bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon regulatory factor 4 (IRF4) directs dendritic cells to promote Th2 responses (57.11)
Authors: Williams Jesse , Clay Bryan , Tjota Melissa , Decker Donna , Singh Harinder , Sciammas Roger , Sperling Anne 
Published: January 2023

Abstract
Respiratory dendritic cells (DC) are the primary initiator of T cells during lung allergic responses. DCs process inhaled allergen, traffic to the lung draining lymph node, present antigen to T cells, and guide the type of T-helper response initiated. However, the mechanisms by which DCs direct Th2 specific differentiation are poorly understood. We previously found that signaling through FcγRIII is able to modulate TLR4 signaling in DCs, and that these DCs now skew toward a predominant Th2 response. Microarray analysis identified IRF4 as a gene downstream of FcγRIII signaling in bone marrow derived DCs (BMDCs). In respiratory DCs, IRF4 was induced within 3 hrs of stimulation with known Th2-agonists. Using mice with conditional deletion of IRF4 in CD11c cells, we demonstrated reduced Th2 responses after house dust mite-induced allergic challenge, while DC trafficking and T cell activation remained intact. Direct effects between IRF4 in DCs and Th2 development was demonstrated using sorted pulmonary DCs from IRF4-deficient mice to skew T cells in vitro. Surprisingly, when IRF4-deficient DCs were used the resulting T cells produced decreased Th2 cytokines, but augmented IFNγ and IL-17. Further, we found that increasing IRF4 expression alone in BMDCs was sufficient to drive T cells toward a Th2 phenotype. Together these data identify IRF4 as a key transcriptional regulator in DCs necessary for the development of Th2 responses.
Th9 cells regulate mast cell recruitment in acute allergic lung inflammation (57.12)
Authors: Sehra Sarita , Yao Weiguo , Nguyen Evelyn , Kaplan Mark 
Published: January 2023

Abstract
Th2 cells are classically thought to contribute to the pathogenesis of asthma. IL-9, long described as a Th2 cytokine has also been shown to mediate allergic inflammation in both human and murine studies. Recently, we have identified an ETS-family transcription factor PU.1 required for generating the Th9 phenotype and in the development of allergic inflammation. Mice with a conditional deletion of PU.1 in T cells demonstrated attenuated allergic inflammation concomitant with decreased levels of IL-9. IL-9 is also well documented to play an important role in mast cell growth and differentiation. To determine if Th9 cells are required for the recruitment of mast cells in vivo, we examined mast cell infiltration in the lung in mice with blocking IL-9 antibodies as well as in mice with PU.1 deficient T cells. Both experiments with either blockade of IL-9 or PU.1 deficient T cells demonstrated diminished mast cell numbers in the lung. We further examined the effect of transferred Th2 and Th9 cells on mast cell recruitment. Transfer of differentiated Th2 or Th9 cells from D011.10 mice to wild type mice demonstrate that while Th2 cells increase mast cells, as detected by expression of mast cell proteases in the lung by 4-fold, recipients of Th9 cells had over 11-fold increased expression. Therefore, our studies suggest an important role for Th9 cells in mast cell recruitment in models of acute allergic inflammation.
TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease (57.13)
Authors: Jang Sihyug , Lukacs Nicholas 
Published: January 2023

Abstract
Thymic stromal lymphopoietin (TSLP) has been implicated in allergic inflammation by promoting a Th2-type response. Using in vitro cultures we demonstrated that TSLP played a critical role in the development of Th2 immune responses, but its role on an established Th2 immune environment was not significant. Adoptive transfer of naive DO11.10 ovalbumin (OVA)-specific T cells followed by exposure of OVA showed an early impairment of Th2 immune response in TSLP-/- mice compared to wild type (WT) mice. In contrast, transfer of differentiated Th2 cells into TSLP-/- mice did not change lung pathology or Th2 cytokine production compared to transfer into WT mice. Using a well-established allergen-induced Th2 model demonstrated that there was no difference between WT and TSLP-/- mice. Furthermore, when we treated allergic animals with established disease with a neutralizing anti-TSLP antibody there was no change in airway hyerreponsiveness (AHR) or Th2 cytokine production compared to the control antibody treated animals. Collectively, these studies suggest that in mice TSLP has an important role during the early development of Th2 immune responses. However, TSLP appears to have a minimal role at later stages of allergic disease suggesting that it may not be required for maintaining a persistent and established Th2 immune environment. These studies may offer important data for determining whether targeting TSLP would be beneficial for therapy in established Th2 mediated diseases.
Wide-scale and quantitative phosphoproteomic method for analysis of bidirectional signaling within interacting B and T cells (58.11)
Authors: Gu Tao , Ji Qinqin , Salomon Arthur 
Published: January 2023

Abstract
Physiological interactions between T cells and antigen presenting cells (APC) induce the formation of the immunological synapse. The subsequent reversible tyrosine phosphorylation of a variety signaling proteins plays a pivotal role in regulation of T cell activation. Novel phosphoproteomic methods in mass spectrometry can facilitate and accelerate elucidation of cell signaling networks by providing a global picture of cellular phosphorylation. In this study a B and T cell line were labeled with stable isotopes of amino acids in cell culture, using the SILAC method. This labeling helped to differentiate and quantitate phosphopeptides from either type of cell through a timecourse of their interaction. Quantitative phosphoproteomic analysis revealed a wide array of newly discovered phosphorylation sites that changed significantly during B/T cell interaction. Phosphorylation sites were observed and quantified on the earliest upstream signaling components and the following downstream target proteins in both T cell and B cells (T cells: TCR-CD3 subunits, CD28, Erk, Fyn, Lck, P38, PI3K, PLCγ2, Zap-70 et al; B cells: B cell antigen receptor complex, liner protein, CD19, Fyn, Jnk, Lck, Lyn, P38, PI3K, PLCγ2, et al) .
R10K: an international collaborative project for biomarker discovery (58.7)
Authors: Han Jian , Wang Chunlin , Byrne-Steele Miranda , Yang Qunying , Myers Richard 
Published: January 2023

Abstract
The R10K Project is an international collaborative effort to sequence the immune repertoire (T and B cells) from 10,000 samples that cover 100 diseases. We have developed a novel multiplex PCR method, which can amplify targets from a complex genetic material, inclusively and semi-quantitatively. This easy-to-use technology has been successfully applied to amplify immune repertoire libraries from peripheral blood samples or other tissue samples. The natural duty of the adaptive immune system is to detect any internal and external threats and mount specific and measured reactions accordingly. Our pilot studies have demonstrated that immune repertoire sequencing can be used to measure this specific response and identify disease-related T cell CDR3s. Therefore, analyzing the immune repertoire of several disease states with high throughput sequencing may lead to the discovery of disease-specific biomarkers for diagnosis, prognosis, and treatment evaluations. The R10K project is organized and supported by the HudsonAlpha Institute for Biotechnology, a non-profit research institute specialized in genomic research. A Scientific Advisory Board has been established to help identify projects from online submitted proposals. The R10K data will be made public 6 months after it has been generated.
Engineering the Lymph Node Microenvironment via Intranodal Controlled Release Vaccine Depots (58.8)
Authors: Jewell Christopher , Bustamante Lopez Sandra , Irvine Darrell 
Published: January 2023

Abstract
Recent clinical trials of intra-lymph node (i.LN.) vaccine injection have generated promising results in cancer and autoimmunity. We hypothesized that controlled release biomaterials in the context of intranodal vaccination could sustain exposure of the LN to adjuvants or immunomodulatory drugs to augment vaccine responses. To test this idea we encapsulated the TLR3 agonist polyIC in biodegradable polymer particles designed to release this adjuvant within LNs over several days. Using a non-toxic tracer, we developed a non-surgical approach for i.LN. injection and injected polyIC in soluble form or encapsulated in microparticles (MP-polyIC) or nanoparticles (NP-polyIC). MP-polyIC conferred ~4-fold and 2-fold increases in polyIC retention in LNs compared with soluble polyIC or NP-polyIC, respectively; prolonged retention correlated with a dramatic increase in polyIC uptake by LN-resident DCs compared with soluble polyIC, which was quickly cleared from LNs. Mice vaccinated with antigen mixed with MP-polyIC induced antigen-specific CD8+ T cell expansion 4-fold greater than soluble polyIC, which could not be matched by even 10-fold greater doses of soluble polyIC. MP-polyIC vaccination also increased the percentage of IFN-γ and TNF-α secreting T-cells up to ~4-fold, indicating a polyfunctional vaccine enhancement. These results suggest that sustained release directly in the lymph node microenvironment can significantly alter and enhance the function of immunomodulatory compounds.
IL-27 priming of T cells controls IL-17-production in trans via induction of PD-L1 (59.1)
Authors: Hirahara Kiyoshi , Ghoreschi Kamran , Yang Xiang-Ping , Takahashi Hayato , Laurence Arian , Vahedi Golnaz , Sciumè Giuseppe , Hall Aisling , Dupont Christopher , Francisco Loise , Chen Qian , Tanaka Masao , Kanno Yuka , Sun Hong-Wei , Sharpe Arlene , Hunter Christopher , O’Shea John 
Published: January 2023

Abstract
Interleukin (IL)-27 is a key immunosuppressive cytokine that counters Th17-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in naïve CD4+ T cells rapidly induced by IL-27 stimulation for 3 hours. We discovered that IL-27 priming of naïve T cells upregulated expression of the ligand of PD-1 (PD-L1) in a STAT1-dependent manner. To assess the relevance of IL-27 in controlling PD-L1 expression in vivo, we employed a T. gondii infection model in which IL-27 is important for controlling immunopathology. We found that expression of PD-L1 on CD4+ T cells was significantly lower in EBI3-/- mice. When added to naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans in vitro. In vivo, co-administration of IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Moreover this inhibitory effect of IL-27 in vivo was largely reversed by elimination of PD-L1 on T cells. Thus, these data identify a novel suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans. It is conceivable that the strategy of IL-27-pretreatment of naïve T cells ex vivo with subsequent adoptive transfer might be used therapeutically to attenuate autoimmune disease.
A conserved AU-rich element in IL-17A mRNA’s 3’-UTR confers posttranscriptional control (59.4)
Authors: Ramgolam Vinod , Huntenburg Sarah , Yarovinsky Timur , Bender Jeffrey 
Published: January 2023

Abstract
Modulated decay of labile mRNAs encoding inflammatory cytokines provides dynamic posttranscriptional control of their expression. AU-rich elements (AREs) in 3’-UTRs are cis-regulatory elements that determine mRNA half-life, modulated by association with mRNA binding proteins (RBPs) or miRNAs. We hypothesized that human and mouse IL-17A 3’-UTR AREs confer instability to the IL-17A transcript. In mRNA reporter assays, introduction of destabilizing AREs shortens the half-life of the intrinsically stable rabbit β-globin (RBG) transcript. We inserted full-length (FL), fragmented or mutated human and mouse IL-17A 3’-UTRs into the serum-inducible RBG-encoding plasmid pBBB. pBBB-transfected NIH3T3 cells were serum-stimulated and RBG mRNA levels analyzed by qRT-PCR at 5 hr. RBG mRNA levels were dramatically reduced (&gt;50%) in cells transfected with pBBB containing either the mouse-FL or human-FL IL-17A 3’-UTRs, whereas the fragment with a deletion in the ARE lost its RBG-destabilizing effect, maintaining levels identical to those in the wild-type pBBB-expressing cells. Destabilizing activity was also lost with single, double and triple point mutations in IL-17A’s conserved 30 bp ARE, demonstrating its importance. Model analysis predicts that these mutations convert IL-17A mRNA’s secondary folding structure, likely affecting RBP and miRNA binding sites, leading to our future focus on the regulation of IL-17A-mediated disease by IL-17A 3’-UTR-interacting RBPs and miRNAs.
CD4+ T cell affinity can affect gender bias, disease severity and B cell requirement in inflammatory arthritis. (60.6)
Authors: Perng Olivia , Aitken Malinda , Garcia Victoria , Kropf Elizabeth , Caton Andrew 
Published: January 2023

Abstract
CD4+ T cells make a crucial contribution to the development of inflammatory arthritis both in humans and in mouse models. However, how the affinity with which T cells recognize target antigens might shape disease development and influence treatment modalities is poorly understood. We have examined these phenomena in mouse models of autoimmune arthritis: TS1xHACII and TS1(SW)xHACII mice express influenza hemagglutinin (HA) as a neo-self peptide and co-express transgenic TCRs that have either high affinity (TS1xHACII) or low affinity (TS1(SW)xHACII) for the HA-derived MHCII determinant, S1. Despite extensive deletion of autoreactive TCRs, arthritis spontaneously develops in both strains and in each case arthritis can be prevented by IL-17 blockade. Notably, the low affinity model displays less severe extra-articular disease manifestations and a prominent female bias emerges. In addition, B cells are required for arthritis development in the low affinity setting; by contrast, B cells are not required in the high affinity setting where the disease is accompanied by higher levels of pro-inflammatory cytokines. These studies demonstrate that the overall affinity of the CD4+ T cell response to an autoantigen can play a prominent role in guiding the pathways to inflammatory arthritis development and presentation. These studies may also explain why treatment modalities targeting particular pathways (cytokines vs B cells) can exhibit different efficacies in arthritis patients.
Interaction of CR1 with Par3/Par6 polarity complex mediates anti-inflammatory reprogramming of neutrophils during phagocytosis. (61.1)
Authors: Ghiran Ionita , Glodek Alecsandra , Chang Robert , Nicholson-Weller Anne , Lawler Matthew 
Published: January 2023

Abstract
Partitioning defective protein 6 (Par6) belongs to a family of proteins first discovered to mediate partitioning in C. elegans. In mammals, the Par family of proteins is involved in several critical functions such as cell polarity, vesicle trafficking, cell migration, and signal transduction. Presence of Par proteins in T cells, suggests that spatial polarity could play important roles in mediating and/or regulating immune responses. Our data demonstrate that Par proteins, particularly as Par3/Par6/aPKC polarity complex, regulate neutrophil responses during phagocytosis. Our results show that during complement-mediated phagocytosis, engagement complement receptor 1 (CR1) by complement-opsonized particles, promotes the interaction between Par6/Par3 complex and CR1. The binding between CR1 and the Par complex is mediated by the interaction of the PDZ motifs found in the cytoplasmic domain CR1 with the PDZ domains of Par6/Par3. During IgG- and complement-mediated phagocytosis, ligation of CR1 by complement fragments, inhibits FcgammaR-induced ROS production as well as the FcgammaR-mediated release of pro-inflammatory cytokines . In conclusion, our data suggest that during phagocytosis, engagement of CR1 by complement fragments, down regulates the IgG-mediated pro-inflammatory response by disrupting the temporal/spatial assembly of the inflammatory complex at the sites of phagocytosis.
Anti-Obesity Effect of Ethyl Acetate Extracts from Agrimonia pilosa Ledeb. in 3T3-L1 preadipocytes (62.3)
Authors: Lee Jung A , Ahn Eun-Kyung , Hong Seong Su , Oh Joa Sub 
Published: January 2023

Abstract
To evaluate the anti-obesity effect of Agrimoniae pilosa L., this study investigated that ethyl acetate extract from A. pilosa L. (EAAP) suppresses lipid accumulation and inhibits expression of adipogenic marker genes, such as peroxisome proliferator activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), glucose transporter 4 (GLUT4), and adiponectin in 3T3-L1 preadipocytes. We demonstrated that EAAP inhibited adipocyte differentiation and expression of PPARγ and C/EBPα mRNA levels in a dose-dependent manner. In addition, EAAP reduced the PPARγ transcriptional activity stimulated by rosiglitazone in HEK 293T cells and decreased the expression of GLUT4 and adiponectin in 3T3-L1 cells. These results suggest that EAAP inhibits preadipocyte differentiation and adipogenesis by blocking of PPARγ and C/EBPα gene expression in 3T3-L1 cells.
Identification of SNARE Proteins in Dendritic Cell Secretion (62.4)
Authors: Collins Laura , Canavan Mary , Loscher Christine 
Published: January 2023

Abstract
Dendritic cells (DC) act as link between innate and adaptive immunity with the ability to drive a range of T helper cell subsets. The DCs responsible for this differ primarily in the cytokines they secrete. Soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptor (SNARE) family members are proteins that drive membrane fusion and have been shown to play a key role in cytokine release. Little is known about the specific mechanisms involved in cytokine secretion from DCs, Therefore we examined the expression of SNAREs in DCs as they represent potential therapeutic targets. In this study we used JAWS II; a C57BL/6 murine DC line, to examine the expression of SNAREs following stimulation with a range of Toll-Like Receptor (TLR) ligands. We have shown that activation of TLR 4 with lipopolysaccharide (LPS) in these cells results in an increased transcription of the SNAREs Syntaxin 3 and Vti1b mRNA which was concomitant with increased protein expression of these SNAREs. This pattern of expression differed using other TLR ligands. The presented data demonstrates the differential expression of SNARE proteins in DCs following activation of TLRs. Given the different cytokine profiles elicited by activation of different TLRs, this data may provide some information on the SNAREs necessary for secretion of key inflammatory cytokines.
Deletion of NF-κB/p50 influences the outcome of Notch3-dependent T cell leukemia (63.4)
Authors: Campese Antonio , Grazioli Paola , Scafetta Gaia , Noce Claudia , Verkhovskaia Sofia , Mari Chiara , Felli Mari Pia , Gulino Alberto , Screpanti Isabella 
Published: January 2023

Abstract
The deregulation of Notch3 signaling inside T-cell compartment of transgenic (N3-tg) mice, induces an aggressive form of T-cell acute lymphoblastic lymphoma (T-ALL), sustained by a constitutive activation of the NF-κB canonical pathway, mainly represented by the p50/p65 heterodimer. To clarify the Notch/NF-κB relationships in the development of T-ALL, we generated double mutant mice, deleted of the NF-κB/p50 subunit in a Notch3 transgenic background (N3-tg/p50-/-). The follow-up of N3-tg/p50-/- versus N3-tg mice revealed that p50 deletion strongly inhibits the development of Notch3-dependent T-ALL. Surprisingly, double mutant succumb earlier than N3-tg mice, displaying the trait of a myeloproliferative disease, with an aberrant accumulation of Mac1+Gr1+ myeloid cells in both spleen and peripheral blood, as well as of granulocyte/monocyte progenitors in the bone marrow. Our preliminary results suggest that Notch3 overexpression in T-cell compartment is able to influence, possibly in trans, the equilibrium of the myeloid compartment and that the ablation of NF-κB canonical pathway may impact on the outcomes of a T-cell specific deregulation of Notch signaling. We provide a useful experimental model to extend our understanding of Notch/NF-κB interplay in hemopoietic system and to unravel novel relationships between lymphoid and myeloid differentiation.
Haploinsufficiency for the hematopoietic transcription factor IKAROS causes common variable immunodeficiency (63.6)
Authors: Kumanovics Attila , Voelkerding Karl , South Sarah , Rowe Leslie , Crim Jeremy , Stephens Jack , Whitney Tiffany , Martins Thomas , Augustine Nancy , Hill Harry 
Published: January 2023

Abstract
Common variable immunodeficiency (CVID) is characterized by defective immunoglobulin production that leads to recurrent infections and increased risk of autoimmune and malignant diseases. CVID is the most common primary immunodeficiency disease with an estimated 1:25,000 to 1:50,000 population frequency world-wide. Substantial progress has been made in determining the genetic basis of CVID. Mutations in ICOS, TACI, BAFF-R, CD19, CD81, CD21, and CD20, all encoding cell-surface receptors required for B-cell activation, have been found in a few individuals and families and are recognized to cause CVID. Only mutations in TACI are found frequently (both in sporadic cases and familial cases); representing 8-12 % of CVID cases. The cause of CVID is unknown in most patients (&gt;85%). Here, we describe a large family with autosomal dominant hypogammaglobulinemia and B cell deficiency in which all affected members have a 4.7 Mb hemizygous deletion (7p12.3-p12.1) that includes IKZF1, encoding IKAROS, a transcription factor required for B-cell development. This study demonstrates that constitutional hemizygous deletion of IKZF1 leads to IKAROS haploinsufficiency, and patients with hemizygous IKZF1 deletion present with late-onset humoral immunodeficiency and low B-cell counts, complicated in one family member with pre-B-cell acute lymphoblastic leukemia requiring bone marrow transplantation.
Different CD4+ Treg subsets, different suppressive abilities: A comparison of CD27+CD127- and CD39+ Treg cells (65.3)
Authors: Magid-Bernstein Jessica , Rohowsky-Kochan Christine 
Published: January 2023

Abstract
T regulatory (Treg) cells are important in the development of autoimmunity. They are usually identified by their expression of CD25 and Foxp3, although functionally and phenotypically diverse subsets exist. To identify human Treg subsets we analyzed expression of CD27, CD127, CD39, and CTLA4 on CD4 T cells. A CD27+CD127- phenotype correlates with high CD25 and Foxp3 expression. CD39 expression is higher on CD25hi than on CD25med/lo T cells. We co-cultured sorted Treg subsets with T effector (Teff) cells to study suppression of proliferation and cytokine production. CD4+CD25hiCD27+CD127- Treg cells were suppressive of both Teff cell proliferation and cytokine production when activated with anti-CD3 and anti-CD28. CD39+ Treg cells did not inhibit Teff cell proliferation under these culture conditions, but did suppress proliferation and cytokine production when activated with anti-CD3 and antigen-presenting cells (APCs). The varied suppressive abilities of Treg cells in these different culture conditions may be a result of the ability of APCs, but not anti-CD28, to signal through the negative costimulatory molecule CTLA4. We are currently investigating the function of CTLA4 in these Treg populations. We also examined whether these Treg subsets vary in their cytokine profile. Elucidating Treg mechanisms and subsets will enable us to clarify how Treg cells suppress, how they are altered in autoimmunity, and ultimately how this defect can be overcome to treat autoimmunity.