bluuebunny/crossref_metadata_2025_split huggingface dataset:
Th17 responses driven via PPARγ blockade lead to faster recovery from enteroaggregative Escherichia coli infection (49.13)
Authors: Washington Casandra , Bassaganya-Riera Josep , Viladomiu Monica , Pedragosa-Marin Mireia , Guerrant Richard , Roche James , Hontecillas Raquel 
Published: January 2023

Abstract
Enteroaggregative Escherichia coli (EAEC) is a recognized cause of enteric disease in diverse clinical settings. Mucosal immunity towards EAEC infections is poorly understood. To better characterize immunoregulatory mechanisms underlying EAEC infections we constructed a computational model mimicking host responses to EAEC at the gut mucosa. Preliminary model calibration efforts demonstrated remarkable fitting to experimental data. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has been targeted to modulate mucosal immune responses to EAEC. Wild type and conditional knockout mice lacking PPARγ in T cells were fed protein-deficient diets at weaning and challenged with 5x109cfu EAEC strain JM221. Quantitative RT-PCR data reveal that administration of GW9662, a potent PPARγ antagonist, for 7 days post infection or the deletion of PPARγ in T cells results in upregulation of pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β when compared to non-treated infected animals. Histological analysis of colons divulges lower leukocyte infiltration and decreased mucosal thickness 14 days following EAEC infection after pharmacological blockade of PPARγ or deletion of PPARγ in T cells. These findings were accompanied by faster clearance of colonic EAEC in tissue-specific PPARγ null mice. In conclusion, we present a fully integrated approach to study host responses to EAEC that provides new insights on the pathogenesis and treatment of enteric infections.
Allergic Eosinophils Alter Immune Responses to Influenza A Virus. (49.24)
Authors: Samarasinghe Amali , Woolard Stacie , McCullers Jonathan 
Published: January 2023

Abstract
WHO estimates that 235 million people globally suffer from asthma, which was among the important risk factors for hospitalization during the 2009 influenza pandemic. Using a novel co-morbidity model of acute allergic asthma and influenza, we demonstrate that mice with acute asthma are protected from influenza-induced morbidity. Asthmatic mice did not lose weight or exhibit typical, severe, clinical signs of infection. In spite of having a greater infiltration of cells into the airways, these mice had suppressed Th1- and Th2-type cytokines compared to flu-only controls. Resistin-like molecules were highly expressed during early timepoints that correlated with eosinophil influx indicating that responding eosinophils may be mediating protection against influenza. Eosinophils were harvested from allergic airways and adoptively transferred to matched mice infected with pandemic influenza virus. Eosinophil transfer into flu-infected non-allergic mice markedly altered cellular influx into the airways. Significantly more CD4+ Th2 lymphocytes, macrophages, neutrophils, and eosinophils were present compared to control mice. Viral titers were reduced 5 days after eosinophil transfer, and the host immune response was altered. We conclude that allergy-induced eosinophils modulate immune responses to influenza virus. The role of eosinophils in protecting the acutely allergen-sensitized host from viral mediated immunopathology merits further investigation.
The intranasal delivery of non-specific virus-like particles elicits heightened and accelerated immune responses to influenza virus (49.27)
Authors: Richert Laura , Rynda-Apple Agnieszka , Wiley James , Douglas Trevor , Harmsen Allen 
Published: January 2023

Abstract
We have previously shown that the intranasal delivery of a small heat-shock protein cage nanoparticle, a virus-like particle (VLP), elicits the formation of inducible bronchus-associated lymphoid tissue (iBALT), which provides protection against many diverse high-dose pathogen challenges. We demonstrate here that the presence of non-specific, VLP-induced iBALT facilitated accelerated influenza virus clearance and enhanced immunity through accelerated airway (CD103+) and parenchymal (CD11b+) dendritic cell antigen processing and trafficking. These responses were dependent upon the presence of CD11c+ cells, which had been directly exposed to VLPs, and migrated into the lung in a CCR2, VCAM-1, and ICAM-1-dependent manner. The initial innate response to influenza challenge was then followed by an accelerated expansion of influenza-specific CD4+ T cells. The combination of these events resulted in accelerated viral clearance and significantly ameliorated host-derived collateral damage. Furthermore, we show that the presence of iBALT, which is not specific to influenza virus, was efficient at clearing high-dose virus, independently of the TBLN’s help. Thus, we herein demonstrate the mechanism by which the presence of iBALT, derived from non-specific, non-pathogenic VLPs, and lacking any memory cells to agents of subsequent challenge, elicited alternative cellular trafficking and expansion patterns, and thus cleared virus at an accelerated rate, with less harmful consequence.
Commensal flagellated A4 bacteria promote intestinal Th1/Th17 cell development but inhibit Th2 responses (49.3)
Authors: Liu Houpu , Yao Suxia , Cong Yingzi , Elson Charles 
Published: January 2023

Abstract
Host and microbiota interact interdependently to maintain intestinal immune homeostasis. As Th1, Th17, and Tregs are present in lamina propria (LP) in the steady condition, mucosal Th2 cells are hardly detected. Some specific commensal organisms have defined effects on mucosal immune functions, e.g., SFB promotes intestinal Th17 whereas B. fragilis and certain Clostridium spp induce Tregs. However, it is still unclear if there are specific commensal organisms downregulating Th2 responses to microbiota. A4 bacteria, a commensal isolated from mouse cecum, produce CBir1 flagellin, a dominant antigen in Crohn’s disease patients and in experimental colitis. In CBir1 TCR transgenic mice, Th1, Th17 and Treg but no Th2 cells are present in intestinal LP. Upon transferred into TCRβxδ-/- mice, CBir1 Tg T cells differentiated into IFN-γ+, IL-17+, FoxP3+ cells but not IL-4+ cells in LP. When stimulated with CBir1 flagellin in vitro, CBir1 Tg CD4+ T cells were able to differentiate into Th1, Th17 and Tregs but resisted Th2 differentiation. Pretreatment of APC with A4 bacterial lysates or CBir1 flagellin, but not with control E. coli, promoted IFN-γ but inhibited IL-4 production of OTII T cells stimulated with OVA and of wild-type T cells stimulated with anti-CD3 under neutral or Th2 polarizing conditions. Collectively, our data reveal that A4 bacteria inhibit Th2 and favor Th1/Th17 responses in intestinal mucosa via production of flagellin, probably through stimulating IFN-γ production.
CD4+ T cells regulate skin resident memory CD8+ T cells (TRM) (49.8)
Authors: Jiang Xiaodong , Clark Rachael , Liu Luzheng , Seneschal Julien , Purwar Rahul , Tian Tian , Fuhlbrigge Robert , Kupper Thomas 
Published: January 2023

Abstract
The requirement of CD4+ T cell help for CD8+ T cell responses has been extensively explored in secondary lymphoid organs using systemic infection models. Whether such help also exists in peripheral tissues like the skin is unknown. We recently reported that skin resident memory CD8+ T cells (TRM) are non-recirculating and are superior to central memory CD8+ T cells (TCM) in protecting against re-infection. Interestingly, we also found that the acute CD8+ T cell migration into infected skin does not require CD4+ T cell help. Further study showed that the acute protection response of CD8+ T cells in the skin was equivalent in wild type and CD4-deficient mice. We next asked the role of CD4+ T cells in CD8+ TRM protective responses in the skin. To our surprise, the absence of CD4+ T cells did not impair the survival of CD8+ TRM in the skin. However, the recall response of CD8+ TRM in previously infected skin was significantly compromised in CD4-/- mice. The viral load assay further showed that the recall response of CD8+ TRM was significantly compromised when memory CD4+ T cells in the skin were depleted, suggesting that signals from memory CD4+ T cells in the skin are delivered to CD8+ TRM locally. Taken together, these data imply that while CD4+ T cells are not required both for acute CD8+ T cell response and maintenance CD8+ TRM in the skin, they do play an important role in regulating recall responses of CD8+ TRM.
Where will our next antibiotic come from? Investigating the effects of plant extracts on the growth of E. coli (50.2)
Authors: Herrington Lori , Teyton Luc 
Published: January 2023

Abstract
In April 2011, the World Health Organization adopted “Combating Drug Resistance and its Global Spread” for its World Health Day theme. With this recent urgent call for global action and after working at an immunology research laboratory through the American Association of Immunologists High School Teachers Summer Research Program in Immunology, I developed science curriculum that develops students’ understanding of basic human immune responses, how antimicrobial resistance (AMR) develops and how the discovery of new therapies can alleviate problems associated with AMR. Students will perform internet-based research on antimicrobial resistance public health issues and a hands-on experiment to discover if certain plant extracts have antimicrobial properties. Upon completion of the curriculum, students will not only understand the human immune system response and how antimicrobial resistance presents the world with a looming public health issue, but students will also demonstrate, first hand, the process of drug discovery and research. The ultimate goal of this curriculum is to help students understand how science touches their everyday lives and to provide students with the opportunity to learn about the exciting field immunology.
The immune system and the mechanisms of cell proliferation: an introduction to cancer and the IDO pathway (50.3)
Authors: Pascal Lyndonia 
Published: January 2023

Abstract
Cancer is a disease that arises when abnormal cells divide exponentially in any part of the body resulting in tumorigenesis. My lab experience at The University of Miami School of Medicine exposed me to the IDO pathway and its relationship with cancer cells. This introduction to 4T1 IDO knockdown cell lines inspired me to design an Immunology Unit aligned with Florida Biology Next Generation Sunshine State Standards (NGSSS). Students will be introduced to the immune system and the mechanisms of cancer. Students will learn the organization of the immune system. They will also gain an understanding that cancer has many faces. Virtual inquiry and laboratory activities will provide students with an opportunity to practice aseptic technique, cell culture, and cell counting. A research component will require students to construct an explanation of how cancer develops. Students will also be required to identify some of the agents that cause cancer and to differentiate between normal cells and cancer cells.
Treatment of type 1 diabetes by α7nAChR pathway activation. (51.11)
Authors: Hanes William , Chavan Sangeeta , Pavlov Valentin , Tracey Kevin 
Published: January 2023

Abstract
Type 1 diabetes is characterized by autoimmune destruction of insulin-producing pancreatic β cells. The α7 nicotinic acetylcholine receptor (α7nAChR) acts as part of the “cholinergic anti-inflammatory pathway” to inhibit the production of cytokines by monocytes, macrophages, dendritic cells, and other cytokine producing cells. Administration of highly selective α7nAChR agonists in vivo have significantly reversed or prevented the inflammatory damage associated with several preclinical disease models, including collagen induced arthritis, ileus, colitis, ischemia reperfusion injury, sepsis, and autoimmune diabetes. To determine the protective effects of the cholinergic pathway in type 1 diabetes, NOD mice were treated with cholinergic pathway stimulators beginning at an early age (3-4 weeks). Blood glucose was monitored weekly to determine the onset of hyperglycemia, as determined by blood glucose &gt;200 mg/dl. Intervention with cholinergic pathway stimulators at an early age reduced the age of onset of hyperglycemia in NOD mice and reduced the total prevalence of type 1 diabetes. This demonstrates that activation of the α7nAChR may be useful in the early prevention of type 1 diabetes.
TGF-β inhibits central memory cell differentiation in CD8 T-cells (52.14)
Authors: Takai Shinji , Schlom Jeffrey , Greiner John 
Published: January 2023

Abstract
Generation of a robust long-term T-cell memory would be expected to fortify vaccines and enhance host protection against infectious diseases and cancer immunotherapy. TGF-β is a well-known immune suppressive cytokine and in initial studies its ability to interfere with the generation of CD8+ central memory (CM) T-cells was confirmed. Exogenous TGF-β addition to isolated splenocytes from C57BL/6 or T-cells from F5 transgenic mice inhibited the differentiation of CD44+/CD62L+ CM T-cells in a dose-dependent manner. The addition of 0.5 ng/ml of TGF-β reduced the number of CD44+/CD62L+ CM by 50%, independent of any changes in CD8+ T-cell proliferation or apoptosis. Inhibition CM T-cell generation by TGF-β was reversed with the addition of SD208, a TGF-β RI kinase inhibitor. Signal transduction studies revealed that TGF-β selectively activates SMAD2, not SMAD independent pathways such as p38 MAPK in CD8+ T cells. SD208 interfered with SMAD2 activation and reversed the TGF-β-mediated suppression of CM T-cells. Interestingly, the TGF-β RI kinase inhibitor also suppressed S6, a down-stream mTORC1substrate. This study suggests that inhibiting TGF-β with the addition of TGF-β RI kinase inhibitor facilitates the generation of a more robust CM T-cell response, suggesting that combining TGF-β inhibition with vaccination could generate long-lasting CD8+ central memory immunity.
Combination immunotherapy integrating HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment for improved T cell recruitment and anti-tumor efficacy (52.19)
Authors: Rao Aparna , Kawabe Mayumi , Taylor Jennifer , Storkus Walter 
Published: January 2023

Abstract
Deficiencies in MHC Class I antigen presentation by tumor cells is a significant barrier to effective cancer immunotherapy. Therefore, combinational therapies that enhance tumor-associated antigen (TAA) presentation in tumor MHC Class I molecules while coordinately stimulating TAA-specific immunity would be expected to yield a greater clinical benefit. We have previously showed that in vitro treatment of tumor cells with 17-DMAG results in transient (proteasome-dependent) degradation of the EphA2, a TAA that is over expressed in several cancers, accompanied by increased presentation of EphA2 peptides on MHC class I complexes on tumor cells. To further characterize the therapeutic potential of this approach, we assessed the efficacy of a rationally-designed combinational therapy incorporating 17-DMAG and EphA2-targeted immunotherapy in murine tumor models. In vivo administration of 17-DMAG promoted: i) dramatically slowed tumor growth; ii) Enhanced recognition of tumor cells by anti-EphA2 CD8+ T cells; iii) Reduction in the frequency of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) in the tumor microenvironment, and iv) activation of tumor-associated vascular endothelial cells thereby facilitating Type-1 T cell infiltration. When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG co-treatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease.
Immunological Characterization of the Local Tissue Response to Atypical Antipsychotics (52.22)
Authors: Paquette Sara , Hickey Magali , Dawit Had , Deaver Daniel 
Published: January 2023

Abstract
It is recognized that the immune response plays a key role in the progression of many neurological diseases. Orally administered atypical antipsychotics (ATAPs) are generally thought to have anti-inflammatory actions; yet few studies investigating this phenomenon have been conducted. In order to increase patient compliance, injectable formulations of ATAPs that release over time have been developed. However, subcutaneous administration of aripiprazole monohydrate (ARP) and olanzapine pamoate monohydrate (OLZ) leads to a significant local tissue response (LTR) in rat models. Consequently, knowing the effect of long residing injections of ATAPs on the immune system and characterizing the LTR is of interest. LTRs begin to form as early as day 1and can persist for at least 21 days. Currently, there is no detailed immunological description of these LTRs in terms of the cellular or cytokine profile reported. We describe here the immunological characteristics of the LTR to ARP and OLZ. Injection sites and sera were isolated from rats and analyzed for the presence of cytokines. Peripheral blood cells were characterized to determine if circulating cell populations were affected by the LTR. Based on these data, a significant local foreign body reaction occurs at the site of injection following administration of ARP and OLZ. This local response is not associated with changes in circulating immune cells or in serum cytokines.
Interplay of alphavirus-based replicons with dendritic cells induces innate immune activation and enhances adaptive immunity (53.1)
Authors: Tonkin Daniel , Barro Mario , Johnston Robert 
Published: January 2023

Abstract
Venezuelan equine encephalitis virus replicon particles (VRP) are infectious, non-propagating particles which function as a safe and robust humoral, mucosal and cellular adjuvant when codelivered with antigen. VRP are known to infect dendritic cells (DCs) in vitro and in vivo, and we have explored the role of DCs in the adjuvant activity of VRP. Upon footpad injection VRP are rapidly transported to the draining lymph node, resulting in cytokine secretion and recruitment of leukocytes. We found that DCs were preferentially infected in the lymph node, although other cell types were also infected. TNF-secreting monocyte-derived inflammatory DCs were the cell type most dramatically recruited to the lymph node and also the most readily infected by VRP. These inflammatory DCs also efficiently took up antigen. By depletion of DCs we demonstrated that both VRP transport to the lymph node and the subsequent inflammatory response were at least partly DC-dependent. By in vitro analysis we found that VRP-infected DCs can amplify CD4 and CD8 T cell responses to antigen, which is mediated at least partly by DC-secreted factors. We also show that VRP-infected DCs are sufficient generate an adjuvant effect comparable to that achieved by injection of VRP alone. Altogether, these data provide strong evidence that in vivo targeting of DCs by VRP matures and alters those DCs in a manner that potentiates the adjuvant activity of VRP.
Modulation of tumor microenvironment by Staphylococcus aureus and the effects of immunotherapy using novel adjuvants (53.16)
Authors: Roy Chowdhury Roshni , Ghosh Swapan 
Published: January 2023

Abstract
Chronic inflammation of the tumor microenvironment has been attributed as a hallmark of cancer, for its tumor-promoting effects. Staphylococcus aureus pathogenesis is also known to induce chronic inflammation and it is the second most common Gram-positive bacterium in cancer patients causing lethality. However tumor -S. aureus interaction and its effect on tumor growth and microenvironment remains to be elucidated. The objective of this study was to assess changes in host immune microenvironment at the site of tumor growth with the introduction of S. aureus, followed by adjuvant therapy. Immunotherapy designed to eliminate tumor growth is challenging, because this has to contend not only with tumor progression but also chronic inflammation. Our studies have revealed a number of strategies by which S. aureus can modulate the host’s immune system and create an environment favorable for tumor growth. Cytokine antibody arrays showed that S. aureus induces very high levels of such inflammatory cytokines as IL-1β and IL-17. Quantitative real time PCR revealed that S. aureus down regulates four critical genes, namely, CD40L, Bcl2, Nlrp12 and Tnfsf11; all of which lead to the dysfunctioning of the two most critical players of the immune system: T-cells and dendritic cells. A phytol-based immune adjuvant, phytanol (PHIS-01), developed in our laboratory was found to reverse such effects caused by S. aureus and provide augmented immunity against both bacteria and tumor.
Vaccines Targeting Tumor Blood Vessel Antigens Promote CD8+ T Cell-Dependent Tumor Eradication or Dormancy in HLA-A2 Transgenic Mice (53.21)
Authors: Storkus Walter , Zhao Xi , Bose Anamika , Lowe Devin , Taylor Jennifer 
Published: January 2023

Abstract
Using an HHD model in which HLA-A2neg tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8+ T cell repertoire, we now show that vaccines based on tumor-associated blood vessel antigens (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2neg) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8+ (but not CD4+) T cells, in a coordinate reduction of CD31+ blood vessels in the tumor microenvironment (TME) and in the “spreading” of CD8+ T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or VEC flow-sorted from tumor tissue, but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8+, but not CD4+, T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically-preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy.
A novel iNKT cell-mediated vaccine maneuver induces potent long-lasting anti-tumor immunity for advanced prostate cancer by boosting CD8+T cell memory and function (53.24)
Authors: Varghese Bindu , Lynch Lydia , Vriend Lianne , Kissick Haydn , Dunn Laura , Varghese Sharlin , Dranoff Glenn , Arredouani M. Simo , Balk Steven , Exley Mark 
Published: January 2023

Abstract
iNKT cells have considerable therapeutic promise in cancer, but so far this has not been fully realized. At issue has been delivering iNKT ligand and tumor Ag to the same APC for optimal processing and presentation. Also, although tumor-infiltrating APCs express CD1d in both prostate cancer (PCa) models and patients, tumor induced tolerance and suppression leads to defective iNKT activation. Whole-cell tumor vaccines represent a promising treatment approach and prevent tumor progression in multiple models of cancer. Here, we use an optimized approach consisting of alpha-galactosylceramide (aGalCer) and the GM-CSF-based PCa vaccine, ‘GVax’ combined with IL-12. This approach was capable of breaking tumor-induced tolerance and causing dramatic and substantial tumor regression and survival in large advanced prostate tumors in TRAMP mice. Remarkably, 10/12 vaccinated &gt;9 month old mice rejected tumors, 'breaking tolerance', even at this late stage of tumor growth. The vaccine induced strong immune responses capable of reversing INKT defects in tumor-bearing mice as well as in patient iNKT in vitro. Both IL-12 and aGalCer were crucial for this response. Vaccinated mice had higher levels and activation of tumor-specific CD8 T, CD4 T and iNKT cells, and greater memory CD8 T cell expansion capable of producing the effector cytokines IFN-γ and TNF-α in response to tumor. These studies shed light on how whole cell vaccines targeting iNKTs can be utilized in PCa immunotherapy.