bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of murine Sjögren's syndrome by local delivery of adeno-associated virus mediated Cytotoxic T-Lymphocyte Antigen 4 — immunoglobulin G fusion protein (107.1)
Authors: Yin Hongen , Nguyen Cuong , Samani Yuval , Uede Toshimitsu , Peck Ammon , Chiorini John 
Published: January 2023

Abstract
Dysfunction and lymphocytic infiltrations of the salivary and lachrymal glands are hallmarks of primary sjögren's syndrome (pSS), which is a chronic autoimmune epithelitis. Increasing evidence suggests that immunosuppressive agents can interrupt the progression of the disease. Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is a key anti-inflammatory protein for shutting down the costimulatory pathway of B7:CD28, being required in immune suppression of T regulatory cells (Treg), and subsequent immune tolerance. To better understand the modulation of CTLA4-IgG on sjögren's syndrome, we generated a recombinant type 2 adeno-associated virus vector (AAV2) to express a chimera of mouse CTLA-4 fused with a human IgG (AAV2-CTLA4IgG). The recombinant CTLA4IgG was shown to be effective at blocking B7 expression on macrophages in vitro. Expression of the CTLA4IgG in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice, a model of pSS, prevented the loss of salivary gland function and decreased both T-cell and macrophage infiltrates in the glands compared with control mice. Protection of the salivary glands was also accompanied by a decrease in Th1- and Th17- cell cytokines and an increase of TGF-β1 in CTLA4IgG treated mice compared with controls. This data suggests a potential role for CTLA-4IgG in preventing sjögren's syndrome by deactivating proinflammatory T cells and promoting suppressive Treg cells.
Murine bone marrow-derived dendritic cells generated in serum free conditions display an immature phenotype and protect from T1D. (107.11)
Authors: Looney Ben , Xia ChangQing 
Published: January 2023

Abstract
Dendritic cells possess the ability to modulate immune responses and therefore have been investigated as a cell based therapy to prevent or reverse Type 1 Diabetes. In the NOD mouse model, bone marrow-derived DCs (BM-DC) are generated from bone marrow precursors cultured with GM-CSF and IL-4 and also typically containing fetal calf serum (FCS). The effect of FCS on murine BM-DC has not been extensively investigated. In the present study we compare BM-DC generated in FCS free culture media (X-VIVO20) with BM-DC generated in culture media (RPMI1640) containing 10% FCS. Data show that CD11c+ BM-DC generated in a FCS free culture system express the same level of MHC Class II and CD80 and decreased CD86 expression compared to BM-DC derived from culture with 10% FCS. CD11c+ BM-DC from each culture system induce a similar level of Ag-specific CD4+ T cell proliferation and IFNγ production. CD11c+ BM-DC derived from FCS free culture media induce greater expression of IL-10 and IL-17. Additionally, we examine the ability of CD11c+ BM-DC, pulsed with the β cell-specific peptide GAD217-236, to prevent T1D onset. Data show 5 weekly IV administrations of both BM-DC delay T1D but only BM-DC generated in the FCS free culture system are able to prevent the onset of T1D in NOD mice when treatment begins at 9 weeks. Our results demonstrate that using BM-DC developed in FCS free medium not only avoids xenogeneic antigens but also provides better T1D protection.
Immunotherapy with Bet v 1-derived contiguous overlapping peptides leads to long term immunoregulatory responses (107.14)
Authors: Spertini Francois , Barbier Nathalie , Thierry Anne-Christine , Régine Audran , Charlon Vincent , Reymond Christophe 
Published: January 2023

Abstract
Allergen specific immunotherapy with whole pollen extract may induce anaphylaxis, is poorly standardized and of long duration. We thus designed a randomized, placebo-controlled phase I/II trial in volunteers with birch pollen allergic rhinitis and asthma to evaluate the safety and immunogenicity of a novel immunotherapy based on contiguous overlapping peptides (COPs) derived from Bet v 1, the major birch pollen allergen. A mixture of three COPs (AllerT™, Anergis SA, Switzerland) spanning the whole Bet v 1 molecule was selected for its inability to bind IgE. Prior to the pollen season, AllerT (in Alum) was injected subcutaneously to 15 adult volunteers at D0 (57 μg), D7, D14, D21 and D51 (95 μg each). Control volunteers (n=5) received only adjuvant. Overall AllerT was safe. No serious adverse events and no immediate allergic reactions were reported. AllerT induced a vigorous early Bet v 1 specific immune response marked by vaccine associated INFγ and IL-10 secretion. This contributed to a strong anti-Bet v 1-specific IgG4 enhancement. Moreover, two months after the second season post treatment (July 2010), serum Bet v 1 specific IgG4 response was still markedly increased as compared to pre-treatment values and to placebo whereas post seasonal Bet v 1 specific IgE titers were similar to baseline values. Taken together this indicates that immunotherapy with a mixture of three COPs derived from Bet v 1 (AllerT) was safe and immunogenic, and led to long term immunological memory.
Retinoic acid ameliorates experimental autoimmune hepatitis and suppresses the production of cytokine in NKT cells in mice (107.4)
Authors: Lee Kyoo-A , Song You Chan , Lee Yoon-Sook , Lee Jung-Mi , Kang Chang-Yuil 
Published: January 2023

Abstract
Retinoic acid(RA) has been demonstrated as a critical regulator of various immune cells. Especially RA regulates the response of helper T cells skewing to Th2 response during the priming. In spite of abundant studies regarding T cells, the role of RA on natural killer T(NKT) cell mediated response has not been assessed. In the present study, we demonstrated the effect of RA on the experimental autoimmune hepatitis and the response of NKT cells. We first examined whether pretreatment of RA could regulate concanavlin A(Con A)-induced hepatitis, which is initiated by NKT cells. The survival rate was increased dramatically and liver damage was ameliorated when RA was pretreated. And also the levels of IFN-gamma and IL-4 in serum were both reduced significantly in RA treated group and the cytokine expressing cells were reduced in various lymphocytes in liver, especially in NKT cells. Cytokine suppressive effects of RA were observed when NKT cell specific ligand was treated. These regulations were also detected when mononuclear cells of liver or splenocytes were treated with the stimulants in the presence of RA in vitro. These regulations are not related with the early activation of NKT cells. Rather, the apoptosis of lymphocytes in liver after the administration of con A were increased in RA-treated group. These findings implicates that RA ameliorates NKT cell mediated hepatitis and it could be used clinically to liver injury related with NKT cells.
Programming of induced pluripotent stem cells into regulatory T cell for arthritis prevention (107.6)
Authors: Haque Rizwanul , Lei Fengyang , Song Jianxun 
Published: January 2023

Abstract
Forkhead box p3 (FoxP3)-expressing regulatory T cells (Tregs) are involved in the regulation of central immune response and important for maintenance of peripheral immune response. Ectopic expression of FoxP3 conveys Treg phenotype to CD4+ T cells, lending the cells to therapeutic use in the prevention of autoimmune diseases. Previously we reported that induced pluripotent stem (iPS) cells have the capacity to develop into T cells. However, the potential of iPS cells differentiate into functional Tregs are not clear. In this study, we used retrovirus-mediated transduction to introduce mouse iPS cells with the FoxP3 gene and co-cultured the cells with the OP9 cells expressing the Notch ligand Delta like 1 (DL1) protein to induce Treg differentiation. In addition, we used a murine disease model to determine the role of iPS cell-derived Tregs in the treatment of arthritis. We found iPS cells-derived T cells expressed CTLA-4, CD25, and FoxP3 after three-week differentiation both in vitro and in vivo, and were able to secrete cytokines (e.g., IL-10). In addition, adoptive transfer of iPS cell-derived Tregs strongly suppressed arthritis development in the murine model of arthritis induced by collagen. These results indicate that iPS cells can differentiate into functional Tregs. The data suggest a potential novel approach to generate therapeutic Tregs from iPS cells for the treatment of autoimmune diseases Keywords: stem cells, regulatory T cells, FoxP3, T cell differentiation
iNKT cell-dependent activation of Kupffer cells in a mouse model of biliary obstruction (108.5)
Authors: Duwaerts Caroline , Gregory Stephen 
Published: January 2023

Abstract
Background: Previously we reported both Kupffer cells (KC), resident hepatic macrophages, and invariant natural killer T (iNKT) cells suppress liver injury in a mouse model of biliary obstruction. This study aims to clarify the interactions between these two cell populations during the course of cholestatic liver injury. Methods: Wild type (WT) and Ja18-/- (iNKT-deficient) female C57Bl/6 mice between 8 and 12 weeks of age were used for all experiments. Mice were injected with magnetic beads 3 days prior to sham- or bile duct ligation- (BDL) surgery to facilitate separation of KC from infiltrating mononuclear phagocytes. On day 3 post-surgery, animals were euthanized, and bead-containing KC were isolated and analyzed by flow cytometry. KC mRNA levels were analyzed using real-time quantitative PCR. Results: A shift in KC phenotype from CD11blo/Ly-6C- to CD11bhi/Ly-6C+ was more prominent in WT than Jα18-/- BDL mice. This shift was not seen in either sham groups. KC from WT BDL mice express higher mRNA levels of IL-1β, IL-6, IL-12, MCP-1, iNOS, and IL-10 compared to KC from Jα18-/- BDL mice. Conclusion: iNKT cell-activated KC express CD11bhi/Ly-6C+ and produce more pro- and anti-inflammatory cytokines in a mouse model of biliary obstruction.
A novel analog-sensitive allele of Csk reveals its kinase-independent role in the regulation of T cell receptor signaling (109.35)
Authors: Tan Ying Xim , Schoenborn Jamie , Zhang Chao , Shokat Kevan , Weiss Arthur 
Published: January 2023

Abstract
The earliest event in T cell receptor(TCR) signaling is the activation of the Src family kinase(SFK) Lck. Phosphorylation of a conserved tyrosine in the C-terminal tail of Lck inhibits its kinase activity and is reciprocally regulated by the protein tyrosine kinase, C-terminal Src kinase(Csk), and the protein tyrosine phosphatase, CD45. Using a chemical-genetic approach, our lab has generated a novel analog-sensitive dominant inhibitory allele of Csk(CskAS) that can be specifically inhibited by a small molecule. Surprisingly, inhibition of the CskAS allele leads to rapid T cell activation in the absence of any TCR stimulation, indicating that Lck activity is dynamically regulated by an equilibrium between Csk and CD45 activities and that there is an adaptive response to the reduced basal signaling imposed by the dominant inhibitory CskAS. Moreover, mutating the SH2 and SH3 domains of CskAS results in reduced T cell activation upon inhibition of CskAS, suggesting that protein-protein interactions are important for this ligand-independent activation. We have identified Dok-1(downstream of tyrosine kinases-1), an adaptor protein that inhibits tyrosine kinase signaling, as a candidate in controlling the adaptive response responsible for ligand-independent T cell activation. Dok-1 is hyperphosphorylated and interacts with Csk via its SH2 domain upon CskAS inhibition. We suggest that Dok-1 is part of a negative feedback loop that acts to dampen TCR signals.
Lipoteichoic acid from Lactobacillus plantarum induces nitric oxide release in interferon-γ-primed macrophages (110.12)
Authors: Kang Seok-Seong , Ryu Young Hee , Baik Jung Eun , Yun Cheol-Heui , Han Seung Hyun 
Published: January 2023

Abstract
Lactic acid bacteria are beneficial for human health by preventing microbial infections and reinforcing innate immunity in the gastrointestinal tract. Lipoteichoic acid (LTA) is known as a major immuno-stimulating agent of Gram-positive bacteria because of its potential to induce various inflammatory effector molecules. In the present study, we investigated whether highly-pure LTA from Lactobacillus plantarum induces nitric oxide (NO) in a murine macrophage-like cell line, RAW 264.7 cells. The LTA alone could not induce NO release even at 30 μg/ml but the combination of LTA and interferon (IFN)-γ enhanced NO release. The NO release was mainly mediated by inducible NO synthase (iNOS) since the NO release was inhibited by iNOS inhibitors, L-NIL or L-NAME, but not its stereoisomer, D-NAME. Upregulated mRNA and protein expression of iNOS was also observed in the presence of LTA and IFN-γ. In addition, LTA in the presence of IFN-γ induced IFN-γ expression and STAT-1 phosphorylation, both of which are the key pathways for inducing iNOS expression. Electrophoretic-mobility shift assay demonstrated that stimulation with the combination of LTA and IFN-γ remarkably increased the DNA-binding activities of NF-κB and AP-1 transcription factors which regulate the induction of iNOS gene expression. Collectively, these results indicate that LTA from L. plantarum alone has no inflammatory potential but it induces NO release under the inflamed conditions such as the presence of IFN-γ.
Protein kinase A RII directs prostaglandin E2 inhibitory effects on alveolar macrophage phagocytosis of Candida albicans via modulation of actin polymerization (110.16)
Authors: Serezani C. Henrique , Medeiros Alexandra , Kane Steve , Kim Sang-hoon , Lee Sang Pyo , Lewis Casey , Bourdonnay Emilie , Ballinger Megan , Peters-Golden Marc 
Published: January 2023

Abstract
Prostaglandin E2 (PGE2) is an eicosanoid that suppresses alveolar macrophage (AM) functions by activating two distinct stimulatory G protein (Gs)-coupled E prostanoid (EP) receptors (EP2 and EP4), increase in cyclic AMP (cAMP), and the actions of guanine nucleotide exchange protein activated by cAMP (Epac) and/or protein kinase A (PKA). Here, we investigated the role and cAMP effectors for PGE2 modulation of ingestion of C. albicans (Ca) and its effects on F-actin polymerization. PGE2 suppressed phagocytosis of Ca and agonists for both EP2 and EP4 receptors as well as PKA, but not Epac, mimicked this effect. Phagocytosis was augmented by the cyclooxygenase inhibitor indomethacin, antagonists of EP2 and EP4, inhibitors of adenylyl cyclase (AC), and PKA RII but not PKA RI. Confocal microscopy showed that Ca ingestion was associated with an increase in F-actin and a decrease in G-actin. COX and AC inhibitors further increased F-actin content, while PGE2 and PKA, but not Epac agonist decreased it. PGE2 decreased phosphorylation (associated with increased activity) of the actin depolymerizing factor cofilin-1 upon Ca challenge. PGE2-induced cofilin-1 dephosphorylation was mediated by the phosphatase PTEN. In summary, PGE2 inhibits Ca phagocytosis via an EP2/EP4-cAMP/PKARII axis which inhibits actin polymerization by increasing cofilin-1 activity. As PGE2 is overproduced in many immunosupressive states, these effects may contribute to impaired antifungal defense of the lung.
Novel quantitative proteomic analysis of influenza infected dendritic cells reveals a previously unappreciated immune modulatory protein and infection induced differential expression of DC proteins, with unexpectedly high membrane protein dynamics. (110.24)
Authors: Smallwood Heather , Lopez-Ferrer Daniel , Zink Erika , Pasa-Tolic Ljiljana , Thomas Paul 
Published: January 2023

Abstract
Airway dendritic cells (DC) initiate the immune response (IR) to respiratory pathogens (e.g.influenza). DC respond by releasing cytokines and presenting antigen to T cells, which activate on encountering the MCHI/peptide complex. This DC-T cell interaction dictates the IR to a given pathogen. Given that antigen presentation couples the innate and adaptive immune responses, a better understanding of these processes is vital to basic immune research and to therapeutic and vaccine development. To elucidate the underlying mechanisms of these processes we elected to identify DC proteins and quantify their changes in abundance using 18O labeling and LTQ-Orbit-trap-MS. Presuming the import of membrane protein dynamics on DCs, we developed a high pressure trypsinization technique to denature and digest insoluble proteins. We identified &gt;1500 DC proteins, 20% of which change in abundance (i.e. ≥ 2 fold) early in infection. Unexpectedly this method detected infection induced changes in membrane proteins exceeding soluble protein dynamics. Analysis of these preliminary data indicates major shifts in DC metabolic and antigen processing and presentation pathways occur as a result of infection. Network analysis resulted in the identification of two critical modulator proteins; one of these was NFκB, a well known modulator of the immune response and another protein previously unidentified as an IR modulator. Together these data revealed new and important aspects of the immune response.
Overexpression of EAT-2, a SLAM family receptor adaptor molecule, suppresses CRACC receptor expression on Antigen Presenting Cells in an ERK MAP kinase dependent mechanism (110.26)
Authors: Aldhamen Yasser , Seregin Sergey , Liu Chyong-jy , Aylsworth Charles , Godbehere Sarah , Amalfitano Andrea 
Published: January 2023

Abstract
SLAM family receptors play a critical role in immune regulation. Their function is controlled primarily by SAP, EAT-2, and ERT adaptors. We have previously described a novel immunostimulatory function for EAT-2 in a vaccine model system. In the current work we sought to examine the mechanism of action of EAT-2 in APCs. Our results demonstrated that Ad vector infection itself of macrophages significantly (p&lt;0.001) induced the transcription of the SLAM family member CRACC, but not other SLAM family members. In dramatic contrast, infection of macrophages with Ad-EAT2 significantly prevented Ad induced CRACC expression (p&lt;0.001). FACS analysis confirmed that Ad mediated expression of EAT-2 also resulted in decreased protein levels of CRACC on APCs. By utilization of a variety of inhibitors, we confirmed that EAT-2 mediated suppression of CRACC required a functional ERK, but not Src-kinase, PI3K, or p38 pathways. In addition, blockade of ERK signaling abolished the ability of Ad-EAT2 to induce other innate immune response genes in APCs. Finally, utilization of immunoblot confirmed that Ad-EAT-2 significantly induced ERK activation in macrophages. Thus, EAT-2 over-expression by Adenovirus activates ERK pathway that inhibits Ad mediated induction of CRACC in APCs, an activity that correlates with increased induction of several innate immune response genes, as well the improved induction of antigen specific adaptive immune responses after Ad mediated transfer of immunogenic antigens.
Phosphorylation regulates RPS3-conferred specific NF-κB signaling during foodborne pathogen infection (110.7)
Authors: Wan Fengyi , Lenardo Michael 
Published: January 2023

Abstract
Rapid transcription of NF-kappaB target genes is vital for an effective immune response. We identified ribosomal protein S3 (RPS3) as an intrinsic NF-kappaB subunit that synergistically interacts with Rel subunit p65 to direct specific target gene transcription. Upon stimulation, RPS3 translocates to the nucleus, where it facilitates high affinity binding of NF-kappaB to certain kappaB sites. However, it still remains largely unknown how specific activating signals dissociate RPS3 from its cytoplasmic berth to execute the NF-kappaB “specifier” function in the nucleus. Here we report that the Inhibitor of kappaB (IkappaB) kinase 2 (IKK2), when activated, specifically phosphorylates RPS3. Serine phosphorylation of RPS3 augments its association with importin-alpha and subsequent nuclear translocation. Moreover, the foodborne pathogen Escherichia coli O157:H7 type III secretion system effector NleH1 specifically inhibits RPS3 phosphorylation to block subsequent RPS3 nuclear translocation. By selectively attenuating transcription of certain RPS3-dependent NF-kappaB target genes, E. coli O157:H7 alters the host innate NF-kappaB response in the gut to promote colonization and diarrhea but decrease mortality. In summary, our results indicate that the IKK2-dependent modification of a single amino acid in RPS3 promotes the specific recognition of certain kappaB sites by NF-kappaB, and provides new molecular insights into the complex pathogenetic mechanisms of foodborne pathogens.
Super resolution microscopy reveals that Caveolin-1 is required for antiviral immune response (110.8)
Authors: Gabor Kristin , Stevens Chad , Pietraszewski Matthew , Gould Travis , Lam Siew , Gong Zhiyuan , Hess Samuel , Kim Carol 
Published: January 2023

Abstract
Caveolae are integral to numerous signaling pathways but their function in antiviral signaling is largely unexplored. Understanding spatial distribution and dynamics of receptors within unperturbed membranes is essential for elucidating their role in antiviral signaling, but conventional studies of detergent-resistant membrane fractions cannot provide this information. While it is known that viruses exploit caveolae for entry into host cells, this study instead demonstrates an entry-independent mechanism for virus evasion of host cell defenses through disruption of clusters of signaling molecules organized within caveolae. Super-resolution microscopy has enabled the first single-molecule imaging of interactions between type I interferon receptors (IFN-R) and caveolae. In particular, cav-1b knockdown caused IFN-R clusters to disperse, suppressing antiviral immune response through abrogation of downstream signaling, a response strongly suggesting that IFN-R organization within caveolae is critical for IFN-mediated antiviral defense.
E. coli infection and endotoxic shock induce the expansion of regulatory dendritic cells (111.2)
Authors: Zhang Jiyan , Li Yajing , Guo Xiangrui 
Published: January 2023

Abstract
Regulatory dendritic cells (DCs) have been reported recently. However, whether regulatory DCs are induced in a natural immune response to an infectious disease or endotoxic shock remains to be explored. Here we report that regulatory CD11clowCD45RBhigh DCs become the predominant CD11c-expressing cells in the spleen during E. coli K12 infection, whereas i.p. injection of 2 ml of thioglycolate, which elicits aseptic peritonitis, does not induce regulatory CD11clowCD45RBhigh DCs. On the other hand, injection of isoproterenol for 5 consecutive days before E. coli K12 infection shows little effect on the induction of regulatory CD11clowCD45RBhigh DCs. A similar increase of regulatory CD11clowCD45RBhigh DCs is seen in mice injected with sublethal doses of LPS. The regulatory DCs secret little IL-10 and show marginal effect on the proliferation of T cells, but induce IL-10-expressing CD4 T cells. Taken together our data suggest that a natural immune response to an infectious disease or endotoxic shock induces regulatory CD11clowCD45RBhigh DCs.