering RNA for PI3Kδ. The expression of p110δ was detected by Western blot and suppressed by PI3Kδ siRNA. Poly IC-induced activation of NF-κB was suppressed by a pan-PI3K inhibitor but not by a PI3Kδ inhibitor. The transcriptional activity of NF-κB is regulated by histone deacetylase. The activity of histone deacetylase was suppressed by poly IC, which was protected by a PI3Kδ inhibitor. The activation of PI3Kδ is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant. These results suggest that PI3Kδ mediates dsRNA-induced upregulation of B7-H1 in airway mucosa and a causal link between oxidative stress and epigenetic regulation in virus-associated B7-H1 upregulation.
Identification of risk genes linking inflammation and fibrosis in passively acquired autoimmune disease. (P4170)
Authors: Reed Joanne , Clancy Robert , Zavadil Jiri , Buyon Jill 
Published: January 2023

Abstract
Fetuses exposed to maternal Ro60 autoantibodies can develop life threatening cardiac conduction disease and cardiomyopathy, manifestations of neonatal lupus (NL). Recent data support an injury model where immune complexes (IC) comprised of Ro60 autoantigen, hY3 single stranded RNA, and anti-Ro60 engage Toll-like receptor (TLR) 7 and promote secretion of inflammatory and fibrotic factors by macrophages. This study sought to identify candidate risk genes based on:1) expression arrays from IC-stimulated human macrophages with and without TLR7 inhibitor; and 2) single nucleotide polymorphism (SNP) genotyping of 116 children with cardiac NL. In IC stimulated macrophages, 891 upregulated genes were reduced by at least 50% with the TLR7 inhibitor. Among these, there was an enrichment of genes related to inflammation and fibrosis. Ingenuity Pathway Analysis was used to generate a list of 327 genes with fibrotic functions that showed a significant enrichment of associations with cardiac NL (P=2.27x10-9). Joint analysis of these fibrotic genes identified 20 candidates which were also overexpressed by macrophages in TLR7-dependent arrays. Among the dataset was Relaxin receptor 1 (RXFP1), a G-protein coupled receptor that binds relaxin and plays a role in collagen and connective tissue remodeling. Key inflammatory mediators included IL6 and TNF. These data support the applicability of a novel model which can help uncover biological pathways underlying autoantibody-mediated tissue injury.
CD4 T cells license dendritic cells to enhance polyfunctional anti-viral T helper cell responses (P6094)
Authors: Olson Matthew , Turner Stephen 
Published: January 2023

Abstract
CD4 T cell help is critical for the generation of optimal B cell and CD8 T cell responses after immunization or infection. Robust and polyfunctional CD4 T cells are also generated after exposure to antigen, however, the factors that govern the development of potent CD4 T cell immunity are less clear. We demonstrate here that augmenting CD4 T cell help by adoptive transfer of increasing numbers of influenza A virus (IAV)-specific T cell receptor transgenic T cells resulted in enhanced polyclonal IAV-specific CD4 T cell responses after infection. Virus-specific CD4 T cells in mice that received augmented help also exhibited a greater capacity to produce multiple cytokines as compared to controls, indicating that CD4 T cell help is a major factor that dictates CD4 T cell polyfunctionality. Mechanistically, CD154 expression on CD4 T cells and CD40 on dendritic cells (DCs) were both necessary and sufficient to induce optimal CD4 T cell responses after infection, suggesting that helper T cells “license” DCs to enhance CD4 T cell responses. Interestingly, augmenting CD4 T cell help also resulted in enhanced IAV-specific CD4 and CD8 T cell memory responses after secondary infection. Taken together, these data define a CD4 T cell-DC circuit that promotes the priming of robust and polyfunctional CD4 T cell responses. These data also suggest that enhancing CD4 T cell help during vaccination could be used as a therapeutic approach to promote overall T cell immunity.
Th9 cells secrete BAFF (P1447)
Authors: Awe Olufolakemi , Jabeen Rukhsana , Kaplan Mark 
Published: January 2023

Abstract
The B-cell activating factor (BAFF) is essential for proper B-cell development. Cells of the innate immune system including macrophages and dendritic cells are the primary source of BAFF. The BAFF protein has two forms, soluble and membrane bound. The membrane bound form of BAFF can become soluble following furin convertase-mediated digestion.. Through microarray analysis comparing the gene profile of Th9, Th2 and T-regulatory cells we found that expression of the gene encoding BAFF (Tnfsf13b) was enriched within the Th9 subset. Using qPCR, intracellular staining, and ELISA, we have confirmed that Th9 cells express BAFF both at the mRNA and protein level. Although Tnfsf13b is expressed at the greatest level in Th9 cells, Th2 cells also express detectable mRNA. Yet, BAFF secretion is only detected in supernatants from Th9 cells. We hypothesized that the absence of soluble BAFF in Th2 supernatants could be due to a difference in the level of Furin expressed by Th9 and Th2 cells. Indeed Th9 cells express a higher level of Furin compared to Th2 cells. Moreover, blocking Furin activity diminishes BAFF secretion from Th9 cells. Together, these data suggest that BAFF production from Th9 cells results from the coordinated expression of both the gene encoding BAFF, and the enzyme required to generate soluble BAFF. Furthermore, Th9 cells may be an important source of BAFF during the development of humoral immunity.