bluuebunny/crossref_metadata_2025_split huggingface dataset:
The sins of first exposure: simultaneous allergen- and influenza-mediated signaling results in mast cell hyperactivity
Authors: Temple Rachel Mary , Obar Joshua J. 
Published: January 2023

Abstract
Each year hundreds of thousands of individuals in United States are hospitalized due to influenza A virus infection (IAV). Asthma is one of the leading co-morbidities among these hospitalized patients. Given the detrimental role mast cells can play during both asthma and IAV infection, we hypothesized simultaneous stimulation of mast cells by allergens and IAV may contribute to the asthmatic exacerbations often accompanying IAV infection. Here we show that signaling by both FcɛRI cross-linking and IAV infection (A/WSN/33 or A/PR/8/34) results in a heightened release of proinflammatory cytokines by these cells in vitro. At the same time, the type I interferon response is suppressed. As early as 1.5 hours post infection Ptgs2 mRNA is upregulated. Furthermore, chemical inhibition of COX-2 or mPGES-1 reduces this heightened proinflammatory response, suggesting a role for prostaglandin E2 in the mast cell hyperactivity. The addition of exogenous prostaglandin E2 can partially mimic this phenotype, though not as drastically as cells infected with IAV, suggesting there is an as yet unidentified viral component contributing to the mast cell hyperactivity. Surprisingly active viral replication is not necessary, as UV-inactivated IAV is capable of inducing mast cell hyperactivity as strongly as untreated virus. Interestingly, within 24–48 hours, infected mast cells die irrespective of FcɛRI stimulation. Taken together, our data suggest that IAV may incite asthmatic exacerbation through enhanced cytokine and prostaglandin production from mast cells receiving two distinct stimuli simultaneously, but ultimately mast cell death induced by IAV infection limits the duration of the asthmatic exacerbation.
TNFα Inhibits the Expression of Germinal Center Phenotype on T-bet+ CD11c+ IgM Memory B Cells without Altering Clonal Diversity
Authors: Popescu Maria , Winslow Gary 
Published: January 2023

Abstract
Our studies have identified a population of T-bet+ CD11c+ IgM memory B cells that arise within 30 days following infection with the intracellular bacterium, E. muris. The memory cells require for their generation T cell help and IL-21; however, they are generated in a GC-independent fashion, because GCs are suppressed during infection. Previous studies have shown that TNFα is necessary for proper GC formation. Given that we detected an increase in serum TNFα following infection, we addressed a role for this cytokine in IgM memory cell development. Relative to wild-type, we observed a substantial increase in the frequency of developing IgM memory. These B cells were positive for GL7+ CD38lo CD95+ on day 16 post-infection. Imaging studies corroborated these findings by demonstrating the appearance of GC-like structures in infected TNFα-deficient, but not in wild-type, mice.
Increased GL7 expression on IgM memory cells in absence of TNFα was not correlated with changes in clonal diversity on day 30 post-infection. This suggests that TNFα does not affect B cell selection.
To address mechanisms whereby the absence of TNFα may facilitate formation of pseudo-GC structures, we quantitated CXCL13, a chemokine known for its role as a chemoattractant during GC morphogenesis. CXCL13 expression was 10-fold lower in TNFα-deficient mice, indicating its requirement, in part, for splenic disorganization in wild-type mice during infection.
Our findings suggest that although GCs are suppressed during ehrlichial and other bacterial infections, GC structures can, when present, magnify IgM memory cell generation. Ongoing studies will address whether changes in lymphoid architecture impact other properties and functions of T-bet+ CD11c+ IgM memory cells.
Dissecting the contribution of antigen-dependent B cell receptor engagement and T cell help to Germinal Center B cell selection and differentiation.
Authors: Grigorova Irina , Turner Jackson S. 
Published: January 2023

Abstract
Proper selection of somatically hyper mutated B cells in the Germinal Centers (GCs) and their differentiation into long-lived plasma cells is key for the development of high-affinity long-term humoral immunity. However, relative contribution towards GC B cell selection by the two key factors: antigen-driven B cell receptor (BCR) signaling and T cell help, remains an open question. We have addressed this long-standing question in the field using an experimental model that enables independent manipulation of both antigen-driven BCR engagement and antigenic peptide presentation in GC B cells. Our studies suggest that in the absence of antigen-driven BCR engagement, T cell help is sufficient for robust selection of GC B cells and their differentiation into plasmablasts. In contrast, neither is induced by antigen-dependent BCR crosslinking in the absence of T cell help. Interestingly, when the levels of MHCII/peptide presentation by GC B cells are suboptimal, antigen-dependent BCR engagement can synergize with T cell help to promote selection of GC B cells and their differentiation into plasmablasts. Our findings reconcile somewhat contradictory data reported in previous studies and point towards the importance of the two signal model in the GC response.
Dendritic cell expressed H-2Db is required for generating antiviral CD8+ T cell responses and blood brain barrier disruption during Theiler’s virus infection
Authors: Tritz Zachariah Peter , Malo Courtney Sarah , Yokanovich Lila , Jin Fang , Hansen Michael J. , Johnson Aaron J. 
Published: January 2023

Abstract
Blood brain barrier (BBB) disruption is a feature of multiple neurological disorders for which there is an increasingly recognized role for CD8+ T cells. Theiler’s murine encephalomyelitis virus (TMEV) infection serves as an excellent model to study CD8+ T cell mediated BBB disruption because of the well-characterized immune response to the immunodominant VP2121–130 peptide presented in the context of the H-2Db class I molecule. Intravenous injection of VP2121–130 peptide seven days post TMEV infection results in severe BBB disruption. BBB disruption is dependent on CD8+ T cell interaction with the Db: VP2121–130 epitope, but the antigen presenting cell required for BBB disruption is undefined. We hypothesized that dendritic cells are responsible for presentation of the immunodominant VP2121–130 peptide. We tested this hypothesis using a novel H-2Db Cre-LoxP conditional knockout mouse bred to MHC class I deficient CD11c-Cre expressing mice. We then evaluated these animals at 7 days post infection for induction of BBB disruption, following VP2121–130 peptide administration, using gadolinium enhanced MRI, fluorescent albumin leakage into the brain, and confocal microscopy for the tight junction protein occludin. Control CD11c-Cre(−) mice generated robust Db: VP2121–130 epitope specific CD8+ T cell responses and displayed extensive BBB disruption. In contrast, CD11c-Cre(+) littermates generated no brain infiltrating antiviral CD8+ T cell responses and were protected from BBB disruption. We conclude that CD11c+ dendritic cells are required for priming of CD8+ T cell responses and are necessary for BBB disruption during neuroinflammation in this model.
Sodium Pyruvate Alters the Immune Response to Influenza A Virus Infection in Macrophages
Authors: Abysalamah Hazzar M. 
Published: January 2023

Abstract
Pyruvate is the end product of glycolysis. It can either be transported into the mitochondria for use in the TCA cycle or be used to regenerate NAD+ during aerobic glycolysis. We recently discovered that addition of sodium pyruvate to the culture medium during infection of macrophages with influenza A virus affects the production of cytokines involved in immune signaling. The purpose of the present study was to determine whether sodium pyruvate’s role in energy production in the macrophages may alter the immune response to the infection. While infection of macrophages with influenza A virus resulted in high levels of cytokines (IL-6, IL-1β, and TNF-α) in the absence of sodium pyruvate, the addition of sodium pyruvate significantly impaired cytokine production. Furthermore, sodium pyruvate did not affect virus growth, suggesting the effect of sodium pyruvate is on the immune response produced by the macrophages and not the viability of the virus.
Ssu72 phosphatase is involved in immunometabolism
Authors: Lee Si-Yeon , Park Eun-Ji , Kim Sumin , Lee Chang-Woo 
Published: January 2023

Abstract
Reversible protein phosphorylation is the primary type of various post-translational modifications in multiple cellular signaling pathways of eukaryotic cell. Dynamic alterations of phosphorylation state of many cellular signaling-mediated proteins including adipogenesis and thermogenesis regulate their molecular and cellular fates. Ssu72 is dual protein phosphatase that can act upon tyrosine or serine/threonine residues and transcription/RNA-processing factor. Recently, we found that Ssu72 expressed in adipose tissue, especially strongly in BAT, indicating that the potential involvement of Ssu72 in regulating BAT function. In this aspect, we generated conditional knock out mice which Ssu72 is deleted specifically in adipose tissue and found that the deficiency of Ssu72 leads to BAT dysfunction and abnormal thermoregulation compared to wild type mice. Moreover, we observed not only dramatically reduction of macrophage population but also defective M2 macrophage generation in Ssu72-deficient BAT. Notably, it has been reported that IL-4-induced M2 activation of macrophages is required for adaptive thermogenesis in mice. Thus, we further generated Ssu72-deleted macrophage mouse model. This study includes the physiological relevance of Ssu72 loss-of-function in macrophage during metabolic and thermogenic responses.
Roles for MS4A4 in FcɛRI signal transduction and store-operated calcium entry in human mast cells.
Authors: Arthur Greer K. , Cruse Glenn 
Published: January 2023

Abstract
The membrane spanning 4A (MS4A) gene family have similar topology to tetraspanins and are clustered around chromosome 11q12-13, a region linked to allergy and asthma susceptibility. However, other than the well-established roles of FcɛRIβ and CD20 in mast cell and B cell signaling, respectively, functional studies for the remaining genes in the MS4A family are lacking. We have demonstrated that MS4A4 promotes recruitment of KIT into caveolin-1-enriched microdomains and signaling through PLCγ1 in mast cells. PLCγ1 signaling and caveolin-1 are important regulators of store-operated Ca2+entry (SOCE) and caveolin-1 promotes expression of the store-operated Ca2+ channel pore-forming unit, Orai1. We thus hypothesized that MS4A4 regulates SOCE in response to FcɛRI-mediated stimulation through PLCγ1 and Orai1-dependent pathways. We began by identifying that human mast cells express a full length and truncated splice variant of MS4A4. Transfection of MS4A4 variants into HEK293 cells demonstrates that the full length variant of MS4A4 traffics to the plasma membrane, but the truncated MS4A4 variant does not. Knockdown of the full length MS4A4 variant with shRNA inhibits IgE-mediated degranulation of human mast cells, signaling through PLCγ1 and SOCE, likely through Orai1. Compound 48/80 and ionomycin stimulation were less affected by knockdown of MS4A4 or Orai1. These data suggest that MS4A4 plays an important role in FcɛRI signaling and suggest a possible novel link between KIT and FcɛRI signaling pathways.
Comparison of the immunomodulatory and epigenetic regulatory effects of natural estrogen 17-β estradiol and its synthetic analog 17α-ethinyl estradiol in NZB/WF1 mice
Authors: Dai Rujuan , Edwards Michael , Heid Bettina , Ahmed S. Ansar 
Published: January 2023

Abstract
Concern is increasing regarding the effects of environmental exposures to different Estrogenic Endocrine Disrupting Chemicals (EEDCs) on immune system function. 17α-ethinyl estradiol (EE), a synthetic analog of natural estrogen 17-β estradiol (E2), is a primary component in oral contraceptive pills (OCP) and has been found in sewage effluents. In this study, to compare the immune and epigenetic regulatory effects of environmental E2 and EE exposure in NZB/WF1 mice, we implanted gonadal intact female NZB/WF1 mice with E2 or EE. While the effect of EE was more profound, both E2 and EE exposures caused splenomegaly, altered splenic and thymic T cell composition and activation, increased splenic neutrophil percentage, and promoted inflammatory molecules iNOS/NO and the chemokine MCP-1 in ex vivo-activated splenocytes. Impressively, we found that E2 and EE had differential effects on the induction of different inflammatory cytokines in ex vivo activated splenocytes (e.g. IFNβ and IL-1β were increased in LPS-activated splenocytes from EE-treated NZB/WF1 mice, but were decreased in LPS-activated splenocytes from E2-treated mice when compared to placebo controls). Also, in vivo EE exposure promoted, and E2 reduced, TLR9 agonist-induced IFNα production in splenocytes. We further demonstrated that E2 and EE regulated the expression of numerous immune-related genes and miRNAs in a similar manner, while EE had a stronger effect than E2 on the regulation of miRNAs expression. Moreover, we found that EE, but not E2 treatment, significantly reduced the global DNA methylation level in NZB/WF1 splenocytes. Together, our data revealed similar and also differential regulatory effects of E2 and EE on the different aspects of immune function.
Effects of TLR 7 and 8 agonists on human monocyte activation and differentiation
Authors: Kayraklioglu Neslihan , Klinman Dennis M. 
Published: January 2023

Abstract
TLR7 and TLR8 are located on endosomal membranes and function to detect ssRNA released by viral or bacterial pathogens. Differences in the response characteristics of these two receptors, in terms of cell type preference and cytokine profile of human PBMC was being revealed. However, the effect of these two agonists on the same cell still remains as a question. Human monocytes express both TLR7 and TLR8 are highly plastic cells which is an important feature for immunotherapies. This study investigates the effects of TLR7 and 8 agonists on human classical monocytes in terms of activation and differentiation into macrophages. CD14+ HLA DR+ monocytes from healthy donors were cultured with the TLR7 specific agonist 3M-055, TLR8 specific agonist CL-075, and TLR7/8 dual agonist R848. All three agonists induced human monocytes to mature into macrophage significantly when compared to the unstimulated monocytes. A majority of those macrophages were 25F9+/CD200R−/CD206+ with an increased CD163 expression observed only with TLR8 agonists. Although CD163 and CD206 are commonly expressed on M2-like macrophage, functional analysis revealed that the macrophages differentiated by TLR7 or TLR8 agonists overall does not have significant endocytic ability (a prominent M2-macrophage function). TLR8 stimulation resulted in prominent pro-inflammatory cytokine increase whereas TLR7 agonist stimulation did not. Furthermore, TLR7 agonists decreased the cytokine induction by TLR8 agonists and this decrease was more prominent when TLR7 agonists were given prior to the TLR8 agonist. This study reveals differences in TLR7 vs TLR8 response of the monocytes and regulatory role of TLR7 on TLR8.
NF-kB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor
Authors: Ramakrishnan Parameswaran , de Jesus Tristan , Shukla Sudhanshu 
Published: January 2023

Abstract
Unresolved inflammation is an underlying reason for several immune and inflammatory diseases as well as cancer. Both initiation and resolution of inflammatory response rely largely on the genes induced by NF-kB/Rel family of transcription factors. Previous studies have categorized NF-kB family proteins as transcriptional activators (homo or hetero dimers containing RelA, RelB or c-Rel) and transcriptional inhibitors (homodimers of p50 or p52). Here, we report the function of the subunit c-Rel with a transactivation domain, as a transcriptional repressor of selected proinflammatory genes. Genetic deletion of c-Rel enhances the expression of a subset of proinflammatory genes and also potentiates the expression of TNF-induced RelA-dependent mediators of inflammation. Interestingly, v-Rel, the viral homologue of c-Rel, also possesses this repressive function, indicating that the repressive function of c-Rel is evolutionarily conserved. We also found that c-Rel’s ability to repress transcription depends on it competency to bind consensus NF-kB-binding sites in the DNA. Our findings reveal a novel role of c-Rel as a transcriptional repressor in the maintenance of inflammatory homeostasis.
Pioneer transcription factor BATF controls chromatin accessibility and CTCF-mediated chromatin architecture in CD4+ T cells
Authors: Pham Duy , Moseley Carson E. , Savic Daniel , Myers Richard , Kee Barbara L. , Hatton Robin D. , Weaver Casey T. 
Published: January 2023

Abstract
Pioneer transcription factors are a unique class of proteins that access heterochromatin, facilitate chromatin accessibility, and recruit other transcription factors to regulate gene transcription. The basic leucine zipper transcription factor ATF-like (BATF) is a critical factor for the development of T helper cell lineages. While BATF has been proposed as a pioneer factor in both T and B cells, its molecular functions are incompletely understood. In this study, we have identified a novel aspect of the pioneer function of BATF in controlling the chromatin landscape in developing effector T cells. We find that BATF is indispensable for the recruitment of chromatin-organizing complexes containing the DNA binding factor CTCF and other co-factors such as Oct1 and Ets1 to a subset of enhancer and chromatin-looping nodes during effector T cell lineage specification. Accordingly, BATF has a unique function in modulating genomic spatial organization in a CTCF-dependent manner. This study establishes BATF as a bona fide pioneer factor and provides novel insight into its role as a spatial genome organizer that modulates chromatin accessibility and initiates chromatin looping for the coordinate and differential gene expression in CD4+ T cells.
IL-6 counteracts IL-2-dependent suppression of T follicular helper cell responses
Authors: Papillion Amber M. , Bachus Holly , Fuller Michael , León Beatriz , Ballesteros-Tato Andre 
Published: January 2023

Abstract
T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells that aide in the production of high-affinity antibody (Ab) responses. In the absence of Tfh cells, there is impairment in the generation of protective Ab responses to pathogens. In autoimmune patients, however, the expansion of unwanted self-reactive Tfh cells favor auto-Ab responses and subsequent Ab-mediated pathology. Thus, understanding the factors that regulate the generation of Tfh cells is critical for developing more efficient vaccination strategies and for designing new therapeutic approaches to prevent Ab-mediated autoimmune diseases. In this regard, it is generally acknowledged that IL-2 inhibits CD4 T cells from differentiating into Tfh cells. Conversely, previous studies suggest that IL-6 signaling is required for normal Tfh cell responses. However, Tfh cells normally differentiate in the absence of IL-6 in some experimental models, suggesting that IL-6 is not absolutely necessary for Tfh cell formation. Thus, the exact role played by IL-6 in controlling Tfh cell responses remains elusive. Using an influenza infection model, we found that IL-6 is dispensable for the priming of influenza-specific Tfh cell precursors, but essential for the maintenance of the Tfh cells at the peak of the influenza immune response. Mechanistically, our results demonstrate that already differentiated Tfh cells produce large amounts of IL-2 in the GCs and that intrinsic IL-6 signaling is needed to antagonize the negative impact of IL-2 in the ongoing Tfh cell response. Collectively, our data demonstrate that IL-6 induces a program that allows for Tfh cells to produce IL-2 without succumbing to the deleterious effects of IL-2 on Tfh cell differentiation.
Regulation of Notch activation in CD4+ T cells
Authors: Mitra Ankita , Torres Joe Angel , Shanthalingam Sudarvili , Vijayaraghavan Jyothi , Lawlor Rebecca , Osborne Barbara Anne 
Published: January 2023

Abstract
Notch signaling provides an important cue in the mammalian developmental process. It is a key player in T cell development and function. Mature T cells express Notch receptors 1, 2 and 3. Data from our lab and others indicate that T cell receptor (TCR) signaling activates Notch. Conventional ligand dependent Notch signaling involves, interaction of the Notch receptor with ligands such as Delta like ligand (DLL) 1,3, 4 or Jagged (JAG) 1, 2. However, in T cells it is unclear whether TCR induced activation of Notch is dependent upon engagement of Notch receptor with ligand. In-vitro stimulation of purified CD4+T cells, using antibodies against CD3 and costimulatory molecule CD28, results in activation of Notch. This occurs in absence of APC or any apparent ligand presenting cell. Thus, the mechanism that drives Notch activation during TCR stimulation is unclear. When naïve CD4+ T cells were cultured with bone marrow derived dendritic cells pulsed with antigen, we observed activation of Notch in the apparent absence of ligand on APC or activated T cells. However, when we examined ligand expression on naïve CD4+ T cell, activated by anti-CD3/CD28, we found resting T cells express constitutively low levels of DLL1 which increases with activation and is maintained through activated state. Additionally, DLL4 and JAG1 are expressed only after T cell activation and maintained only for 24hrs after activation. This upregulation is completely dependent upon signaling through CD28. However, whether the expression of ligand is sufficient to activate Notch remains unclear. Our preliminary data thus suggests that TCR mediated signaling in the absence of ligand may be is sufficient to activate Notch.
Critical role of ASK signaling in promoting inflammatory disease in Ptpn6spin mice
Authors: Tartey Sarang , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated pivotal role for several kinases, such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice. In order to identify new kinases involved in SHP1 mediated inflammation, we undertook genetic approach and discovered Apoptosis signal-regulating kinases (ASK1 and ASK2) as novel kinases regulating the Ptpn6 mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin mediated disease by controlling pro-inflammatory signaling in the neutrophils. Collectively, this study identifies SHP1 and ASK signaling crosstalk as a critical regulator of IL-1α driven inflammation and open future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.