bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pulmonary Infection with Multiple Strains of Aspergillus fumigatus Reveals a Critical Role for IL-1α Signaling in Host Resistance Against Strains that Rapidly Germinate in the Lungs
Authors: Obar Joshua J , Caffrey-Carr Alayna Katherine , Kowalski Caitlin , Beattie Sarah , Blaseg Nathan , Upshaw Chanell , Tang Yi-Wei , Hohl Tobias , Cramer Robert 
Published: January 2023

Abstract
Aspergillus fumigatus strain diversity is reflected in heterogeneous virulence and inflammatory responses. Mechanisms underlying A. fumigatus strain specific immune responses and how this affects disease outcome is unresolved. We observe that the CEA10 strain is able to rapidly efficiently within the airway environment and induces greater lung damage, vascular leakage, and IL-1α release compared to the Af293 strain. Fungal clearance is dependent on IL-1α in mice inoculated with the CEA10 strain, while clearance of AF293 does not require IL-1α. Importantly, both swollen conidia and germlings of the CEA10 strain induce robust IL-1α secretion from macrophages in vitro, whereas only germlings of Af293 induce strong production of IL-1α. Our finding that early fungal germination in the airways drives greater pathology and IL-1α dependent inflammation is further supported by similar results with additional strains. First, serial passage of a non-airway germinating strain (Af293) in low-oxygen conditions results in a strain (EVOL20) that germinates more efficiently in the airways leading to enhanced lung damage, vascular leakage, and IL-1α dependent inflammation. Second, using primary clinical and environmental isolates of A. fumigatus that are able to rapidly germinate in airway conditions follows the same trend. Clinically, our data support the idea that A. fumigatus strain phenotypic variation significantly contributes to disease outcomes. Understanding why different A. fumigatus strains induce distinct immune pathology can reveal novel immunotherapeutic and antifungal targets for the treatment of invasive aspergillosis.
Th17 immunity to tuberculosis requires CD40-CD40L interaction and is enhanced by CD40 engagement on Mycobacterium tuberculosis-infected dendritic cells
Authors: Sia Jonathan Kevin , Madan-Lala Ranjna , Rengarajan Jyothi 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) impairs dendritic (DC) cell functions and induces suboptimal antigen-specific CD4 T cell immune responses that are poorly protective. Mucosal T-helper 17 (Th17) cells have emerged as important for protecting against tuberculosis (TB), but the mechanisms involved in generating antigen-specific Th17 responses during Mtb infection are not well defined. We previously reported that Mtb restricts Th17 responses and impairs CD40 expression on dendritic cells (DCs). We now demonstrate that generating IL-17 responses to Mtb requires CD40-dependent costimulation. CD40-deficient DCs were unable to induce antigen-specific IL-17 responses after Mtb infection despite the production of Th17-polarizing innate cytokines. Disrupting the interaction between CD40 on DCs and its ligand CD40L on antigen-specific CD4 T cells, genetically or via antibody blockade, significantly reduced generation of antigen specific IL-17 responses; cytokines were unable to compensate for this reduction. Importantly, engaging CD40 on DCs with a multimeric CD40 agonist (CD40LT) enhanced antigen-specific IL-17 generation in ex vivo DC-T cell co-culture assays. Further, intratracheal instillation of Mtb-infected DCs treated with CD40LT significantly augmented antigen-specific Th17 responses in vivo in the lungs and lung-draining lymph nodes of mice. Finally, boosting CD40-CD40L interactions promoted balanced Th1/Th17 responses in a setting of mucosal DC transfer, and conferred enhanced control of lung bacterial burdens following aerosol challenge with Mtb. Our results demonstrate that targeting the CD40-CD40L pathway represents a novel strategy to enhance early Th17 responses and improves adaptive immunity to TB.
Conditional silencing of the H-2Db class I molecule on CD11c+ Dendritic Cells inhibits the generation of antiviral CD8 T Cells during acute Theiler’s Murine Encephalomyelitis Virus (TMEV) infection in the CNS
Authors: Willenbring Robin , Settell Megan L , Malo Courtney Sarah , Goddery Emma N , Hansen Michael J , Pavelko Kevin D , Pease Larry R , Johnson Aaron J 
Published: January 2023

Abstract
The generation of an effective antiviral CD8 T cell response is required to protect C57BL/6 mice from Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating syndrome. Our group previously defined the VP2 121-130 peptide presented in the context of the H-2Db class I molecule as the immunodominant antigen recognized by the majority of brain infiltrating CD8 T cells during acute TMEV infection. Our group also determined that this Db:VP2 121-130 epitope specific CD8 T cell response was required for virus clearance. However, the mechanism by which virus antigen-specific CD8 T cells are generated in the brain remained undefined. Therefore, our laboratory generated a novel transgenic mouse system that enables conditional ablation of the H-2Db class I gene in specific antigen presenting cell types (APCs). Previously, analysis of class I-restricted antigen presentation required genetic disruption or depletion of entire APC subsets. We used this novel Cre-Lox transgenic mouse system to define the APC required to generate the immunodominant Db:VP2 121-130 epitope specific CD8 T cell response during acute TMEV infection. In the course of this analysis, we determined that silencing of class I-restricted antigen presentation on CD11c+ dendritic cells (DCs) did not affect thymic development of CD8 T cells. However, loss of Db expression by CD11c+ DCs completely abolished the generation of Db:VP2 121-130 epitope-specific CD8 T cell responses during acute TMEV infection. These findings demonstrate the importance of DCs in generating CD8 T cell responses against a neurotropic virus. We also provide a novel transgenic mouse for future studies involving class I-restricted antigen presentation.
Type I interferon signaling attenuates Regulatory T cells function in LCMV infection
Authors: Gangaplara Arunakumar , Martens Criag , Metidji Amina , Schmidt Rachel , Kanakabandi Kishore , Glass Deborah , Gokhale Ameya S , Lopez-Ocasio Maria , Porcella Stephen F , Shevach Ethan M 
Published: January 2023

Abstract
Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute and chronic infectious diseases remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. To dissect the functional role of IFNAR-signaling in Tregs during acute and chronic viral infection, we infected Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice with LCMV Armstrong and Clone-13. In both models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced expression of Treg associated activation antigens. The enhanced activated phenotype was also seen when we compared the transcriptomes of IFNARfl/flxFoxp3YFP-Cre and wild type (WT) Tregs by RNA-Seq on day 25-post Clone-13 infection. LCMV-specific CD8+ T cells from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral IFNγ and TNFα in both acute and chronic LCMV. In the chronic model, the numbers of anti-viral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs than WT mice during chronic infection. Thus, type I IFN signaling in Tregs is context-dependent, resulting in enhanced suppressor function in some models of autoimmunity, but decreased suppressor function in acute and chronic viral infection.
Dichotomous regulation of progenitor-like CD8 T cells during chronic viral infection by TCF1 and type I interferon
Authors: Wu Tuoqi , Ji Yun , Moseman E Ashley , Xu Haifeng , Manglani Monica , Lang Philipp A , Gattinoni Luca , McGavern Dorian B , Schwartzberg Pamela L 
Published: January 2023

Abstract
T cells develop into a dysfunctional state, called T-cell exhaustion, during chronic viral infections and cancer. However, how antigen-specific T cells persist in these situations is poorly understood. Here, we show that CD8 T cells differentiate into a less exhausted TCF1highTim3low subset and a more exhausted TCF1lowTim3high subset in chronic viral infection as well as human and mouse solid tumors. The TCF1highTim3low CD8 T cells, generated early after chronic lymphocytic choriomeningitis virus (LCMV) infection, persist better and mount a far stronger secondary response than TCF1lowTim3high cells. Importantly, TCF1highTim3low cells act as progenitor cells that are capable of both self-renewal and terminally differentiating into TCF1lowTim3high cells. We have further shown that cell-intrinsic TCF1 signaling is necessary and sufficient to program these progenitors early after infection. Cell-intrinsic TCF1 deficiency led to a progressive loss of anti-viral CD4 and CD8 T cell responses during the chronic phase of infection. Several pro-exhaustion factors, including Tim3, Cish, and Blimp1, are suppressed by TCF1. Conversely, TCF1 up-regulates Bcl6, which strongly enforces the progenitor fate. Moreover, cell-intrinsic type I interferon signal suppresses the differentiation of progenitor-like CD8 T cells, and antibody-mediated blockade of IFNAR1 enhances the differentiation of these CD8 T cells in a TCF1-dependent manner. Thus, our study not only identifies a CD8 progenitor population, which is critical for long-term persistence of anti-viral CD8 responses during chronic viral infection, but also uncovers both positive and negative regulators of the early programming of this population.
Tissue-specific requirements for IL-10 in maintaining homeostasis in response to chronic virus infection
Authors: Clambey Eric T , Kimball Abigail K. , Baessler Andrew , Oko Lauren M. , Niemeyer Brian F , Van Dyk Linda F 
Published: January 2023

Abstract
Herpesviruses have co-evolved with their hosts for million of years, establishing an intimate balancing act of lifelong infection with minimal damage to the host. Interleukin (IL)-10 is a major inhibitory cytokine that has been usurped by many herpesviruses to facilitate infection. Here we tested the consequence of IL-10 deficiency on the outcome of murine gammaherpesvirus 68 (γHV68) infection, a small animal model of γHV pathogenesis. While IL-10 deficiency had minimal impact on the control of virus infection, IL-10 deficient mice showed hyper-activation of the immune response with increased levels of T cell activation, effector T cells and prolonged neutrophilia in the infected lung. IL-10 further had a non-redundant role in limiting intestinal inflammation with chronically infected mice showing a prolonged failure to thrive following infection, associated with enhanced colonic Th1 responses. CD4 T cells were a prominent source of IL10 during acute and chronic infection, with IL10+ interferon-gamma+ FoxP3- type 1 regulatory CD4 T cells as the major early source of IL10. High-dimensional mass cytometric analysis of IL10 expressing cells, and IL10 responsive cells, identified a constellation of phenotypes that correlate with robust IL10 expression, and further identified direct and indirect targets of IL10. In total, these data demonstrate the context dependent role of IL10 in constraining the antiviral host response and identify IL10-dependent and –independent regulatory pathways in regulating chronic herpesvirus infection.
This research was funded by grants from the American Heart Association, Crohn’s and Colitis Foundation of America and the UC Department of Anesthesiology (ETC).
The pursuit of better vaccines: uncovering the functional capacity of human cytomegalovirus-induced subsets of NK cells
Authors: Gyurova Ivayla E , Bernstein David , Schlums Heinrich , Bryceson Yenan , Waggoner Stephen N 
Published: January 2023

Abstract
Cytomegalovirus infection (CMV) poses a considerable burden to public health due to significant morbidity and mortality in immunocompromised patients and babies born with the infection, thus highlighting the priority of developing a successful CMV vaccine. Whereas previous CMV vaccination strategies have aimed to induce T- and B-cell responses, we speculate that natural killer (NK) cells hold the key to protective immunity based on the evidence that patients lacking NK cells suffer recurrent, severe infections with multiple herpesviruses, including CMV. Notably, CMV infections in both mice and humans triggered accumulation of unique adaptive NK-cell subsets that putatively possess enhanced effector functions against CMV. This suggests that a pioneering approach to creating an efficacious CMV vaccine would include stimulation of the accumulation and long-term maintenance of these CMV-reactive NK cells. It remains unknown, however, whether vaccines can be designed to stimulate the expansion of these NK-cell subsets. Here, using a unique set of samples collected during a CMV vaccine trial, we aim to determine whether vaccination promotes accumulation of these NK cells. Moreover, we examined the relationship between the activity of NK cells and stimulation of virus-specific T and B cell responses during immunization and in cell culture. Preliminary analysis revealed a supportive role for NK cells in stimulation of CMV-specific T cells during in vitro culture with peptide which correlates to the presence of adaptive NK cells. Our studies represent a key step in understanding the potential role of subsets of human NK cells in primary CMV infection and vaccine-induced immune responses against CMV.
IFN-γ-induced MHCII+ inflammatory monocytes play a role for down-regulating CD8 T cell responses in acute LCMV infection
Authors: Shin Kwang-Soo , Park Young-Jun , Koh Choong-Hyun , Bae Eun-Ah , Kim Il-Kyu , Song Boyeong , Seo Hyungseok , Jeon Insu , Kang Chang-Yuil 
Published: January 2023

Abstract
During viral infection, monocytes play a protective role for clearance of pathogens. However, little is known about the role of recruited monocytes after effector phase, especially as regard to their effects to T cells. Here, we have investigated the phenotypes, the origin and inducing factor, and the effects to CD8 T cells of inflammatory monocytes in virus-infected mice. During Lymphocytic choriomeningitis virus (LCMV)-Arm infection, CCR2+ inflammatory monocytes were accumulated in lymphoid organs and reached their peak at day 8 post infections. Inflammatory monocytes of infected mice expressed high levels of MHCII and low levels of CD11c, which overlap with phenotypes of DC and those of macrophage, respectively. We found that IFN-gamma (IFN-γ) is a factor that differentiates MHCII+ monocytes from BM progenitor cells. Among the BM progenitor cells, common monocyte progenitors (cMoPs) were rapidly converted to MHCII+ inflammatory monocytes in response to GM-CSF and IFN-γ in vitro. In addition, cMoPs that were adoptively transferred to infected recipients were differentiated to MHCII+ inflammatory monocytes. We also found that MHCII+ monocytes-primed CD8 T cells could not produce inflammatory cytokine and granzymeB efficiently, implicating their lowered effector functions, despite their comparable proliferative capacity to conventional DC-primed CD8 T cells. Overall, our data suggest that IFN-γ-induced MHCII+ inflammatory monocytes during acute LCMV infection would play a role in down-regulating CD8 T cell responses.
The role of Runx2 in CD8+ T cell memory during acute LCMV Armstrong infection
Authors: Schutten Elizabeth Anne , Nayar Ribhu , Saikumar Priya , Lu Yu Jung , Abramo Kristin , Berg Leslie J 
Published: January 2023

Abstract
During an acute viral infection, CD8+ T lymphocytes with T cell receptors (TCRs) specific for pathogen epitopes undergo clonal expansion and clear viral infection. After infection is cleared, the majority of the pathogen-specific CD8+ T cells undergo apoptosis, leaving a small population of memory CD8+ T cells that rapidly proliferate upon reinfection of the same antigen. How differentiation between the terminal effector cell population (TECs) and the memory cell population (MPECs) is regulated is not completely understood. Our research has focused on the role of the runt-related transcription factor Runx2 in CD8+ T cell memory formation during acute LCMV Armstrong infection. We have found using a mouse line with a T cell-specific deletion of Runx2 that loss of Runx2 leads to a defect in the formation of MPECs. We have also found that this defect is intrinsic to virus-specific CD8+ T cells. To further elucidate the upstream signaling pathways regulating Runx2 we have examined TCR signaling, cytokine signaling, and transcription factor regulation. These studies indicate that IRF4 levels inversely correlate with Runx2 expression in in vitro culture systems. We have also examined downstream pathways regulated by Runx2 in T cells, including gene expression and migration. This analysis has not revealed Runx2-dependent changes in gene expression in T cells isolated from LCMV-infected mice at D6 post-infection, nor in T cells stimulated in vitro; furthermore, we do not observe altered homing properties of Runx2-deficient T cells. Current studies are focused on examining Runx2 phosphorylation during memory CD8+ T cell differentiation. Overall, our data indicate an important role for Runx2 in CD8+ T cell memory during LCMV Armstrong infection.
Entolimod, a clinical-stage TLR5 agonist, activates antitumor T cell immunity against liver and lung metastases through distinct mechanisms
Authors: Brackett Craig M , Kojouharov Bojidar , Greene Kellee , Trageser Nicholas , Gollnick Sandra , Burdelya Lyudmila , Abrams Scott I , Gudkov Andrei 
Published: January 2023

Abstract
Innate immune modulators can generate an antitumor T cell response. However, significant toxicities associated with systemic administration have significantly limited their clinical use. The natural TLR5 agonist flagellin is unique amonginnate immune modulators because the tissue specificity of TLR5 expression induces a uniquely safe profile of cytokines following systemic TLR5 activation. Entolimod, a pharmacologically optimized flagellin derivative, was initially developed to treat and prevent acute radiation syndrome. Systemic administration of entolimod also showed antitumor effects in multiple preclinical mouse models mimicking clinically occurring liver metastasis. Entolimod suppresses liver metastasis through activation of NF-κB-, AP-1-, and STAT-3-driven immunomodulatory pathways in hepatocytes and a highly coordinated CD4+ T cell independent NK-DC-CD8+ T cell response. Although these studies characterized entolimod as a liver tropic immunotherapy, entolimod also suppresses spontaneous mammary lung metastasis. In contrast to the liver metastatic model, CD4+ T cells are required for the antitumor NK and CD8+ T cell response, indicating that the etiology of the cancer may explain the difference in the therapeutic effects ofTLR5 agonists. These results further strengthen that TLR5 agonists are a safe, effective and broadly applicable immunotherapeutic agent against metastases, which are currently a major cause of cancer-associated mortality. Recent completion of a phase I trial of entolimod in patients with advanced metastatic solid tumors has provided the rationale to test that the efficacy demonstrated in animal cancer models can be translated into immunotherapy of human tumors.
Engineering of novel Class II Transactivator gene delivery systems as molecular adjuvants to improve genetic immunotherapies by inducing de novo MHC II expression in human cells
Authors: de Lucena Palma Mariana , Duangkhae Parichat , Douradinha Bruno , Dhalia Rafael , Mailliard Robbie B , Barratt-Boyes Simon , Oshiro Telma Miyuki , de Azevedo Marques Ernesto Torres , da Silva Duarte Alberto José 
Published: January 2023

Abstract
Class II Transactivator (CIITA) induces transcription of MHC class II genes. This protein can potentially be used to improve genetic immunotherapies by converting non-immune cells into cells capable of presenting antigens to CD4+ T helper cells. However, CIITA expression is complex, tightly controlled and remains unclear whether distinct non-immune cells differ in the regulation of this transcription factor. In the present study, we describe a strategy to develop gene delivery systems capable of promoting the efficient expression of CIITA in non-immune cell lines and in primary human cells in an ex vivo skin explant model. A DNA plasmid and a lentiviral vector were produced, both carrying the human CIITA DNA sequence in silico designed to avoid cis-regulatory elements, and genetically optimized for expression efficacy in human cells. Different human cell types undergoing CIITA overexpression presented high-level de novo expression of MHC II molecules, validating the delivery systems as suitable tools for the evaluation of CIITA potential as a molecular adjuvant for genetic immunizations. Further, we directly compared different non-immune cells according to exogenous CIITA transcriptional activity, protein expression levels and proteasome degradation. Here we show for the first time that distinct types of non-immune cells differentially regulate the transcription factor, and ultimately the cell surface expression of MHC II, through a cell type-specific control of CIITA proteasomal degradation. Our findings contribute to the understanding of the CIITA post-translational regulation by non-immune cells, which can greatly influence the use of this regulator of MHC II genes as a vaccine adjuvant.
HER-2+ breast cancer cells expressing GPI-anchored cytokines induce long lasting antitumor memory response
Authors: Munoz Luis E , Bommireddy Ramireddy , Margaroli Camilla , Shafizadeh Yalda , Bozeman Erica N , Menon Ashwathi P , Kumar Jayanth , Lakshmanan Ramana , Selvaraj Periasamy 
Published: January 2023

Abstract
Breast cancer is the leading cause of death among female cancer patients. Human epidermal growth factor receptor 2 (HER-2) overexpression is associated with poor prognosis in 15–20% of breast cancer patients. Anti-HER-2 antibody (Herceptin) prolongs the survival of the HER-2+ breast cancer patients. However, resistance to Herceptin is a cause for relapse of aggressive metastatic cancer in these patients. Our earlier studies have demonstrated that PD-L1 blockade enhances the efficacy of HER-2+ breast cancer whole cell vaccine by increasing infiltration of T cells into the tumor. The goal of the present study is to determine the duration of protective anti-tumor memory response to HER-2+ breast cancer. Here, we demonstrate the beneficial effect of GPI-anchored cytokine molecules as adjuvants for generating long lasting memory response against HER-2+ as well as HER-2 negative breast cancer in syngeneic tumor models. Female BALB/c mice were challenged with D2F2/E2 (HER-2 transfected D2F2) cells or D2F2/E2 transfected with GPI-IL-12 or GPI-GM-CSF. While the wild-type challenged mice developed tumors, the mice challenged with transfected D2F2/E2 cells were protected. Protected mice were re-challenged with D2F2/E2 cells 3 months later and D2F2 cells 4 months later. All the mice challenged with D2F2 or D2F2/E2 were protected. We have observed strong antibody response against HER-2 and D2F2 cells in these mice. Our results show that long lasting protective anti-tumor memory response against D2F2 and D2F2/E2 is generated by vaccination with D2F2/E2 cells expressing GPI-anchored immunostimulatory molecules.