bluuebunny/crossref_metadata_2025_split huggingface dataset:
B7-H1 negatively regulates IL-12 production by dendritic cells (165.10)
Authors: Gibbons Rachel , Liu Xin , Dong Haidong 
Published: January 2023

Abstract
A promising strategy in tumor immunotherapy is the use of activated dendritic cells as vehicles for tumor vaccines. Clinical trials of dendritic cell-based immunotherapies have proven successful, resulting in recent FDA approval for their use in the treatment of late-stage prostate cancer. Current formulations for dendritic cell-based immunotherapies are capable of prolonging patient survival by only four months, providing motivation for further investigation of ways to enhance dendritic cell priming of anti-tumor T cell responses. Since the discovery of B7-H1 by our laboratory, we have been investigating the regulatory function of B7-H1 expressed by immune cells. In preliminary studies investigating the use of B7-H1 knockout dendritic cells as tumor vaccines, we found that B7-H1 knockout dendritic cells prime enhanced anti-tumor CD8 T cell responses. Further investigations revealed that the enhanced CD8 T cell response raised by B7-H1 knockout dendritic cells is not due to a lack of signaling through the receptors for B7-H1 on CD8 T cells. We observed that B7-H1 knockout dendritic cells produced increased levels of IL-12, a key cytokine that is centrally involved in both innate and adaptive immunity. Our results suggest that B7-H1 expressed by dendritic cells has a role in negatively regulating IL-12 production, and as a result B7-H1 deficient dendritic cells are able to prime enhanced anti-tumor CD8 T cell responses.
Adoptive transfer of Tc17 CD8 T cells as an approach to elicit a better immune response to vaccination (165.3)
Authors: Yen Hung-Rong , Huang Ching-Tai , Lin Tzou-Yien , Pardoll Drew , Drake Charles 
Published: January 2023

Abstract
CD8 T cells that produce IL-17 is an unknown field with lots to explore. In our previous studies, we found a novel subset of IL-17 producing CD8 T cells persisted longer in a self-antigen autoimmune model versus conventional IFN-g producing Tc1 cells; furthermore, Tc17 can convert to an IFN-g producing phenotype in vivo. In the present study, we adoptively transferred a relatively small numbers (100,000) of IL-17 secreting TCR-transgenic antigen-specific CD8 T cells one day before vaccination by recombinant vaccinia virus encoded with full-length hemagglutinin. Tc 17 cells activated, expanded better than Tc1 cells 9 days after vaccination (Mean = 7.425x10e6 versus 1.350x10e6, p&lt;0.05). Interestingly, Tc17 can convert to an IFN-g producing phenotype after vaccination. Our preliminary data fit the niche that is required to improve vaccination and immunotherapy and we suggest that, to treat infectious disease, CD8 Tc17 could be a promising effector T cell subset to achieve the goal. Additional mechanisms are being explored.
A New Rip2 Kinase Inhibitor for the Treatment of Intestinal Inflammation (169.5)
Authors: Zhao Yun , Song Joo Hye , Ajami Alfred M , Reinecker Hans-Christian 
Published: January 2023

Abstract
AIM: RIP2 is a critical mediator of NLRs signaling for innate immune activation. GEF-H1 interacts with NLRs and is responsible for initiating tyrosine phosphorylation of RIP2 required for the activation of NF-κB. We identified DCAM-253, 2-dialkylamino-9-indazolyl-purine, as a potent small molecule tyrosine kinase inhibitor of Rip2. Results: Gene specific siRNA mediated knockdown and expression of signaling intermediates in macrophages, and HEK293 cells was used to determine the mechanisms by which DCAM-253 inhibits Rip2 mediated induction of cytokine expression. DCAM-253 prevented the recruitment of GEF-H1 to the Rip2/NLR signaling complexes and subsequent tyrosine phosphorylation of Rip2. DCAM-253 inhibited TNFα production induced by GEF-H1 dependent NLR activation. DCAM-253 was able to protect mice from intestinal inflammation induced by epithelial barrier disruption and microbial defense activation in the DSS-induced colitis model. Contol group Mice presented with transmural leukocyte infiltration and crypt damage with tissue destruction indicating severe persistent colitis. In contrast, low cellular infiltration and intact intestinal epithelium were observed in the colon sections of mice treated with 2 oral doses of DCAM-253. Conclusion: We have identified a new small molecule inhibitor, which protects mice from colitis and promotes mucosal recovery by preventing Rip2 tyrosine phosphorylation upon intestinal barrier disruption and subsequent innate immune activation.
Mechanism of sophorolipid (SL) suppression of nitric oxide production in models of septic or endotoxic shock. (169.9)
Authors: Watson Michelle , Wu Brian , Bluth Martin , Nowakowski Maja 
Published: January 2023

Abstract
Introduction: Severe sepsis often leads to endotoxic shock and is reported to account for 9% of all deaths in the United States annually. Clinical manifestations of severe sepsis and shock are believed to result from the host’s overwhelming inflammatory reaction to infection and bacterial endotoxins. There is a clear need for new therapeutic approaches and agents based on a better understanding of the physiologic pathways underlying endotoxic shock. Objective: The aim of this project is to determine the mechanism of action of sophorolipids (SL) as novel therapeutic agents to block severe sepsis and shock. We established that SL were protective in vivo when injected following the initiation of endotoxic shock and in vitro when added to macrophage cultures following the addition of LPS. Methods: Cultured macrophages (RAW 264.7) were incubated for 1-5 days with LPS (0-200 ng/ml) and SL (100 ng/ml). Accumulated nitric oxide was measured using Griess reaction. Surface expression of CD14 and TLR4 was determined using specific antibodies (Santa Cruz Biotechnology, immunohistochemistry). Results: LPS induced nitric oxide production was inhibited by 70% in the presence of SL (SL alone had no effect on nitric oxide production). Surface expression of CD14 (macrophage LPS receptor) was also inhibited by 70% in the presence of SL; expression of TLR4 was inhibited by 15%. Conclusions: SL may interfere with binding and intracellular steps in the LPS-mediated gene activation cascade.
Myeloid-Derived suppressor cells in murine retrovirus-induced AIDS: inhibition of the T-cell and B-cell responsiveness that define the immunodeficiency (170.7)
Authors: Green Kathy , Cook W. James , Green William 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) have been characterized in several tumor settings however, they have been less well studied in response to infectious disease processes, in particular against retroviruses that induce immunodeficiency. Here we demonstrate for the first time the development of a highly immunosuppressive MDSC population that is dependent on LP-BM5 retrovirus infection, which causes murine acquired immunodeficiency. This MDSC population is CD11b+, Gr-1+, Ly6C+ , exhibits profound inhibition of immune responsiveness by a cell-dose and substantially iNOS-dependent mechanism that is independent of arginase activity, PD-1/PD-L1 expression, and IL-10; and the degree of immunosuppression parallels the extent of disease in differentially LP-BM5 susceptible w.t. vs. knock-out mouse strains. Not only T-cell, but also interestingly B-cell host responses, were suppressed by these MDSCs. The direct immunosuppression of B cell responses was confirmed by use of: purified B responder cells, multiple B-cell specific stimuli, and independent assays measuring B-cell expansion. This suppressive MDSC subset is positive for proviral LP-BM5 RNA, albeit at a significantly lower level than LP-BM5 infected non-fractionated spleen cells. These results, including the strong, direct MDSC inhibition of B-cell responsiveness, are novel for murine retrovirus-induced immunosuppression, and support a possible pathogenic effector role for these retrovirus-induced MDSCs.
Cannabinoid receptor 2 agonists inhibit migration of activated dendritic cells via modulation of MMP-9 (173.23)
Authors: Adhikary Sabina , Kocieda Virginia , Ganea Doina 
Published: January 2023

Abstract
In murine models of multiple sclerosis (experimental autoimmune encephalomyelitis or EAE), cannabinoid receptor 2 (CB2) agonists have been shown to be beneficial, reducing the number of CNS infiltrating leukocytes. Adhesion molecules, chemokines, and matrix metalloproteinases (MMPs), particularly MMP-9, play important roles in migration to the CNS. Antigen presenting cells such as dendritic cells (DC) and macrophages, as well as activated microglia are major producers of MMP-9. In this study, we investigated the effects of CB2 receptor agonists on DC migration and MMP-9 production utilizing both in vitro and in vivo migration assays. DC activated with cytokine cocktail (TNFα+IL-1β+IL-6+PGE2) in the presence or absence of CB2R agonist exhibited similar migratory capacity in transwell migration assays. However, the CB2R agonist treated cells migrated less in matrigel migration assays as compared to untreated cells. We found that this effect was due to reduced MMP-9 production in CB2R agonist treated cells. Also, in the in vivo migration assay using cytokine cocktail-activated DCs injected into mice footpads, we found significantly fewer CB2R agonist-treated DCs in the draining lymph nodes. Our data indicate that one of the mechanisms by which CB2R agonists attenuate inflammation is the inhibition of MMP-9 release which results in decreased migration of activated dendritic cells.
Trem-like 4-expressing dendritic cells and macrophages exhibit distinct inflammatory chemokine receptors (173.33)
Authors: Moyron-Quiroz Juan , Ampudia Jeanette , Yang Xifeng 
Published: January 2023

Abstract
Trem-like 4 (Treml4) is a recently identified type I transmembrane protein, member of the Trem (Triggering receptor expressed on myeloid cells) family. It is mainly expressed on splenic CD8α+ dendritic cells (DCs) and marginal metallophilic and red pulp macrophages. The natural ligand of Treml4 remains to be identified, but a fusion protein containing the extracellular domains of Treml4 is able to bind apoptotic and necrotic cells, suggesting it potentially plays a role in the clearance of dead cells, a process associated with anti-inflammatory and immunosuppressive effects. To further characterize the cell subsets expressing Treml4, we stained splenic DCs and macrophages with various flourochrome conjugated antibodies, including the anti-Treml4 antibody, 16E5. Our data demonstrated that both Treml4+ DCs and macrophages also express CCR6, but neither population expresses CXCR2 nor CCR5. In addition, Treml4+ DCs, but not Treml4+ macrophages, express CXCR3. Conversely, Treml4+ macrophages, but not Treml4+ DCs, express the receptor for the anaphylatoxin C5a. Taken together, these findings suggest that Treml4+ DCs and Treml4+ macrophages might be recruited to inflammation sites depending on the different chemoattractants produced.
Antibiotic induced alterations in the commensal microbiome reduce CD4+Foxp3+ Tregs in the colonic lamina propria and increase allergic responses to food (175.14)
Authors: Tripathi Prabhanshu , Stefka Andrew , Feehley Taylor , Patton Tiffany , Chang Eugene , Antonopoulos Dionysios , Pei Zhiheng , Nagler Cathryn 
Published: January 2023

Abstract
Antibiotic (Abx) use in early life has been implicated in the increasing prevalence of food allergy, presumably due to its effects on the commensal bacterial microbiome. To gain insight into the mechanisms by which commensal bacteria regulate allergic responses to food, C57Bl/6 mice were treated with a cocktail of Abx, beginning by gavage at two weeks of age and continuing in the drinking water after weaning. 16S rDNA based pyrosequence analysis demonstrated that Abx treatment significantly altered the composition and diversity of the fecal microbiota; Lachnospiraceae (Clostridia) were significantly reduced and Bacteroidaceae were enriched in fecal samples obtained from Abx treated mice. Reduced Clostridia abundance correlated with significantly decreased proportions of CD4+Foxp3+ Tregs in the colonic lamina propria, but not the spleen or mesenteric lymph node, of Abx treated mice compared to untreated controls. Elevated allergen specific IgE and IgG1 responses were induced in Abx treated (but not untreated) mice sensitized with purified peanut extract plus cholera toxin. Transfer of CD4+Foxp3+Tregs from untreated mice, prior to sensitization, blocked the allergen specific IgE response induced by Abx treatment. Our data supports the hypothesis that bacteria (Clostridia) induce CD4+Foxp3+ Tregs in the colonic mucosa. These Tregs are depleted (and protection against an allergic response to food is reduced) in Abx treated mice.
Anti-Allergic Asthma Properties of Brazilin through Inhibition of TH2 Responses in T Cells and in a Murine Model of Asthma (175.8)
Authors: Wang Chien-Neng , Kang Jaw-Jou , Liao Jiunn-Wang , Chiang Bor-Luen , Chen Hui-Chen , Lin Chia-Der , Huang Shih-Hsuan , Lai Yu-Ting , Lee Chen-Chen 
Published: January 2023

Abstract
The aim of the study was to determine whether brazilin exhibits any anti-inflammatory effects that inhibit T helper cell type II (TH2) responses and whether it suppresses allergic inflammation reactions in a murine model of asthma. We found that brazilin inhibited phorbol myristate acetate (PMA) + cyclic adenosine monophosphate (cAMP)-induced IL-4 and IL-5 expression in EL-4 T cells with respect to both RNA and protein levels in a dose-dependent manner. After intratracheal instillation of brazilin in ovalbumin (OVA)-immunized mice, we found that brazilin-treated mice exhibited decreases in the release of IL-4, IL-5, IL-13, eotaxin, and TNF-α in bronchoalveolar lavage fluid (BALF), inhibited TH2 functioning by a decrease in IL-4 production, and the attenuation of the OVA-induced lung eosinophilia, and airway hyperresponsiveness and remodeling. These results suggest that brazilin exhibits an anti-TH2 reaction both in vitro and in vivo. Brazilin as demonstrates therapeutic potential for allergic diseases.
B cell antigen presentation plays a limited role in primary and secondary CD4 T cell responses (176.16)
Authors: Wu Gregory , Archambault Angela , McGee Gretchen , Dragatsis Ioannis , Allenspach Eric , Raabe Tobias , Russell John , Laufer Terri 
Published: January 2023

Abstract
The activation and differentiation of effector CD4 T cells depends on interactions with MHCII-expressing antigen presenting cells (APCs). While several APC populations coordinate CD4 T cell function, several lines of evidence indicate that antigen presentation by B cells is a critical element to the cellular immune response. We have sought to determine the contribution of B cell antigen presentation to CD4 T cell priming and secondary responses. To address the hypothesis that B cells are sufficient APCs for CD4 T cell responses, we have designed a new tool in which individual subsets of APCs conditionally express MHCII in vivo. We successfully targeted a loxP-flanked stop sequence to the murine IA-β chain locus to utilize the Cre/lox system for conditional expression of MHCII. Conditional manipulation was achieved using CD19-Cre mice, restricting expression of MHCII to B cells. After priming, sub-optimal proliferation and activation of CD4 T cells was observed in mice expressing MHCII only by B cells. Further, limiting MHCII expression to B cells constrained secondary CD4 T cell responses in vivo. In a CD4 T cell-dependent model of autoimmunity, EAE, B cell expression of MHCII was not sufficient to support secondary autoreactive CD4 T cell responses targeting the CNS. These results demonstrate a novel capacity to conditionally express MHCII in vivo and highlight the limitations of B cell antigen presentation during the initiation and propagation of CD4 T cell function
A Distinct Population of Lipid Sensing iNKT Cells are Enriched in Fat and Protect Against Diet-Induced Obesity and Insulin Resistance (176.26)
Authors: Lynch Lydia , Tatitori Raju , Patrick Brennan , Stutte Susanne , Varghese Bindu , Hogan Andrew , Balk Steven , O'Shea Donal , O'Farrelly Cliona , von Andrian Ulrich , Brenner Michael , Mark Exley 
Published: January 2023

Abstract
Immunometabolic interactions regulate adipose tissue inflammation in obesity and subsequent development of insulin resistance. We have shown that human and murine fat contains the largest population of iNKT cells in the body. Fat resident iNKT cells are a distinct subset with unique phenotype and anti-inflammatory cytokine profile. These iNKT cells are depleted in diet-induced obesity and removal of high fat diet results in iNKT restoration in mice and humans. Furthermore, mice lacking iNKT cells have enhanced weight gain, larger adipocyte size, fatty liver infiltration and insulin resistance. Adoptive transfer of iNKT from WT mice into obese mice or activation of remaining iNKT in obese fat by through injection of alpha- galactosylceramide (aGC) had a profound improvement in insulin sensitivity and glucose handling, a decrease in serum triglycerides, leptin, body fat, fatty liver infiltration and proinflammatory macrophage levels. It is therefore beneficial to identify what causes iNKT cells depletion in obesity. We have purified lipids from obese and lean adipose tissue, to identify which, if any, lipid fraction may activate iNKT cells. Early preliminary data suggest that a HFD abherrently activate iNKT cells in obesity, leading to their loss, and subsequent development of insulin resistance. In summary, we have identified a distinct population if iNKT cells in fat and describe a unique role for iNKT in protection against obesity and related metabolic disease. .
Identification of the v-SNARE required for lytic granule fusion in cytotoxic T lymphocytes (176.27)
Authors: Pattu Varsha , Matti Ulf , Halimani Mahantappa , Weins Lisa , Rettig Jens 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTLs) kill target cells by secretion of cytotoxic components such as perforin and granzymes, which are contained in lytic granules. Fusion of lytic granules occurs at the contact zone between the target cell and the CTL, the immunological synapse. Soluble NSF attachment receptor (SNARE) proteins are required for all fusion events in cells, but the SNARE proteins involved in lytic granule fusion in CTLs remain unknown. Using a targeted gene knock in strategy we identified the v-SNARE that is required for lytic granule fusion in CTLs. We first used super resolution microscopy combined with careful quantification to identify the v-SNARE that is localized exclusively to lytic granules in primary mouse CTLs. By specifically cleaving the v-SNARE with a bacterial neurotoxin and by gene knock down we show a complete loss of lytic granule fusion by two independent methods - 1) LAMP1 based degranulation assay and 2) real time imaging of exocytosis using TIRF microscopy. We therefore conclude that the v-SNARE that is localizing to the lytic granules is mediating their final fusion at the IS, thereby delivering the lethal hit needed for target cell killing.
Determination of protein-protein interactions of human eleven-nineteen lysine-rich leukemia protein ELL2 (176.8)
Authors: Arumemi Fortuna , Milcarek Christine 
Published: January 2023

Abstract
Eleven-nineteen lysine-rich leukemia (ELL) genes produce protein factors that aid in transcription elongation. ELL1 was originally found as a fusion partner with MLL in some multiple lineage leukemias. ELL2 mRNA and protein are induced 6-fold in plasma cells. ELL1 and ELL2 are very similar except for 2 regions between amino acids 352 - 443 and 473 - 516, indicating that they may have different sets of interacting proteins. Yeast two-hybrid (Y2H) assays were performed to determine what proteins might interact with each ELL. ELL2, was subcloned into four main sections (A1, A2, B, and C) to determine specific locations of interaction. The C portion of ELL2, aa 516 to 640, autoactivated transcription in the Y2H and was not further analyzed. Meanwhile, the A1 region interacted with CEP192 (regulator of pericentriolar material recruitment, centrosome maturation, and centriole duplication in mammalian cells); the A2 region interacted with RP3 gene (XLRP gene 3), FIGNLI (new subfamily member of ATPases associated with diverse cellular activities); and the B region interacted with HIFIA (transcription factor found in mammalian cells under reduced oxygen tension that plays an essential role in hypoxia) and SEC63 (a translocation protein). Further mapping of the interactions of the ELLs may help us to clarify their functions in gene regulation and plasma cell development.
Intracellular adenosine inhibits IgE-dependent degranulation of human skin mast cells (177.19)
Authors: Gomez Gregorio , Schwartz Lawrence 
Published: January 2023

Abstract
Adenosine is a purine nucleoside that modulates the immediate release (degranulation) of allergic mediators from mast cells. We show that adenosine at relatively high concentrations (IC50=245 µM) inhibits IgE-dependent degranulation of human skin mast cells by a non-toxic intracellular mechanism. We demonstrate that pre-treatment with the specific inhibitor of equilibrative nucleoside transporter 1 (ENT1/SLC29A1), NBMPR, dose-dependently prevented the inhibitory effect of adenosine. In contrast, blocking adenosine A2a receptor (A2aAR) signaling with the specific antagonist ZM241385 was ineffective. Thus, blocking the influx of extracellular adenosine, but not A2aAR signals, was necessary and sufficient to prevent the adenosine-mediated inhibition of degranulation. The inhibitory effect of adenosine was not due to acute toxicity since human skin mast cells cultured up to 3 days with adenosine at concentrations as high as 0.5 mM remained completely viable and activation-competent. Importantly, the inhibitory action of intracellular adenosine was specific for FcϵRI-induced signaling pathways since degranulation induced by Complement Factor 5a, Substance P, or calcium ionophore A23187 was not affected. Moreover, activation (phosphorylation) of the FcϵRI-proximal and critical signaling molecule Syk was significantly inhibited in adenosine-treated mast cells. Overall, these findings provide the first evidence of an inhibitory anti-allergic effect of intracellular adenosine.
STAT5 activity downstream of IgE and IgG receptors in mast cells (177.8)
Authors: Pullen Nicholas , Barnstein Brian , Falanga Yves , Lama Tamang Tenchee , Ryan John 
Published: January 2023

Abstract
Removal of STAT5 impairs mast cell development, survival, and IgE-mediated cytokine production, justifying a need to closely investigate its activity downstream of Fc receptors. We found that STAT5 tyrosine phosphorylation occurs shortly after FcϵRI crosslinking in a Fyn-dependent manner, while the suppression of Lyn, and other negative regulators of IgE signaling, appears to enhance STAT5 activation. Tyrosine phosphorylation of STAT5 also occured during IgG-mediated activity, suggesting some overlap in the signaling proximal to different Fc receptors in mast cells. Additionally, IgE- and IgG-mediated signaling elicited serine phosphorylation of both STAT5A and STAT5B, possibly in a divergent manner. Inhibition of Syk ablated IgE-mediated pS-STAT5, but affected to a lesser extent, if at all, pS-STAT5B and IgG-mediated total pS-STAT5. Furthermore, inhibition of JNK reduced pS-STAT5 during FcγR crosslinking. Collectively, these data highlight similarities and differences from variable receptor inputs as well as the different STAT5 proteins, supporting their essential roles in mast cell biology.