bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-associated decreases in influenza-specific CD8+ T cell immunity and the effect of androgen removal (B18)
Authors: Reiseger Jessica , Fletcher Anne , Boyd Richard , Turner Stephen 
Published: January 2023

Abstract
Age-associated decreases in the CD8+ T cell primary and secondary responses of mice to influenza A virus infection were examined by comparing young (2 months) and aged (22–24 months) C57BL/6 mice. A significant age-associated decrease was seen in both the percentage and number of virus-specific CD8+ T cells following both primary and secondary infection. In both age groups there was a strong correlation between influenza peptide-specific tetramer+ and IFNg+ cells. Clearance of virus from the lungs, following primary infection corresponded with the time point at which maximal levels of both percentages and numbers of virus-specific CD8+ T cells were seen for both age groups. There was a delay in the maximal expansion of virus-specific CD8+ T cells in the aged mice compared to young mice following primary infection and a corresponding delay in viral clearance. A significant age-associated decrease in the cytotoxic activity was seen. Cytotoxic activity was closely correlated with the numbers of virus-specific CD8+ T cells suggesting that the age-associated problems with CD8+ T cell activity against influenza are due to decreased numbers of cells able to respond initially or a defect in expansion of these cells once exposed to the virus, rather than effector activity on a per cell basis.
This was further supported by the fact that following thymic regeneration, caused by castration, there was an increase in the numbers of naïve T cells in the periphery of aged-mice with a consequent increase in the numbers of virus-specific cells and an increased ability to clear virus.
PKCζ is a novel signal transducer in TLR4-mediated NF-κB activation (B186)
Authors: Huang Xuesong , Pan Zhixing Kevin 
Published: January 2023

Abstract
NF-κB is a key transcription factor mediating a wide spectrum of innate immune responses induced by bacterial lipopolysaccharide (LPS). Although LPS activating NF-κB through TLR4-TRAF6-IKK signaling cascade has been extensively studied, the detailed signal transduction pathways induced by LPS that lead to NF-κB activation, still need to be defined. Recently we found that atypical PKCζ is involved in LPS-induced activation of NF-κB in macrophages. LPS induces time-dependent activation of PKCζ, and blocking PKCζ activity by PKCζ pseudosubstrate inhibitor or siRNA effectively inhibits LPS-induced NF-kB activation. Co-immunoprecipitation with anti-PKCζ antibody indicates association between PKCζ, and TRAF6 or TAK1. PKCζ activity is TRAF6-dependent because inhibition of TRAF6 by transfection with siRNA and dominant-negative mutant attenuates LPS-induced PKCζ activation. PKCζ activating NF-κB is mediated by TAK1, which is supported by the observation that inhibition of PKCζ impairs activation of TAK1 and knock-down of TAK1 attenuates the activation of NF-κB induced by constitutively active PKCζ. The results demonstrate a signaling pathway involving PKCζ, presents in TLR4-mediated NF-κB activation, and the function of PKCζ is TRAF6-dependent and via TAK1.
Virulent Mycobacterium tuberculosis H37Rv suppresses cell membrane repair of host macrophages (B187)
Authors: Chen Minjian , Remold Heinz G. 
Published: January 2023

Abstract
Virulent Mycobacterium tuberculosis (Mtb) H37Rv induces necrosis of host macrophages (Mφ), initiated by mitochondrial inner membrane perturbation and plasma membrane disruption, which serves as a microbial virulence mechanism allowing dissemination of the pathogen. Infection of Mφ with Mtb creates a local disruption of the plasma membrane, which can be repaired in a Ca2+dependent manner by trafficking of intracellular vesicles to the plasma membrane as membrane donors. We demonstrate that attenuated H37Ra induce significant exocytosis of LAMP1, a lysosome marker, and mannosidase 2, a Golgi apparatus marker, to the plasma membrane surface leading to cell membrane repair. Successful membrane repair prevents fluorescent dextran (FDx) diffusion into the cytosol. In contrast, Mφ infected with virulent H37Rv show much less LAMP1 and mannosidase 2 exocytosis and more FDx diffusion. Confocal analysis indicates that plasma membrane LAMP1 is partially colocalized with synaptotagmin7 (Syt 7), an essential regulator of exocytosis. Silencing of Syt 7 leads to less LAMP1 exocytosis and increases FDx diffusion and necrosis. Suppression of mannosidase 2 exocytosis by Brefeldin A implies the endoplasmic reticulum indirectly as a contributor to membrane repair. These findings reveal a virulence mechanism of H37Rv that blocks plasma membrane repair and leads to necrosis
(Supported by NIH grant AI50216).
The Histamine H4 Receptor (H4R) Mediates Inflammatory Responses in a Th2-dependent, FITC-induced Atopic Dermatitis Model (B199)
Authors: Zhang Mai , Cowden Jeffery M. , Dunford Paul J. , Thurmond Robin L. 
Published: January 2023

Abstract
Histamine is an important inflammatory mediator in atopic dermatitis. The histamine H4 receptor (H4R), primarily expressed on immune cells, affects Th2 responses, dendritic cell functions, eosinophil and mast cell chemotaxis. Recent studies also demonstrate its role in experimental pruritus. In this study, we investigated the function of H4R in a Th2-dependent mouse model of atopic dermatitis. Mice were sensitized with Fluorescein isothiocyanate (FITC) on the abdominal skin, and later challenged with FITC on the ear. Ear edema and pruritic response were then evaluated. The experimental group that received JNJ7777120, a potent and specific H4R antagonist, developed less edema (28%, P &lt;0.01) and pruritic response (68%, P &lt;0.05). JNJ7777120 administration also inhibits cytokine and chemokine production measured from homogenates of inflamed ear. Taken together, these results suggest that the H4R is involved in inflammatory responses in this Th2-dependent atopic dermatitis model. Therefore, antagonists to the H4R may be an effective treatment for atopic dermatitis, given their dual anti-inflammatory and anti-pruritic effects.
Primary and memory B cells occupy independent homeostatic niches (B20)
Authors: Crowley Jenni Eileen , Scholz Jean L. , Migone Thi-Sau , Cancro Michael P. 
Published: January 2023

Abstract
The cytokines BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) interact with three receptors – BR3, TACI, and BCMA – to regulate peripheral B cell homeostasis. Experimental evidence indicates that the BLyS-BR3 interaction governs the size and composition of primary B cell subsets by controlling the proportion of transitional (TR) cells that complete differentiation and determining the lifespan of follicular (FO) and marginal zone (MZ) B cells. The role of the BLyS family in the regulation and maintenance of memory B cell subsets remains less understood. Accordingly, we have directly tested the role of BLyS in the maintenance of memory B cells in vivo using a neutralizing anti-BLyS antibody. Mice injected with anti-BLyS show profoundly reduced numbers of TR, FO, and MZ B cells within two weeks following treatment, as well as significantly reduced serum BLyS levels. However, for mice previously immunized with NP-CGG and injected with anti-BLyS, this treatment, while similarly reducing primary B cell pools, has no effect on NP-specific memory B cell numbers. Further, upon rechallenge, the expansion of NP specific memory B cells and serum anti-NP antibody levels are similar to controls that did not receive anti-BLyS. Together, these findings indicate that memory B cells are largely independent of BLyS availability, and therefore occupy a separate homeostatic niche from primary B cells.
Supported by USPHS AI054488 to MPC and T32-AI-055428 to JEC
ISS (ImmunoStimulatory Sequences) and Iscomatrix boost vaccine-generated HBV-specific immunity in mice (B202)
Authors: Marshall Jason D , Gesner Marianne L , Heeke Darren S , Livingston Brian , Van Nest Gary 
Published: January 2023

Abstract
We have investigated the adjuvant activity of both CpG motif-containing ImmunoStimulatory Sequences (ISS) and the saponin/phospholipid-based Iscomatrix (IMX) on HBV-specific humoral and cell-mediated immunity in C57BL/6 mice. Mice were immunized at weeks 0 and 2 with several formulations that incorporated HBV surface antigen (HBsAg), HBV core antigen (HBcAg), ISS, and IMX. ISS was added to antigen in soluble form or conjugated with HBsAg or HBcAg. Bleeds were performed 2 weeks post 1st immunization (2wp1) and 2wp2 and sera analyzed for anti-HBV IgG1 and IgG2a levels. Mice were also splenectomized at 2wp2 and HBV-specific cell-mediated immunity was examined. HBsAg + HBcAg + 1018 ISS + IMX resulted in high levels of HBsAg-specific and HBcAg-specific IFN-g induction that exceeded that induced by either adjuvant alone. Conjugates of HBV surface or core protein to ISS ODNs also provided for higher levels of antigen-specific IFN-g production and CTL activation. These results indicate that HBV therapeutic formulations that incorporate ISS and/or IMX may stimulate for enhanced levels of anti-HBsAg antibody and augmented anti-HBcAg CMI (cell-mediated immunity) and are promising candidates to test in human clinical trials.
Subcutaneous 21-day Administration of 17alpha-ethinyl estradiol or 17beta-estradiol alters the thymus of 8-week-old C57BL/6 Mice (B217)
Authors: Brummer Tyson Peter Thomas , Phillips Rebecca A , Kerr Richard P , Gogal Robert M , Ahmed Ansar 
Published: January 2023

Abstract
Exposure to exogenous estrogens occurs via multiple sources (i.e. environmental contamination, contraceptives). Presently, little data exist regarding the immune effects of the synthetic estrogen 17α-ethinyl estradiol (EE) and its relative potency compared to 17β-estradiol (E2). In this study, we investigated the immune effects of daily subcutaneous injections of either EE or E2 on intact juvenile male and female C57BL/6 mice for 21 days with concentrations of 0.04 μg/25 g BW, 0.4 μg/25 g BW, or 4.0 μg/25 g BW. In male mice, thymus weight and thymus to BW ratio were significantly decreased at 4.0 EE dose, whereas in female mice significant decreases were noticed at 0.4 and 4.0 doses of both E2 and EE. Thymocyte absolute numbers were significantly diminished at both 4.0 E2 and EE dosing levels in males, and decreased at the 0.4 and 4.0 doses of E2 and EE in females. Decreasing trends in CD4+/CD8+ expression were observed in EE-treated mice, reaching significance at 4.0 EE in the females. The male spleen NK 1.1 cell surface marker was significantly increased at 0.04 and 4.0 EE treatments, as well as at 0.4 E2. In summary, results of these data suggest that a 21-day subcutaneous exposure of either E2 or EE is sufficient to significantly alter thymic endpoints. With the exception of the NK 1.1 subset, splenic endpoints did not yield any remarkable results. These findings suggest that the thymus is a more sensitive target than the spleen with regard to subacute exposure of 17α-ethinyl estradiol.
Stochastic simulation of B cell signaling reveals affinity discrimination through B cell synapse formation (B36)
Authors: raychaudhuri subhadip , tsourkas philippos , simon scott i. , baumgarth nicole 
Published: January 2023

Abstract
We have developed a Monte Carlo based stochastic computer simulation model to investigate the mechanisms of differential B cell signaling upon ligation with antigens of varying affinity. Recent experiments have revealed that B cell signaling is modulated through the immune synapse upon ligation with membrane bound antigens. The immune synapse is an ordered structure consisting of segregated BCR-antigen and LFA1-ICAM1 molecules that is formed at the cell-cell contact area. Our computational model elucidates affinity and diffusion dependent biophysical mechanisms of such B cell immune synapse formation. For a given antigenic affinity, our numerical experiments gave rise to stochastically varying levels of activated signaling molecules such as phosphorylated BCR Igα/Igβ and Syk molecules. Such stochastic outcome of B cell signaling determines how affinity discrimination is achieved by signaling through immunological synapses. For soluble antigens, a diffusion-dependent coarse-grained model of receptor clustering (capping) at the B cell surface yields similar stochastically varying levels of signaling molecules and results in affinity discrimination through receptor cap formation.
Generation of MHC class I-presented peptides in cells over-expressing a dominant interfering ubiquitin (B43)
Authors: Huang Lan , Marvin Julie , Golovina Tania , Eisenlohr Laurence C 
Published: January 2023

Abstract
The participation of the proteasome in MHC class I-restricted antigen processing is well documented, but the degree to which targeting of antigenic proteins to this multicatalytic protease is ubiquitin-dependent remains unclear. To address this question, we over-expressed wild type ubiquitin (Ub-WT) and lysineless ubiquitin (Ub-K0) in mammalian cells using an inducible vaccinia system. Compared to Ub-WT, the Ub-K0 potently abrogated the conjugation of ubiquitin to protein substrates, and subsequently attenuated total protein degradation. In co-infection assays, the Ub-K0 significantly inhibited specific epitope presentation from cytosolic N-end Rule substrates and an exocytic model antigen, but had little effect on antigen presentation from a stable cytosolic antigen. Interestingly, the inhibitory effect on antigen presentation by Ub-K0 decreased when the exocytic model antigen is directed to the cytoplasm, and increased when the stable cytosolic antigen is directed to the endoplasmic reticulum (ER). Despite similar levels of surface MHC class I molecules, different peptide profiles bound to surface class I molecules were observed from cells over-expressing Ub-WT and Ub-K0. The results suggest that cytosolic proteins and glycoproteins may be targeted to proteasome through different pathways to generate MHC class I peptides.
This study is supported by NIH grant AI39501.
Tumor Associated Ascites Inhibits CD1d-Mediated Antigen Presentation (B44)
Authors: Webb Tonya J , Rogers Ophelia , Giuntoli Robert L. , Schneck Jonathan , Oelke Mathias 
Published: January 2023

Abstract
Natural killer T (NKT) cells recognize lipid antigen presented by CD1 molecules. Recently, it has been shown that NKT cells can both directly and indirectly mediate anti-tumor immunity. However, it is thought that the anti-tumor effects mediated by these cells are being hampered because the number and function of NKT cells is reduced in cancer patients. Moreover, it has been shown that tumor associated glycolipids are frequently shed into the tumor microenvironment, which can mediate immunosuppressive activity. In these studies we examined antigen presentation by CD1d following treatment with ascites from cancer patients. It was found that pretreatment with ascites inhibited the ability of CD1d molecules to present endogenous antigen to NKT cells in a dose-dependent manner. We found that this inhibition does not require antigen processing, as canonical (Vα14+) and noncanonical NKT cells, which do not require trafficking through endocytic compartments, were both inhibited. Also, ascites treatment of artificial Antigen Presenting Cells (aAPC) preloaded with α-GalCer, abrogated their ability to present antigen to NKT cells, which further suggests that the inhibition is antigen processing independent. In addition, our data demonstrate that treatment with ascites does not inhibit antigen presentation to classical CD8+ T cells. Together, these data suggest that glycolipid shedding in ascites may be a mechanism of immune evasion specifically utilized used by cancers to inhibit CD1d- mediated activation of NKT cells.
The RING E3 ubiquitin ligase Trim13 (Rfp2) influences αβ and γδ T cell development (B5)
Authors: Narayan Kavitha , Kang Joonsoo 
Published: January 2023

Abstract
αβ and γδ T cells arise from a common precursor in the thymus, but the mechanisms involved in this lineage specification remain poorly defined. We identified Tripartite Motif 13 (Trim13) as a γδ lineage biased gene. TRIM13, an RBCC protein, is an ER/nuclear membrane localized RING E3 ubiquitin ligase involved the ER-associated degradation pathway. Similar to other γδ lineage biased genes, the expression of Trim13 in γδ T cells is regulated in part by trans priming signals from αβ lineage DP thymocytes, and Trim13 is also expressed in some unconventional αβ lineage subsets. Interestingly, Trim13 is only expressed in about half of γδ thymocytes, suggesting that Trim13 may mark a subset of γδ T cells distinguishable by different thymic selection requirements, different stages of maturity, and/or functional competence. Preliminary results indicate that ectopic Trim13 expression is detrimental to αβ T cell development, but is conducive for enhanced γδ T cell generation and B cell development and/or expansion. These results suggest that Trim13 may play a role in T and B cell development, and that its expression may segregate specific subsets of T cells. Given its role as a nuclear membrane E3 ubiquitin ligase, it is possible that TRIM13 functions, in part, by controlling the relative abundance of transcription factors involved in lineage differentiation or maturation, resulting in different developmental outcomes.
NF-κB is transported into the nucleus by a subset of importin α molecules (B51)
Authors: Fagerlund Riku , Melen Krister , Kinnunen Leena , Julkunen Ilkka 
Published: January 2023

Abstract
NF-κB transcription factors are retained in the cytoplasm in an inactive form until they are activated and rapidly imported into the nucleus, where they bind to the promoter elements of their target genes. The molecular mechanisms of nuclear import of various members of the NF-κB family of transcription factors have remained relatively poorly studied. By using E. coli-expressed GST-importin α isoform constructs we previously identified importin α3 and importin α4 as the main importin α isoforms binding to TNF-α activated p50-p65 heterodimers. Altogether 6 different importin α isoforms have been identified in humans. NF-κB p50 and p65 protein binding to importin α3 was found to be mediated by the previously identified nuclear localization signals (NLSs) of these proteins. Baculovirus-expressed importin α5 was also found to bind activated p50-p65 heterodimers. We also found that TNF-α or Sendai virus infection-activated alternative NF-κB pathway components, p52 and RelB bound to baculovirus-produced importin α3, α4 and α5 isoforms. Importin α5 was found to directly bind to NLSs of NF-κB p52, RelB and c-rel proteins. Our findings suggest that the nuclear import of both the classical and alternative NF-κB pathway molecules is a regulated process mediated by a subset of importin α isoforms.
CXCL10 is required for resistance to dengue virus infection independent of effects on leukocyte recruitment (B54)
Authors: Ip Peng Peng , Liao Fang 
Published: January 2023

Abstract
CXCL10 is an interferon-inducible chemokine ligand for CXCR3, a receptor that is expressed on lymphocytes and that CXCL10 shares with CXCL9 and CXCL11. Previously, we found that CXCL10−/− mice were more susceptible to dengue virus infection as compared with wild-type controls. In this study, we explored the mechanisms underlying this enhanced susceptibility. Viral loads were higher in the brains of CXCL10−/− mice vs. control animals. Presuming a defect in lymphocyte migration, we next investigated whether recruitment of effector T cells and antibody-secreting cells (ASC) to the infected tissues were impaired in CXCL10−/− mice. Unexpectedly, CXCL10−/− mice showed only slightly lower numbers of infiltrating total T cells, higher numbers of CXCR3+ T cells, and higher numbers of ASC in the brain as compared with control mice. These results demonstrate that
CXCL10 is not required for recruitment of CXCR3+ T cells to the brain in dengue virus-infected mice, andthe enhanced susceptibility of CXCL10−/− mice to dengue virus infection is not due to a defect in recruitment of effector lymphocytes, but may be due instead to an anti-viral activity of the chemokine.
Norepinephrine-dependent activation of the neuroimmune system is counter-regulated by IL-1RA (B59)
Authors: Park Min Jung , Johnson Daniel R , Martin Jonathan , Freund Gregory G 
Published: January 2023

Abstract
Stress negatively impacts well-being and is linked to a variety of diseases including heart disease and cancer. It is known that stress modulates the immune defense system, but the mechanisms involved are not well established. Here we report that norepinephrine (NE) is a rapid activator of the neuroimmune system as measured by a loss of interest in the social environment. C57BL/6J mice were injected with 1.5 mg/kg of NE (I.P.) and social exploration (SE) was measured over a 24-hour period. Peak decrease in SE was observed 30 min after NE injection (74.1 ± 4.7 % reduction in SE) and full recovery was observed 8 hours following NE treatment. This decrease appears linked to a brain-based up-regulation of IL-1 alpha (370 %) and TNF alpha mRNA (260 %). Additionally, Kineret®, a derivatized recombinant IL-1RA used in the treatment of rheumatoid arthritis, hastened recovery from NE-induced neuroimmune system activation by 31.1%. These results show that NE actives the neuroimmune system, which IL-1RA treatment can ameliorate.
High Affinity Humanized Monoclonal Antibody to Human IL 1&#946; Potently Inhibits Toll-like Receptor (TLR) Agonists in Whole Blood (B61)
Authors: Reznikov leonid , Solinger Alan , dinarello charles 
Published: January 2023

Abstract
XOMA 052, a Human Engineered™ monoclonal antibody, was developed to the mature form of human IL-1β following selection from multiple phage display libraries. This antibody has a binding constant for human IL-1β of 300 fM. Human blood cultures were used to evaluate the biological effects of this antibody. The cultures were stimulated with TLR ligands. After 24 hours, the cultures were lysed with Triton®-X to extract membrane and intracellular cytokines. XOMA 052 inhibited the production of IL-1β induced by Staphylococcus epidermidis by 50% at 0.1 pM and by 75% at 3 pM; IL-1β induced by LPS was reduced by 75% at 10 pM. At 100 pM, inhibition was 100% whether induced by Staphylococcus epidermidis or LPS. LPS-induced TNFα was reduced by 75% at 100 pM. Interferon-γ (IFNγ) was induced by Staphylococcus epidermidis and by LPS. XOMA 052 reduced IFNγ induced by Staphylococcus epidermidis by 75% at 100 pM and LPS-induced IFNγ by 75% at 100 pM.We conclude that the data from the whole blood cultures are consistent with the high 300 fM affinity of XOMA 052 for IL-1β.