bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dexamethasone inhibits tumor cell lysate induction of a pro-inflammatory dendritic cell phenotype and function modulating T cell cytokine profiles (P4246)
Authors: Falcon Cristian , Tempio Fabian , Perez Claudio , Behrens Carolina , Riberos Ana-Adelia , Falcon Felipe , Salazar-Onfray Flavio , Lopez Mercedes 
Published: January 2023

Abstract
Recently, we showed the effectiveness of a DCs-based immunotherapy for improving long-term survival in patients with melanoma using an allogeneic melanoma cell lysate. Glucocorticoids are used in cancer patients being implicated in immune suppression. Here, we aim to study the effect of dexamethasone on the inhibition of the pro-inflammatory phenotype and immunogenicity capacity of melanoma cell lysate-loaded DCs. Monocytes were differentiated to DCs as previously described. Dexamethasone was given at day 1 and 2 to obtain tolerogenic DCs. DCs maturation markers and TH1, TH17 phenotype were determined by flow cytometry. T cell cytokines were measured by ELISA and proliferation evaluated by CFSE dilution assay. We show that dexametasone stimulus elicits a semi-mature DC phenotype (low MHC II, CD83, CD80 and CD86) sharing mature and immature DCs characteristics, secreting low levels of IL1β, IL-6 and IL-12 and high levels of IL-10, but not affecting DC phagocytosis capacity. TolDCs inhibited T cell proliferation and IFNγ, IL-17 and TNF-α release by T helper cells. At contrary, an augment of Treg cells could be observed. The used glucocorticoids affects the maturation of newly differentiated monocytes-derived DCs in presence of immunogenic tumor cells, affecting the activation of a correct adaptive anti tumor immunity.
Scavenger receptor-mediated dendritic cell internalization and activation by Polyguanine-conjugated antigen (P4234)
Authors: Narciso Jo Erika , Toussaint Helene , Erdos Geza , Carey Cara , Watkins Simon , Falo, Jr. Louis 
Published: January 2023

Abstract
Targeting specific antigens to antigen presenting cells for efficient antigen processing and immune activation is an essential design consideration for vaccine development. Our group has developed polyguanine (Poly(dG))-conjugated antigens with intrinsic antigen targeting and adjuvant properties. These antigen conjugates can potentially increase vaccine efficiency by transforming soluble antigens into aggregated particulates that are targeted to the scavenger receptor in dendritic cells (DCs), resulting in efficient internalization, activation, and cross-presentation. We have successfully conjugated Poly(dG) residues to the model Ag ovalbumin (OVA) and found that Poly(dG)-OVA can induce robust antigen-specific helper, cytotoxic, memory T cell, and antibody responses. In this study, we measure DC internalization and demonstrate that Poly(dG)-OVA is internalized several times more efficiently than OVA alone. This internalization is specifically inhibited by scavenger receptor ligands. Treatment with Poly(dG)-OVA also resulted in upregulation of CCR7 expression and secretion of MCP-1, TNF-α, and IL-6 by DCs in vitro. These results suggest that coupling Poly(dG) to antigens enables efficient DC targeting and activation through the scavenger receptor. This vaccine design can be applied to viral or tumor protein or peptide antigens for the production of more efficient antiviral and antitumor vaccines without the need for additional adjuvants.
Enhanced cancer immunotherapy using nanoparticle-based modulation of SOCS1 genes in dendritic cells (P4242)
Authors: Lim Yong Taik , Heo Min Beom , Noh Young-Woock 
Published: January 2023

Abstract
Although dendritic cells have important roles in cancer immunotherapy, their therapeutic efficiencies were limited due to the presence of immunosuppressive factors. Here, we report the fabrication and use of polymer nanoparticles for the simultaneous delivery of antigens and small interference RNA (siRNA) of immune suppressor genes into dendritic cells. The polymer nanoparticles containing ovalbumin (OVA, as a model antigen) and siRNA of suppressor of cytokine signaling 1 (SOCS1) were fabricated by double emulsion solvent evaporation method. The encapsulation of siRNA was about 57.6 % when OVA was present during the preparation, while that was only 2 % without the OVA. The polymer nanoparticles containing OVA and siRNA of SOCS1 were efficiently taken up by the dendritic cells and showed no detectable toxicity. The knockdown of SOCS1 genes in dendritic cells induced pro-inflammatory and anti-inflammatory cytokine expression. The polymer nanoparticles are expected to be potent nanotechnology platform for targeted delivery of siRNA and antigens into dendritic cells, and use as CD8+ T cells-based cancer immunotherapy.
A novel ligand-independent peptide inhibitor of TREM-1 modulates the inflammatory response and improves survival in septic mice (P4210)
Authors: Sigalov Alexander 
Published: January 2023

Abstract
Sepsis is a serious medical condition characterized by systemic inflammation and is associated with high mortality and morbidity rates. Currently, no FDA-approved sepsis drugs are available and over 30 drug candidates have failed late-stage clinical trials, which highlights the urgent need for novel therapeutic approaches. Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the sepsis-associated systemic inflammatory response. TREM-1 upregulation on peritoneal neutrophils has been found in human patients with sepsis and in mice with experimental lipopolysaccharide (LPS)-induced septic shock. However, the precise function of TREM-1 and the nature of its ligand are not yet known. Here we show that TREM-1 can be specifically silenced in vitro and in vivo using a novel ligand-independent peptide inhibitor, which was designed using a new model of immune signaling, the signaling chain homooligomerization (SCHOOL) model. Blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) protects mice against LPS-induced shock and 2) substantially decreases pro-inflammatory cytokine production in vitro and in vivo. In addition, macrophage-targeted delivery of SCHOOL peptides utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for sepsis.
Identification of a new cell therapy candidate reveals immunological specialization and robust therapeutic efficacy against high-mortality sepsis (P4212)
Authors: Fletcher Anne , Elman Jessica , Knoblich Konstantin , Armant Myriam , Parekkadan Biju , Boyd Richard , Turley Shannon 
Published: January 2023

Abstract
Sepsis is an aggressive inflammatory syndrome, killing 7.3 million people per year. In mouse and human systems, we have identified highly differentiated, immune-specialized myofibroblasts called Fibroblastic Reticular Cells (FRCs) as a new cell therapy candidate for sepsis. One injection of ex-vivo expanded allogeneic FRCs significantly reduced mortality when administered at therapeutic timepoints. When administered 4 hrs after cecal ligation and puncture (CLP) in mice, FRCs prevented peritonitis progressing to blood sepsis, reducing deaths by 50%, while mesenchymal stromal cells (MSCs) were ineffective. FRCs also reduced lung pathology and lowered systemic concentrations of pathogenic cytokines. Rarely for putative sepsis therapies, we found that when FRCs were administered very late, as mice approached euthanasia endpoints (16 hrs), survival was still extremely robust: 44% of FRC-treated mice survived compared to 9% of controls. Production of the prominent vasodilator and immunosuppressant NOS2 was a primary molecular mechanism. Human FRCs showed strong similarities to mouse FRCs and exhibited desirable traits for a cell therapy candidate, including low variance between unrelated donors. Importantly, human FRCs constitutively secrete high levels of soluble cytokine decoy receptors against major mediators of sepsis. Together these data describe a novel anti-inflammatory cell type and provide robust pre-clinical evidence for therapeutic efficacy in multiple models of sepsis.
Metilprednisolone and dialyzable leukocytes extracts induce changes in frequency of CLA+ T cells in patients with atopic dermatitis (P4196)
Authors: Estrada Alejandro , Ramirez Erika , Toledo Mirna , Galicia Jorge , Estrada-Garcia I Iris , Jimenez-Martinez Maria , Perez-Tapia Mayra 
Published: January 2023

Abstract
Atopic dermatitis(AD) is a T cell-mediated skin disease associated with a Th2 local response and skin inflammation is associated with CLA expression. In this work we evaluated expression of CLA on CD4 and CD8 T cells in 2 groups of patients one of them received metilprednisolone(mP-Advantan-) as treatment(Group 1) and second group received mP and dialyzable leukocyte extracts(DLE-Transferon-) as immune modulator(Group 2). Methods: Double blind randomized placebo controlled study, approved by hospital ethical committee. PBMC were obtained before, during (14 day) and at the end of treatment (28 day) and CLA expression on CD4 and CD8 was evaluated by flow cytometry. Results: Group 1:Frequency of CD4+CLA+T cells before treatment 1%±0.6 vs 1.9%±0.9 p=0.02 after treatment. CD8+CLA+T cells before treatment 4.5%±0.9 vs 8.1%±1.9 p=0.0002 after treatment. Group 2: CD8+CLA+T cells before treatment 5.3%±2.1 vs 8.8%±1.8 p=0.005 after treatment. Conclusion: We treated 58 AD-pediatric patients with mP or with mP+DLE, in both groups clinical outcome was improved after therapy; mP-treated patients induced CLA on CD4+ and CD8+ Tcells, while DLE-treated patients induced only CD8+CLA+T cells. Despite CLA expression is associated with local skin inflammation, some authors have suggested that CLA expression is also induced in Tregs; it is possible that DLE- induced CD8+CLA+ T could be enriched Tregs since it has been reported a diminished frequency of AD activation after DLE immune modulation.
Antigen-nonspecific memory CD8+ T cells display phenotypic and functional parallels during cancer immunotherapy and influenza infection (P6064)
Authors: Zamora Anthony , Sckisel Gail , Tietze Julia , Baumgarth Nicole , Murphy William 
Published: January 2023

Abstract
One of the hallmarks of the adaptive immune system is the development of specificity towards antigens by immune cells. Memory T cells are an important component of acquired immunity, providing the host a great deal of protection due to their rapid acquisition of effector function and low requirement for co-stimulation. In addition to antigen-specific T cells, the presence of bystander activated T cells has been well documented in various pathogenic infections and autoimmunity. We have recently characterized a population of memory CD8+ T cell following systemic immunotherapy (IT) with agonistic anti-CD40/IL-2 that display increased expression of NKG2D but not CD25, indicating a lack of TCR engagement. Likewise, primary infection with different strains of influenza resulted in rapid expansion of memory CD8+ T cells displaying this same bystander phenotype. IT-based stimulation of memory CD8+ T cells resulted in antigen-nonspecific activation, with NKG2D ligation inducing MHC-unrestricted cytotoxicity and leading to anti-tumor effects. Further characterization of bystander activated versus antigen-specific CD8+ T cells during IT and infection has revealed differential expression of activation and co-inhibitory molecules depending on location in lymphoid or non-lymphoid tissues. These results suggest different functional as well as regulatory mechanisms may occur between these cells depending on their location.
A TH1 immune response efficiently clears rabies virus from the CNS in the absence of inflammation (P6073)
Authors: Lebrun Aurore , Kean Rhonda , Li Jianwei , Hooper Douglas 
Published: January 2023

Abstract
Little is known about CD4+ T cell entry into the central nervous system (CNS) in the absence of inflammation. Attenuated rabies viruses (RABV) are unique tools to study this process, as they spread from the site of inoculation to the CNS trans-axonally, without compromising the blood-brain barrier. Previous studies with live-attenuated RABV showed that CD4+ T cell entry into the CNS is associated with an increase in IFN-g mRNA in the brain and the production of IgG2a antibodies in the periphery, indicating a bias towards TH1 immunity. To further investigate the nature of the CD4+ T cells involved in the CNS response to RABV, we performed a temporal comparison of development of antiviral immunity in C57Bl6 and T-Bet knock-out (T-Bet-/-) mice. In both mouse strains, we observed that virus spread through the CNS is associated with elevated IFN-g mRNA, but that immune cell infiltration and antibody production in CNS tissues differs significantly. Immune cell infiltration into the CNS is significantly lower in T-Bet-/- mice at day 8 post-infection. Moreover, despite the fact that immunized T-Bet-/- mice produce a substantial amount of neutralizing antibody in the periphery and are fully protected against i.m. challenge with pathogenic RABV, they are unable to survive an i.c. challenge with the same virus. Together, these findings suggest that TH1 cells play a critical role in cell infiltration into the CNS and the clearance of RABV despite the absence of inflammatory pathology.
Virus-specific CD4 and CD8 T cell responses in the absence of Th1-associated transcription factors (P6052)
Authors: Harrington Laurie , Mollo Sarah , Ingram Jennifer , Kress Robert , Zajac Allan 
Published: January 2023

Abstract
The eradication of various types of pathogens is mediated by the coordinated efforts of both effector CD4 and CD8 T cells. Following pathogen control, the majority of CD4 and CD8 T cell effector populations undergo apoptosis, but a subset of these cells persists, giving rise to the memory T cell pool. The requirements for the generation of T cell memory have not been completely elucidated, hence we were interested in understanding importance of the Th1 transcription factors Tbet and STAT4 in this process. To interrogate this, we utilized lymphocytic choriomeningitis virus infection of BALB/c mice. Not surprisingly, we observed that in the absence of Tbet, the virus-specific CD4 T cell IFNγ response was ablated but the IL-2 response remained unperturbed. In contrast, we found that STAT4 was not required for IFNγ production by virus-specific CD4 T cells. Conversely, the functional virus-specific CD8 T cell response was intact in the absence of Tbet, STAT4, or both, although increases in the proportion of effector cells competent for IL-2 production were noted in mice that lacked Tbet expression. We did detect marked differences in the expression of CD127 and KLRG1 on virus-specific effector CD8 T cells, however this did not translate into alterations in the numbers of memory CD8 T cells after the resolution of the infection. Collectively, we discovered distinct roles for Tbet and STAT4 in shaping the phenotype and function of virus-specific T cell responses.
Calmodulin boosts Itk activity to induce sustained calcium responses in T cells (P1117)
Authors: Huang Yina , Wang Xinxin , Boyken Scott , Hu Jiancheng , Xu Xiaolu , Suleiman Hani , Shea Madeline , Shaw Andrey , Andreotti Amy 
Published: January 2023

Abstract
The Tec family tyrosine kinase Itk is an important transducer of T cell activating signals. Itk regulates the levels of two second messengers Ca2+ and diacylglycerol, which are required for initiating transcriptional programs important for T cell priming and differentiation. How T cells translate intracellular signaling cascades into distinct functional outcomes remains a fundamentally important question. We hypothesize that distinct mechanisms of Itk activation lead to Ca2+ patterns that result in divergent T cell responses. Itk activation requires recruitment via its Pleckstrin homology (PH) domain to its membrane ligand PIP3, which is generated by PI-3 kinase. Here, we report a role for Calmodulin (CaM) in sustaining Itk activity and Ca2+ responses. CaM is a downstream Ca2+ sensor that controls numerous cellular enzymes, including Calcineurin. We have identified a novel interaction between the Itk PH domain and CaM. NMR analyses revealed that CaM binds adjacent to the PIP3 binding pocket, leading us to hypothesize that CaM regulates PIP3 binding. CaM inhibition or genetic mutation of the CaM binding site resulted in decreased PIP3 association and Itk activation, resulting in less sustained Ca2+ responses. We propose a model in which initial Itk activation results in low Ca2+ increases that feedback to boost membrane recruitment of Itk via CaM. We speculate that T cell responses requiring sustained Ca2+ signals, such as T cell differentiation require this feedback loop.
Using reporter mouse models to track CD4 T cell differentiation and fate based on IL-2 expression (P1199)
Authors: Winstead Colleen , Way Sing Sing , Moon James , Weaver Casey 
Published: January 2023

Abstract
CD4 T cells respond to in vivo activation stimuli, in part, by rapidly producing the homeostatic cytokine IL-2. It is thought that this acute production of IL-2 is necessary for full activation and fate determination of both the conventional CD4 T cells themselves, as well as other components of the adaptive (Tregs/CD8/B cells) and innate immune responses (NK/NKT/DC) to infection. Within a population of responding CD4 T cells, only a percentage of cells will secrete IL-2. Though much is known regarding regulation of IL-2 production by CD4 T cells and the downstream consequences of autocrine and paracrine signaling, little is known about the quantity, quality, or fate of CD4 T cells that produce IL-2. Using L. monocytogenes engineered to express foreign MHCII peptides and peptide-loaded MHCII tetramers, we are able to track and assess the fate of endogenous, antigen-specific CD4 T cells in infected mice. Combining this methodology with novel transgenic IL-2 reporter mouse models, we are able to address questions regarding fate by isolating, depleting, and/or adoptively transferring live, antigen-specific CD4 T cells to secondary hosts based on acute expression of IL-2. Preliminary data suggests IL-2-‘competent’ and -‘incompetent’ cells differ in their ability to traffic to peripheral tissues following an acute, systemic infection, resulting in a potential functional, as well as proliferative and survival advantage for competent cells over those incompetent for IL-2 expression.
Comparison of the T cell surface glycome of activated and naïve T cells (P1210)
Authors: Maverakis Emanual , Ono Yoko , Marusina Alina , Bustos Villalobos Itzel , Rizzo Amilcar , Dimapasoc Lauren , Hua Serenus , Williams Cynthia , Lebrilla Carlito 
Published: January 2023

Abstract
Protein glycosylation plays an important role in a variety of cellular activities including migration, activation, and adhesion. Although the majority of cellular proteins are glycosylated, little is known about the cell surface glycome of the T cell. Here we characterize the glycans expressed on the surface of naïve, activated and malignant T cells. Using a variety of techniques including density centrifugation, PNGase F enzyme glycan release, lectin column affinity chromatography, nanospray HPLC-chip/time-of-flight mass spectrometry, and flow cytometry we were able to characterize the entire surface glycome of naïve T cells and the associated changes following T cell activation with anti-CD3/CD28. The cell surface proteins expressing these glycans were also identified. Using specific-exoglycosidases to remove the glycans of interest, while leaving their associated proteins intact, the effects of these glycans on T cell proliferation, TCR signal transduction, and TCR down-regulation was determined.
CASPASE-12 is not a protective factor for rheumatoid arthritis in African-Americans (P4106)
Authors: Hermel Evan , Marshall Laura , Obaidullah Mohammad , Fuchs Trista , Brinkley Garland , Velasco H. Eduardo , Mikuls Ted , Bridges Jr S. Louis 
Published: January 2023

Abstract
CASPASE-12 (CASP12) modulates inflammation due to its ability to down-regulate inflammatory cytokines, particularly interleukin-1. Most humans possess the inactive pseudogene allele (CASP12p1) but a functional, non-truncated CASP12 allele [single nucleotide polymorphism #rs497116; A-&gt;G; ter124R] is found in 20% of persons of African descent. CASP12 is a risk factor for sepsis in persons of African descent. Rheumatoid arthritis (RA) is a serious and complex autoimmune disease that involves significant joint inflammation and destruction, and interleukin-1 contributes to the pathogenesis of RA. To determine if CASP12 may be protective against RA due to its anti-inflammatory functions, we genotyped 742 patients with rheumatoid arthritis and 342 controls from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis and the Veterans Affairs Rheumatoid Arthritis registries. Of RA patients, 17 (2.29%) were homozygous for CASP12, 146 (19.7%) were heterozygous, and 579 (78%) were homozygous for CASP12p1. These numbers did not vary significantly from controls. No significant differences were observed for CASP12 genotype on age of disease onset, seropositivity for rheumatoid factor or anti-CCP, baseline joint erosion, joint space narrowing scores, overall disease scores, C-reactive protein levels or erythrocyte sedimentation rates. Thus, CASP12 does not protect against RA in African-American patients, nor mitigates disease parameters.
Deletion of Snai2 and Snai3 results in impaired physical development compounded by lymphocyte deficiency (P4380)
Authors: Pioli Peter , Dahlem Timothy , Weis Janis , Weis John 
Published: January 2023

Abstract
The Snail family of transcriptional regulators consists of three highly conserved members. These proteins regulate (repress) transcription via the recruitment of histone deacetylases to target gene promoters that possess the appropriate E-box binding sequences, specifically with GC-rich central dinucleotides. Murine Snai1 is required for mouse development while Snai2 deficient animals develop normally but have been reported to have thymic T cell deficiencies. Less is known about the third member of the family, Snai3. To investigate the function of Snai3, we generated a conditional knockin mouse. Utilizing Cre-mediated deletion to facilitate the ablation of Snai3 in T cells or the entire animal, we found little to no effect of the loss of Snai3 suggesting possible compensation with another family member. To test this, we created Snai2/Snai3 double deficient mice. The developmental consequences of lacking both of these proteins was manifested in stunted growth, a paucity of offspring including a dramatic deficiency of female mice, an overgrowth of the eyelids and impaired immune cell development particularly within the lymphoid lineages.