bluuebunny/crossref_metadata_2025_split huggingface dataset:
The trancriptional factor, Nrf2 is critical for the protection against pneumococcal pneumonia. (INM3P.400)
Authors: Ludewick Herbert , Metzger Dennis 
Published: January 2023

Abstract
Pneumonia is one of the major clinical complications of pneumococcal disease. Innate immunity provides an immediate response to S. pneumoniae that can be protective, but if not controlled, can also lead to deleterious inflammation, extensive tissue damage and mortality. A complete understanding of the regulation of innate immunity and attendant inflammatory responses are critical for clinical control of respiratory bacterial infections. To better comprehend this dynamic process during pneumococcal infection, we specifically focused on the transcriptional factor, Nrf2, which can be both induced by inflammation and critically regulates inflammatory responses. Of interest, acute lung injury (ALI) in humans is correlated with functional polymorphisms in the Nrf2 promoter region. Our studies showed that mice deficient in Nrf2 were highly susceptible to in vivo pneumococcal pneumonia. Nrf2 deficiency was associated with enhanced production of pro-inflammatory cytokines and infiltration of neutrophils into the lungs following infection. However, immunization with the polysaccharide conjugate vaccine completely protected both Nrf2-/- and Nrf2+/- mice against pneumococcal challenge. This study provides evidence that Nrf2 is critical for protection against pneumococcal pneumonia by suppressing deleterious inflammation. In addition, the results suggest that pneumococcal vaccination should be performed to protect humans who have an Nrf2-associated genetic predisposition to develop ALI &lt;!--EndFragment--&gt;
Induction of lipoxin A4 by Francisella tularensis: a mechanism for regulation of pro-inflammatory responses during early-phase tularemia (INM3P.401)
Authors: Singh Anju , rahman tabassum , Bartiss Rose , Musteata Florin , Sellati Timothy 
Published: January 2023

Abstract
During respiratory tularemia, caused by inhalation of Francisella tularensis (Ft), we postulate that bacteria establish a principally anti-inflammatory environment and subvert host cell death programs to facilitate their unfettered replication within various cell types. Here we have explored the role of lipid mediators such as lipoxin A4 (LXA4) and prostaglandin E2 (PGE2) in host inflammatory responses manifested early during infection with Ft. An inverse relationship was observed between the production of LXA4 and PGE2 suggesting that Ft induces the generation of these eicosanoids to modulate cell death and enhance its own survival. This notion is supported by our findings that Ft triggers the release of LXA4, which inhibits apoptosis of macrophages. We also have elucidated the course of tularemia in mice deficient for 5-lipoxygenase (5-LO), leaving them incapable of generating LXA4, and observed elevated levels of PGE2, increased apoptosis, increased neutrophil recruitment and elevated release of pro-inflammatory cytokines and chemokines as compared to their wild-type counterparts. 5-LO deficient mice also were found to be less susceptible to lethal doses of Ft LVS as compared to wild-type mice. Our results suggests that 5-LO activity increases susceptibility to Ft infection, suggesting that targeting this pathway may have therapeutic benefit by limiting bacterial growth in tularemic individuals and perhaps those infected with other virulent respiratory pathogens.
IFNγ-mediated exacerbation of Saccharopolyspora rectivirgula-induced proinflammatory responses is dependent on interferon regulatory factor 1 (INM3P.403)
Authors: Yi Ae-Kyung , Park Jeoung-Eun 
Published: January 2023

Abstract
Saccharopolyspora rectivirgula (SR) is a thermophilic actinomycetes that causes hypersensitivity pneumonitis (HP). Interferon γ (IFNγ) produced after exposure to SR has been demonstrated to be necessary for development of HP. However, the molecular mechanism by which IFNγ enhances SR-mediated inflammatory responses is not completely understood. We investigated how IFNγ alters SR-induced expression of cytokines/chemokines. IFNγ pretreatment substantially enhanced expression of TNFα, IL-6, IL-23, IFNβ, MIP-1α, and MIP-2, without affecting IL-10 expression, in response to SR. Expression of interferon regulatory factor 1 (IRF1) was rapidly increased in cells pre-exposed to IFNγ, and inhibition of IRF1 synthesis abolished IFNγ-enhanced gene expression in response to SR. In contrast, suppression of IRF1 expression did not alter SR-mediated expression of IL-10. SR stimulation led to the binding of IRF1 to the IL-6 promoter region, but not to the IL-10 promoter region in IFNγ-pretreated cells. This indicates that IRF1 expressed in cells pre-exposed to IFNγ is activated by subsequent SR stimulation and contributes to the synergistic expression of certain proinflammatory genes. Our results imply that IFNγ produced after initial exposure to SR may help direct the proinflammatory responses to subsequent SR exposure toward to pathogenic Th1/Th17 development by selectively amplifying expression of certain cytokines/chemokines without affecting expression of regulatory cytokine IL-10.
Novel role for inflammasome-dependent IL-18 in promoting Th2 responses during Leishmania infections (IRC7P.420)
Authors: Gurung Prajwal , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Leishmaniasis is a global health disease and is categorized under neglected tropical disease by WHO. Despite tremendous amount of economic burden and morbidity and mortality associated with Leishmania infections, studies to understand these parasitic bugs are nevertheless lacking. As a result, specific targeted treatment options or vaccines to treat Leishmaniasis are still missing. Herein, we sought to understand how inflammasomes are involved in host responses during Leishmania major infection. One of the hallmarks of inflammasome is the activation of caspase-1 and ultimate release of bioactive IL-1β and IL-18. Interestingly, we found that mice lacking components of the NLRP3 inflammasome were resistant to L. major infections in comparison to their WT counterparts. Using in vitro and in vivo approaches, we showed that L. major activates NLRP3 inflammasome. We further demonstrated that NLRP3 inflammasome induced IL-18, but not IL-1β, promoted Th2 responses during L. major infection. Mechanistically, IL-18 enhanced expression of Th2 transcription factors GATA3 and cMAF in T cells. Finally, we were able to show that IL-18 neutralization in WT mice protected from L. major infections. In conclusion, our study uncovered a novel role for inflammasome-induced IL-18 in promoting Th2 responses and Leishmaniasis, which can potentially be targeted for therapeutic benefits during L. major infections.
IFNγ signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells (IRC7P.421)
Authors: Lu Li-Fan , Lee Hyang-Mi , Fleige Anne , Forman Ruth , Khan Aly , Cho Sunglim , Lin Ling-Li , Nguyen Duc , O'Hara Aisling , Yin Zhinan , Hunter Christopher , Muller Werner 
Published: January 2023

Abstract
IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.
The prostaglandin D2 receptor chemoattractant receptor homologous molecule expressed on Th2 cells regulates accumulation of group 2 innate lymphoid cells in the inflamed lung (IRC7P.426)
Authors: Tait Wojno Elia , Monticelli Laurel , Tran Sara , Alenghat Theresa , Osborne Lisa , Thome Joseph , Willis Cynthia , Budelsky Alison , Farber Donna , Artis David 
Published: January 2023

Abstract
Group 2 innate lymphoid cells (ILC2s) promote type 2 immunity and inflammation, but the pathways that control ILC2 migration into inflamed tissues remain poorly understood. Here, we show that the prostaglandin D2 (PGD2) receptor chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) regulates ILC2 accumulation in the lung in vivo. The frequency of ILC2s that expressed CRTH2 was significantly higher in healthy human and murine peripheral blood than in the lung, suggesting that regulation of CRTH2 expression might be associated with ILC2 accumulation in the lung. Consistent with this, CRTH2-expressing murine ILC2s accumulated in the lung in response to PGD2. Further, CRTH2-deficient mice exhibited reduced ILC2 accumulation and helminth-induced type 2 inflammation in the lung compared to wild-type mice. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored helminth-induced pulmonary inflammation in CRTH2-deficient mice. Together, these data suggest that the PGD2-CRTH2 pathway regulates ILC2 accumulation and type 2 inflammation in the lung in vivo.
Multi-enzyme aminoacyl tRNA synthetase complex component AIMp1/p43 as an important Th1 mediator (IRC7P.428)
Authors: Liang Dan , Halpert Matthew , Konduri Vanaja , Chen Yunyu , Kim Doyeun , Kim Sunghoon , Levitt Jonathan , Decker William 
Published: January 2023

Abstract
Of professional antigen presenting cells, only the dendritic cells (DC) are regarded as initiators of adaptive immune responses. Previously we identified a Th1 polarizing phenotype from DCs loaded with overlapping (homologous) MHC class I and II determinants, including augmented DC IL-12 production, generation of CD8+ cytolytic effectors, and T cell IFNγ secretion, suggesting DC intrinsic mechanisms to recognize and compare antigenic epitopes. AIMp1/p43 is a structural component of the multi-enzyme aminoacyl-tRNA synthetase complex (mARS) and indicated by previous studies to be a pro-inflammatory cytokine. We identified high levels of p43 release correlated with degree of homology between antigenic epitopes on DC class I and II molecules. In vitro studies confirmed p43 deficiency impairs DC costimulatory and Th1 polarizing functions. It also reversely regulates the production of IFNγ and IL4 within T cells. In vivo, p43 deficiency abolishes the ability of DC to mediate effective response against B16 melanoma tumors, and leads to higher susceptibility to influenza viral infections. These data support our hypothesis that p43 is a critical Th1 polarizing effector molecule. We will investigate further into p43 functions in DC and T cell crosstalk, targeting candidate cell surface receptors and intracellular signaling pathways. Additionally, we will better characterize in vivo roles of p43 in anti-tumor and anti-viral models and seek to apply it as a novel vaccination adjuvant.
Bidirectional polarization of T cell function via CD43 (IRC8P.437)
Authors: Modak Madhura , Majdic Otto , Cejka Petra , Waidhofer-Söllner Petra , Jutz Sabrina , Steinberger Peter , Zlabinger Gerhard , Stoeckl Johannes 
Published: January 2023

Abstract
Co-receptors, being either co-stimulatory or co-inhibitory, play a pivotal role in T cell immunity, as they decide the fate of T cell function. CD43 is one of the abundant cell surface glycoproteins expressed on T cells. CD43 has been demonstrated to act as not only a potent co-receptor but also a negative regulator for T cell activation. To further investigate role of CD43 in T cell activation and subsequent function, peripheral blood T cells were activated via two distinct CD43 epitopes recognized by monoclonal antibodies (mAbs) 6E5 (T6E5-act) and 10G7 (T10G7-act) along with TCR signalling. Both the CD43 mAbs could potently induce T cell activation when immobilized but exerted differential downstream effects including differential activation of signalling pathways, T cell cytokine production and also distinct effector function. T10G7-act poorly responded in re-stimulation assay and further acquired suppressive function compared to T6E5-act or to T cells activated via CD28 (TCD28-act). Furthermore, T10G7-act did not directly inhibit responder T cells, but rather exhibited their effect via dendritic cells when added to allogenic mixed leukocyte reaction. Together our data suggests a unique role of CD43 in bidirectional polarization of T cell immunity, a positive co-stimulatory role and a negative role in down-modulation of immune response, depending on its targeted epitope.
Antigen level, OX40 (CD134) and 4-1BB (CD137) costimulation, and IL-33 support CD4 T cell differentiation and functionality (IRC8P.448)
Authors: Morales Crystal , Maxwell Joseph , Adler Adam , Vella Anthony 
Published: January 2023

Abstract
We set out to determine how costimulation induces cytotoxic CD4 T cells. In our in vivo model, CD11c+ cells express varying levels of Eα antigen linked to MHC II. To study CD4 T cell differentiation we transferred in Eα-specific T cells and monitored functionality. Mice were treated with OX40 and 4-1BB agonists, and cytotoxic CD4 T cells were assessed. In high antigen presenters (Eαhi) the T cells became primarily T-bet+ GzmB+ IL-33R++ and clonally expanded, while low antigen presenters (Eαlo) induced T cells that were mostly Gata3+ or Eomes+ KLRG1+ IL-33R+ with reduced expansion levels. Upon ex vivo stimulation with Eα, T cells from Eαhi mice produced higher IFNɣ levels than T cells from Eαlo mice, whereas IL-4 levels were low in both. Since IL-33R was expressed, we showed that higher IL-33R on specific T cells from Eαhi mice conferred greater production of IFNɣ by demonstrating that IL-33 synergized with IL-2, IL-12 and IL-36β independent of TCR signals. The decreased functionality of T cells from Eαlo mice may be due to more Tregs since exhaustion markers were unexpectedly higher on T cells from Eαhi mice. These novel findings demonstrate that 1) cytotoxic CD4 T cells can be induced by costimulation therapy but may be a heterogeneous population, 2) antigen presentation levels have a substantial effect on T cell differentiation programming and 3) IL-33 can act as a Th1 activating cytokine. Thus, this data will greatly impact CD4 T cell immunotherapeutic approaches.
Role of microtubule acetylation in T cell activation and downstream function (IRC8P.450)
Authors: Hu Kenneth 
Published: January 2023

Abstract
Microtubules (MTs) play a number of important roles in antigen-mediated T cell activation and effector functions. Tubulin can undergo a number of post-translational modifications including acetylation of alpha tubulin. This acetylation affects MT growth dynamics and ability of motor proteins to traffic along them. We investigated the role of this acetylation in T cell function by using a mouse bearing deletion of the gene for alpha tubulin acetyltransferase 1 (aTAT1), the main acetyltransferase tubulin. Absence of aTAT1 leads to complete loss of acetylated alpha-tubulin. We found that CD4+ T cells from an aTAT1 deficient mouse showed more proliferation than controls upon stimulation with intermediate levels of antigen. We observed no difference in the level of calcium influx between WT and KO CD4+ T cells upon antigen stimulation. An important function of microtubules in CD8+ T cells is trafficking of cytolytic vesicles. Given that acetylation can affect the movement of motor proteins, we tested whether aTAT1 KO CD8+ and Natural Killer (NK) showed altered ability to kill target cells. These findings indicate that acetylation of alpha-tubulin is important in regulating T cell effector responses.
Mammalian target of rapamycin inhibition with enterically given rapamycin alters immunity and gut flora in young and aged wild type mice and extends life of immunodeficient mice (IRC8P.452)
Authors: Hurez Vincent , Dao Vinh , Liu Aijie , Pandeswara Srilakshmi , Gelfond Jonathan , Sun Lishi , Svatek Robert , Bergman Molly , Padron Alvaro , Drerup Justin , Liu Yang , Dodds Sherry , Hasty Paul , Sharp Zelton , Curiel Tyler 
Published: January 2023

Abstract
mTOR regulates many important immune processes. Interest in immune effects of mTOR inhibitors is heightened by recent findings of ability to boost specific immunity and vaccine response in elderly humans, treat cancers and autoimmunity, and extend life and healthspan in mice, suggesting important new clinical applications. However, immune toxicity concerns for long-term mTOR inhibition, particularly immunosuppression, persist. We comprehensively analyzed immune effects of long-term rapamycin in mice. Gene expression profiling of purified T and B cells (CD4+PD1+, CD4+PD1-, CD8+PD1+, CD8+PD1-, B220+), CD11b+CD11c- myeloid cells and CD11c+ dendritic cells showed numerous, novel changes in genes affecting differentiation, function, homeostasis, migration, exhaustion, cell death and inflammation. Novel effects on Th9, Th22 and Tfh differentiation were seen as was improved function of exhausted PD1+ T cells (supported by human clinical data) and increased numbers and function of innate lymphoid cells. Immune functions relevant to cancer, infections, aging and inflammation, and innate lymphoid cell effects were validated in vitro and in vivo. eRapa prolonged life in RAG KO mice (without T or B cells) &gt;12x and in IFN-γ KO mice &gt;3x over wild type mice, supporting mTOR suppression immune effects mitigating disease as a mechanism for longevity extension. Metagenomic effects were linked to immune outcomes. Our data demonstrate novel mTOR immune effects meriting further investigations.
T cells and dendritic cells release chemokines to recruit innate immune cells after intranasal staphylococcal enterotoxin A exposure (IRC8P.438)
Authors: Svedova Julia , Vella Anthony 
Published: January 2023

Abstract
Staphylococcus aureus, an important cause of life-threatening infections, produces a number of virulence factors including superantigens. Staphylococcal enterotoxin A (SEA) is a superantigen that directly binds to MHC II on antigen presenting cells and then crosslinks with specific T cell receptor (TCR) Vβ chains on T cells (e.g. Vβ3). We hypothesized that SEA-activated T cells guide dendritic cells to release chemokines causing a systemic recruitment of innate immune cells. Here we showed that intranasal SEA exposure in mice caused a rapid influx of neutrophils and monocytes to peripheral blood, spleen, and lymph nodes. This migration was dependent on T cells since TCR βδ-/- mice were unable to recruit these cells unless they received an adoptive T cell transfer. Confocal microscopy imaging demonstrated that the recruited neutrophils localized to the T cell zone of lymph nodes. Increased expression of several neutrophil and monocyte chemotactic factors, including CXCL1, CXCL2, CCL2, CCL3, and CCL4, was detected in lymph nodes as early as one hour after SEA exposure. By sorting specific cell populations we found that these chemokines were differentially expressed. While CXCL1 and CXCL2 were mostly produced by migratory dendritic cells, CCL3 and CCL4 were made by SEA-activated Vβ3+ T cells. Our future studies will focus on determining the mechanism of chemokine release and on describing the consequences of innate immune cell recruitment to lymph nodes.
Effects of leucine metabolism on T cell activation: a potential target for nutritional immunotherapy (IRC8P.439)
Authors: Ananieva-Stoyanova Elitsa , Powell Jonathan , Patel Chirag , Hutson Susan 
Published: January 2023

Abstract
T cells are essential for cell-mediated defense against pathogens and cancer. Recent advances in understanding T cell regulation reveal that cell metabolism can greatly impact the final outcome of the immune response. A primary regulator of cell growth and proliferation, the mammalian target of rapamycin (mTOR), is critical for T cell activation and differentiation. Leucine is a nutritional activator of mTOR and its intracellular concentrations are regulated by the branched chain aminotransferase (BCAT) isoenzymes, cytosolic BCATc and mitochondrial BCATm. We showed recently that activated CD4+ T cells, lacking cytosolic leucine transamination (BCATc KO), had up-regulated mTOR signaling and glycolysis. To explore further the role of BCATc in T cell activation, we measured INFƴ production and proliferation in T cells from BCATc KO and wildtype mice. Loss of BCATc increased INFƴ by 2.8-fold in activated T cells but did not impact T cell proliferation. Knocking out the mitochondrial BCATm had a robust effect on T cell glycolytic rate (3.1-fold increase) upon activation but only mild effects on mTOR and INFƴ. The results suggest that loss of either enzyme is sufficient to increase T cell glycolysis and mTOR signaling but not T cell proliferation. Thus, BCATc and BCATm are critical players in T cell activation by providing negative feedback regulation of mTOR and glycolysis. Manipulating leucine metabolism may be one mechanism to modulate activation and differentiation of T cells.
Differential regulation of alloreactive CD8 T cell responses by inflammation. (IRC8P.440)
Authors: Jangalwe Sonal , Greiner Dale , Brehm Michael 
Published: January 2023

Abstract
Tissue transplantation results in the release of endogenous danger molecules that stimulate inflammation by activating the innate immune system. Inflammatory signals regulate the magnitude and functionality of T cell responses during infection, but the direct impact of inflammation on alloreactive T cell responses has not been extensively studied. Understanding the role of inflammation in regulating the activation of alloreactive T cells will aid in the development of novel therapies to prolong allograft survival. We have used a TCR-transgenic alloreactive CD8 T cell model to study the response of alloreactive T cells in the presence of inflammation. Our results show that stimuli inducing different inflammatory profiles have significant effects on the size, phenotype and quality of alloreactive CD8 T cell responses as compared to stimulation with alloantigen alone. Inflammation induced by exposure to poly(I:C) and LPS increased the number of alloreactive CD8 T cells at the peak of the response. The ability of effector alloreactive CD8 T cells to produce IFN-g was enhanced with poly(I:C) but decreased with LPS, while cytotoxic activity was similar. LPS slowed the contraction phase of the alloantigen response, resulting in higher levels of memory CD8 T cells as compared to poly(I:C). These data indicate that inflammatory signals differentially regulate the kinetics and functionality of alloreactive CD8 T cell responses and may determine susceptibility to immune suppression.