bluuebunny/crossref_metadata_2025_split huggingface dataset:
The size effects of amorphous silica nanoparticles on atopic dermatitis-like skin lesion (P6259)
Authors: Takahashi Hideki , Yoshioka Yasuo , Hirai Toshiro , Ichihashi Ko-ichi , Nishijima Nobuo , Yoshida Tokuyuki , Nabeshi Hiromi , Yoshikawa Tomoaki , Tsunoda Shin-ichi , Higashisaka Kazuma , Tsutsumi Yasuo 
Published: January 2023

Abstract
Exposure to environmental factors, such as microbes, diesel exhaust, and other chemicals are speculated to be associated with atopic dermatitis (AD), however, the detailed relationships between environmental factors and increase in AD are not well understood. Additionally, recent industrialization poses new threats to the development of AD. We recently revealed that amorphous silica nanoparticles (nSP) can penetrate the skin barrier and induce various immunological effects. Thus, nSP in various products may also be associated with development of the other allergic diseases such as AD. Here, we investigated the effect of nSPs on AD like skin lesions. We injected mite antigen (Dp) plus various-sized silica particles (SPs : diameter of 1,000, 300, 100, 70 and 30 nm) intradermally into the ear of NC/Nga mice which develops AD-like skin lesions induced by a mite allergen Dp. Ear thickness measurements and histopathological analysis revealed that a combined injection of SPs and Dp induced aggravation of AD in an SP size-dependent manner compared to that of Dp alone. Furthermore, these effects were correlated with the excessive induction of total IgE and Dp specific IgE. We suggested that these results are associated with the induction of IL-18 and thymic stromal lymphopoietin (TSLP), which leads to systemic Th2 response in the skin lesions. These results indicate that the size of SPs is critical determinant in terms of their safe use.
Chemerin receptor CCRL2 is required for maximal induction of peanut-induced anaphylaxis (P6253)
Authors: Lewen Susanna , Zhang Jian , Zabel Brian 
Published: January 2023

Abstract
Food allergy affects 6-8% of young children and ~2% of adults in the U.S., and is the leading cause of life-threatening anaphylactic reactions treated in hospital emergency departments. CCRL2 is an atypical attractant receptor expressed on vascular endothelial cells and mast cells that binds and concentrates chemerin on the cell surface. In vitro, this serves to significantly enhance adhesion of CMKLR1+ cells. We previously showed that CCRL2 is required for maximal tissue swelling and leukocyte infiltration in passive cutaneous anaphylaxis. We therefore hypothesized that CCRL2 plays a pathogenic role in experimental peanut-induced anaphylaxis (PIA). Wild-type (WT) or CCRL2 KO mice were sensitized by repeated oral inoculation with peanut protein and cholera toxin over four weeks, and challenged with systemic injection of peanut protein. CCRL2 was required for maximal peanut-specific immunoglobulin secretion, leukotriene B4 release, and vascular leakiness. Circulating chemerin levels were also significantly increased in the CCRL2 KO mice. Although circulating histamine levels were significantly elevated in CCRL2 KO mice compared with WT, clinical signs of anaphylaxis were significantly reduced. CCRL2 may therefore represent a novel drug target for preventing or treating food allergy in the clinic.
Antigen-specific T cell and B cell responses to the herpes zoster vaccine Zostavax® in the young and elderly. (P6330)
Authors: Sullivan Nicole , McCausland Megan , Chiu Christopher , Sidney John , Rouphael Nadine , Mehta Aneesh , Mulligan Mark , Peters Bjoern , Sette Alessandro , Pulendran Bali , Ahmed Rafi 
Published: January 2023

Abstract
Herpes zoster (HZ or shingles) is the clinical manifestation of varicella zoster virus reactivation. HZ typically develops as people age due to decreased cell mediated immunity. The goal of this study was to characterize adaptive immune responses to HZ vaccination in the young and elderly. Sixteen young (25-40yo) and 23 elderly (60-79yo) patients were enrolled and vaccinated. Longitudinal analysis of B cell responses demonstrated a transient increase in the HZ-specific plasmablast population 7 days post vaccination. Although both groups increased the number of HZ-specific plasmablasts, there was a significant reduction in the magnitude of response in the elderly group (p=0.0158). Next, modest T cell proliferation (Ki67+Bcl2-) was detected after vaccination (CD4 fold change: young=2.04±0.19; elderly=1.64±0.19)(CD8 fold change: young=1.31±0.17;elderly=1.47±0.17). No significant difference in CD4 and CD8 T cell responses was detected in the young vs. elderly (p=0.1511 and p=0.5172 respectively). Finally, we identified several new HZ-specific CD4 T cell epitopes using predictive epitope mapping followed by IFN-γ elispot. The majority of the CD4 epitopes identified were present in several glycoproteins and immediate early genes. Kinetic analysis showed increases in many of these epitopes up to 90 days post vaccination. Ongoing studies will further characterize the quality and quantity of the HZ-specific CD4 T cell response post vaccination.
SLC11A1 is expressed by innate lymphocytes and augments their activation (P4331)
Authors: Hedges Jodi , Kimmel Emily , Snyder Deann , Jerome Maria , Jutila Mark 
Published: January 2023

Abstract
SLC11A1 (formerly NRAMP1 and Bcg/Lsh/Ity locus) was thought to be exclusively expressed in monocyte/macrophages and to function in phagosome maturation and in cell activation through iron-dependent interference with protein tyrosine phosphatase (PTP) activity. We characterized the expression of SLC11A1 in the majority of γδ T cells and NK cells, and in CD3+CD45RO+ T cells. Consistent with a role for iron-dependent inhibition of PTPs, SLC11A1+ lymphocytes were more prone to activation, IFN-γ expression, and retained tyrosine phosphorylation. Transfection of SLC11A1 into a human γδ T cell-like line rendered the cells more prone to activation. Expression of functional SLC11A1 in vivo has been consistently associated with increased IFN-γ expression, during Salmonella infection in particular. We compared non-adherent splenocytes from wild type (Sv/129) to cells from Sv/129 (SLC11A1-/-) mice. Wild type cells expressed significantly greater IFN-γ in response to supernatant fluids from Salmonella-infected monocytes from either strain. Our data suggest that SLC11A1 has a heretofore unknown role in activation of a large subset of innate lymphocytes that are critical sources of IFN-γ. Commonly used inbred laboratory mice lack functional SLC11A1 protein. Expression of SLC11A1 in innate lymphocytes and its role in augmenting their activation may, in part, account for inconsistencies in studies of innate lymphocytes in different animal models.
Cytokine activation induces CD25 expression and a functional high-affinity IL-2 receptor on CD56dim human NK Cells (P4349)
Authors: Leong Jeff , Chase Julie , Romee Rizwan , Schneider Stephanie , Sullivan Ryan , Fehniger Todd 
Published: January 2023

Abstract
The heterotrimeric high affinity IL-2 receptor (IL-2Rαβγ) is expressed on CD56bright human NK cells and confers responsiveness to picomolar concentrations of IL-2. In contrast, resting CD56dim NK cells lack IL-2Rα (CD25), but constitutively express the intermediate affinity IL-2Rβγ chains. Here, we show that cytokine-activation induces rapid and prolonged expression of CD25 on CD56dim NK cells, especially the combination of IL-15 plus IL-18. This expression of CD25 correlated with STAT5 phosphorylation in response to picomolar concentrations of IL-2, indicating the presence of a signal-competent IL-2Rαβγ. Furthermore, picomolar concentrations of IL-2 acted synergistically with IL-12 to co-stimulate IFN-γ production by pre-activated CD56dim NK cells. Similarly, low dose IL-2 enhanced the cytotoxicity of pre-activated CD56dim NK cells against K562 tumor targets. Both effects were dependent on the expression of CD25. Preliminary experiments also suggest that the induction of CD25 on CD56dim NK cells enhances proliferative capacity and survival in cultures supplemented with low dose IL-2. Since CD56dim NK cells represent the major subset of human peripheral blood NK cells, these data support a rationale for immunotherapeutic strategies that include cytokine pre-activation prior to adoptive NK cell transfer, followed by low dose IL-2 therapy.
Malfunction of dendritic cells from aged mice leads to loss of activation of Natural Killer cells (P4353)
Authors: Guo Zhenhong , Strominger Jack 
Published: January 2023

Abstract
The interaction between dendritic cells (DC ) and Natural killer cells (NK) plays a key role in infectious disease and tumor immunology. However, the effect of aging on the crosstalk of DC and NK, a critical step in immune activation, has never been elucidated. In our study, we purified splenic DC and NK from young and old C57BL/6 mice and cocultured them in the presence of Poly I:C. Then the activation of NK cells including the expression of CD69 and IFN-gamma secretion was analyzed. The results showed that DC from old mice could not activate NK cells from either young or old mice; in contrast, DC from young mice could activate NK from both young and old mice. In vivo injection of Poly I:C efficiently activated NK cells in young mice, but not in old mice. Further investigation showed that NK cells from young and old mice secreted similar levels of IFN-gamma in response to IL-2. However, old DC secreted less IL-15, IL-18 and IFN-alpha upon stimulation by Poly I:C than young DC, but no significant difference in IL-12 and TNF-alpha production was seen. Moreover, CD48, CD86, MHC class II, GITRL and RAE expression were significantly down-regulated in old DC. All the data suggested that the lost activation of NK in NK/DC coculture using aged mice is caused by the malfunction of DC. Investigation by microarray analysis of DC differences from young and old mice and whether the defect in DC from aged mice extends to a defect in tumor eradiation will be carried out.
IL-25 and innate lymphoid cells induce pulmonary fibrosis (P4357)
Authors: Hams Emily , Armstrong Michelle , Barlow Jillian , Kubica Malgorzata , Saunders Sean , Cooke Gordon , Crotty Thomas , Hirani Nik , Flynn Robin , Donnelly Seamas , McKenzie Andrew , Fallon Padraic 
Published: January 2023

Abstract
Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Currently there are limited effective therapeutics for pulmonary fibrosis due to an inadequate understanding of the pathogenic process and underlying mechanisms. We now show that in human idiopathic pulmonary fibrosis (IPF) the cytokine interleukin (IL)-25 positively correlates with periostin a marker human pulmonary fibrosis, and the presence of IL-13-producing type 2 innate lymphoid cells (ILC2) in the lung. Using murine models of pulmonary fibrosis we demonstrate an essential role for IL-25-elicited ILC2 in the generation of pulmonary collagen deposition, independent of an adaptive T cell response. Furthermore, we define a mechanism whereby IL-25 evokes ILC2 to induce pulmonary fibrosis via the alternative activation of macrophages in the lung. Collectively, we present a new innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2 that occurs independently of T cell-mediated antigen-specific immune responses. These results indicate that IL-25 and ILC2 are potential therapeutic targets for the treatment of human fibrotic diseases where antigen-independent damage responses may magnify the disease.
Effect of oenothein B, a cyclic dimeric ellagitannin isolated from Epilobium angustifolium, on the antiviral responses of innate lymphocytes. (P4365)
Authors: Ramstead Andrew , Schepetkin Igor , Robison Amanda , Quinn Mark , Jutila Mark 
Published: January 2023

Abstract
Oenothein B is an ellagitannin isolated from the Epilobium angustifolium plant, which has been shown to have immunomodulatory properties. This compound is known to activate myeloid cells, αβ T cells, and innate lymphocytes, such as NK cells, NKT cells, and γδ T cells. Previous work from our laboratory showed that oenothein B primes and enhances the production of interferon-γ by human and bovine NK cells in response to secondary stimuli, including tumor cells and IL-18. Here, we examined whether oenothein B enhances the response of innate lymphocytes to various pathogen associated molecular patterns. We found that oenothein B enhanced interferon-γ production by bovine peripheral blood mononuclear cells in response to several pathogen associated molecular patterns, including the Toll-like receptor 3 agonist poly I:C. We have also found that intranasal administration of oenothein B to mice before infection with influenza can reduce the morbidity of the infection. Our preliminary results suggest that oenothein B is capable of enhancing innate immunity against viral infections, possibly through the enhanced production of interferon-γ by NK cells. The effect of oenothein B on the antiviral activity, including interferon-γ production, of innate lymphocytes during viral infection is currently under investigation in both human cells and mouse models. This work is funded by NIH NCCAM P01 AT004986 and P20 GM103500.
Monkeypox virus infection of rhesus macaques induces massive expansion of NK cells, but suppresses NK cell function (P4369)
Authors: Song Haifeng , Josleyn Nicole , Janosko Krisztina , Skinner Jeff , Reeves R. Keith , Cohen Melanie , Blaney Joe , Jahrling Peter 
Published: January 2023

Abstract
In the current study of MPXV infection in rhesus macaques, we analyzed the NK cell responses in absolute cell numbers, cell proliferation, chemokine receptor expression, and function. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by similar increases in CD56+, CD16+ and CD16-CD56- double negative (DN) NK cells. Similarly, the frequency and NK cell number in the lymph nodes also largely increased with total NK cell number increasing nearly 50-fold. Ki67 staining showed that NK cells both in the blood and lymph nodes proliferated during acute infection. Chemokine analysis revealed an early reduction of CXCR3, CCR7 and CCR6 on NK cells, followed with an increased expression of CXCR3 and CCR5 at later time points (day 7). Furthermore, MPXV infection impaired NK cell degranulation and ablated secretion of IFN-g and TNF-a. Taken together, MPXV infection induced massive NK cell proliferation, but suppressed NK cell function.
Characterization of lacrimal gland NK cells (P4341)
Authors: Erick Timothy , Reilly Emma , Biron Bethany , Peterson Nicole , Brossay Laurent 
Published: January 2023

Abstract
The β-herpes virus murine cytomegalovirus (MCMV), a homologue of HCMV, is a well-characterized animal model of viral infection that results in a non-replicative, chronic infection of an immune-competent animal. MCMV is cleared efficiently by cytotoxic lymphocytes in most organs of the infected host but persists in salivary glands for several weeks after primary infection. Interestingly, it has also been shown that MCMV remains active in the lacrimal gland (LG) for several weeks after infection. Here, we investigate the phenotype of NK cells in the naïve LG and their response to MCMV infection. In naïve mice, we found that the LG contains a resident NK cell population with a mostly immature phenotype (CD27 high/CD11b low). These lymphocytes are absent in E4BP4 deficient mice and present in AhR deficient mice, indicating that these cells belong to the classical NK cell lineage. However, using a variety of cell surface markers we found that the phenotype of LG NK cells is distinct from splenic, liver, or salivary gland NK cells suggesting that the NK cell peripheral phenotype is shaped by the tissue microenvironment. LG NK cells become activated during MCMV infection and release low amount of cytokines. We are currently evaluating in more details the role of LG NK cells during MCMV infection.
High perforin levels in freshly isolated human CD56neg NK cells (P4345)
Authors: Barao Isabel , Redelman Doug , Hunter Kenneth , Hudig Dorothy 
Published: January 2023

Abstract
CD56neg NK cells are a subset that is elevated in the blood of patients with HIV and/or hepatitis C virus viremia, but drop when therapies reduce the viremias [Gonzalez VD, Clin Immunol 128: 46, 2008]. CD56neg NK cells of virally infected individuals are thought to be ‘dysfunctional’ with low cytolytic capabilities. Here we questioned whether the cytotoxic protein perforin is lower in CD56neg compared to CD56dim (perforin-high & highly cytolytic) NK cells and thus could affect cytotoxicity. We assessed the perforin levels of lymphocytes of 97 healthy donors by flow cytometry, staining peripheral blood cells with fluor-tagged anti- CD3, CD56 and perforin. The frequency of CD56neg NK cells of total CD3neg perforinpos NK cells ranged from 1.4 - 53.1% with a mean +/-1SD of 9+/-10%. Twelve donors had CD56neg NK frequencies above 1 SD of the mean, &gt;20% of total NK cells, with counts 67-701 cells per ul of blood. Regardless of NK frequencies, for most donors their CD56neg NK cells were bimodal for perforin with the higher perforin mode equivalent to the perforin levels of CD56dim NK cells. Two donors with greatly elevated CD56neg NK cells had mostly perforin-low CD56neg NK cells. In conclusion, a substantial percentage of healthy donors (12%) have highly elevated CD56neg NK cells and the majority (83%) had CD56neg cells with high levels of perforin. Thus, it likely that for healthy donors, the cells of the expandable CD56neg NK subset have sufficient perforin to support killing.
Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the immunological synapse (P6286)
Authors: Choudhuri Kaushik , Beilin Chiara , Bouma Gerben , Llodra Jaime , Malinova Dessislava , Stokes David , Springer Timothy , Shimaoka Motomu , Dustin Michael , Thrasher Adrain , Burns Siobhan 
Published: January 2023

Abstract
Mutations of the common cytokine receptor gamma chain (gc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although these lineages are restored by stem cell therapy, residual immune defects are observed that may result from a selective persistence of gc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed gc to protective immune responses. We examined the importance of gc for myeloid lineage dendritic cell (DC) function, and show that DC-expressed gc is required for effective antigen-induced CD4+ T cell activation. Using a novel lipid bilayer system mimicking T cell interaction, we observed that gc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Ra colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on expression of gc in DC. These findings reveal a novel mechanism for recruitment of DC IL-15/IL-15Ra complexes to the immune synapse, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.
IL-7 suppresses CD127 gene transcription in human CD8 T cells by inducing expression of the transcription factor c-Myb (P6299)
Authors: Al-Ghazawi Feras , Faller Elliott , Parmar Parmvir , Sugden Scott , Kakal Juzer , Cherid Hafsa , MacPherson Paul 
Published: January 2023

Abstract
In view of the role interleukin (IL)-7 plays in T cell survival, homeostasis and function it is no surprise expression of the IL-7 receptor-α (CD127) is tightly regulated. Dysregulation of IL-7 signaling and CD127 expression has been implicated in a number of diseases such as multiple sclerosis, breast cancer, arthritis as well as in HIV infection. Thus it is important to understand how IL-7 regulates its own receptor expression. Here we elucidate the mechanism by which IL-7 suppresses CD127 transcripts in primary human CD8 T cells. We show by qPCR and nuclear run-on assays that IL-7 suppresses CD127 gene transcription in a time- and dose-dependent manner. The IL-7 mediated suppression of CD127 transcripts is dependent on JAK/STAT5 signaling. Notably, cycloheximide blocked IL-7’s ability to down-regulate CD127 transcripts suggesting IL-7 stimulates the de novo synthesis of a transcriptional repressor which in turn suppresses CD127 gene transcription. Through DNA microarrays and PCR arrays, the IL-7 inducible transcription factor c-Myb was identified. The region within the CD127 gene promoter required for IL-7 mediated transcriptional suppression was identified through progressive truncations using firefly luciferase as a reporter gene and is located from -1760 to -2406 bp upstream of the TATA box and contains c-Myb binding sites. Using siRNA-mediated knockdown and transient over-expression, we illustrate c-Myb suppresses CD127 gene transcription in primary human CD8 T cells.
Cytokine receptor signaling in CD4+ T cells (P6305)
Authors: dela Pena Myra Grace , Kartchner Laurel , Abel Kristina 
Published: January 2023

Abstract
Infants compared to adults exhibit reduced immune responsiveness and are biased towards a T helper 2 (Th2) response. We hypothesized that this is due to the presence of intrinsic differences in cytokine receptor signaling in CD4+ T cells. We utilized human adult and cord blood (CB) samples to determine whether age-related differences exist in (i) Th1 and Th2 cytokine receptor (R) expression, (ii) STAT phosphorylation, and/or (iii) JAK/STAT signaling. Our data show that a lower percentage of CB compared to adult CD4+ T cells expresses IFNγR1 (P=0.0053). However, absolute numbers of IFNγR1 are higher on CB compared to CD4+ T cells (P=0.0305). In contrast, we did not detect differences in the levels of IL4Rα expression. Consistent with this data, CB CD4+ T cells show lower phosphorylation levels of STAT1, but not STAT6 in response to IFNγ or IL4 stimulation. Furthermore, several genes of the JAK/STAT signaling pathway (e.g. jak1, ifng, stam, isg15 and oas1) were induced at higher magnitude and with faster kinetics in adult compared to CB PBMC after in vitro stimulation with IFNγ. Thus, our data demonstrate that unique age-related differences exist in CD4+ T cell cytokine receptor signaling that may underlie the reduced immune responsiveness and Th2-biased response of infants. Unraveling these molecular mechanisms may aid in pediatric vaccine and therapeutics design.
Rapid assessment of CD4 + T cell differentiation towards more specialized cell types using impedance based technology (P6325)
Authors: Santos Mark , Zhang Wenying , Whalley Jason , Hsu Matthew 
Published: January 2023

Abstract
Cellular differentiation is a fundamental process in developmental biology. Progenitor cells must have the ability to differentiate into more specialized cell types for the body to respond to infections during autoimmunity. In an immunological response to infections, CD4+ T cells can give rise to a variety of T helper cells depending on the nature of the immune response, and subsequently release a distinct subset of signature cytokines. Similarly, when monocytes are exposed to established lineage specific conditions in vitro, human monocytes differentiate toward mature dendritic cells. In all cases, a characteristic inherent in cell differentiation is that during this process cells undergo a dramatic change in cell size, metabolic activity, and responsiveness to signals. Current methods such as flow cytometry or phase contrast morphology for determining cell differentiation are informative; however, drawbacks to these methods are that either it is too subjective or labor intensive. Here we utilized the coulter principle of impedance based particle detection as an alternative method for rapidly assessing cell differentiation. This study outlines a method for implementing the coulter principle to rapidly analyze CD4+ T cell differentiation towards various Th cell lineages, as well as monocyte differentiaton towards DCs. We have employed impedance based technology for determining cell volume to investigate the relationship between cell differentiation and cell size changes.