bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracheobronchial papillomatosis.
Authors: Somerville Lindsay Ayers Lucas 
Published: January 2023

Abstract
Recurrent respiratory papillomatosis (RRP) is a rare clinical entity characterized by squamous cell papillomas in the tracheobronchial tree. RRP is caused by human papillomavirus (HPV) 6 and 11. HPV-specific memory T cells in adults suggest most infections are asymptomatic or self-limited. However, a small subset of patients develop persistent HPV infection and invasive malignancies. RRP is observed in infants following vertical transmission and in adults in the second and third decade following sexual transmission. There is low malignant potential, although patients with smoking or radiation history, p53 mutations, or HPV-11 subtype have increased risk of transformation into squamous cell cancer.
We present a case of tracheobronchial papillomatosis in a 73-year-old man who presented with exertional dyspnea. History was notable for a laryngeal polyp resected 30 years prior. Pulmonary function testing suggested variable intrathoracic obstruction (Figure A). Computerized tomography of the chest revealed a 1.4 × 1.1 × 2.0 soft tissue mass adherent to the mid thoracic trachea (Figure B). We performed rigid bronchoscopy with laser devascularization and mechanical debridement. Pathology demonstrated well-differentiated squamous epithelium overlying fibrovascular cores (rete ridges) with elongated nuclei characteristic of squamous papillomatosis (Figure C).
The quadrivalent HPV vaccine is approved for prevention of genital warts and gynecologic malignancies caused by HPV 6, 11, 16 and 18. Vaccination could potentially reduce the prevalence of RRP by decreasing vertical and sexual transmission of HPV 6 and 11. Ongoing investigations are currently evaluating the role of vaccination in patients with preexisting RRP.
Crucial role of FOXO1 in inflationary CD8+ T-cell responses during persistent viral infection
Authors: Delpoux Arnaud , Michelini Rodrigo Hess , Verma Shilpi , Wellisch Brittney , Lai ChenYen , Benedict Chris A , Hedrick Stephen M 
Published: January 2023

Abstract
Cytomegalovirus (CMV) establish persistent infection that induce the accumulation of virus-specific T cells over time in a process called memory inflation. Although persistence of antigen (Ag) is considered essential, the molecular pathway for the inflationary T-cell development is poorly understood. Mainly, inflationary CD8 T-cells have an effector-memory phenotype (KLRG1hi CD27−), but a low percentage of them express a central-memory phenotype (KLRG1lo CD27+), which are considered as their memory precursors. To study the role of FOXO1 in CD8 T cells during a persistent viral infection, we analyzed mouse bone marrow chimeras in which FOXO1 was specifically deleted in CD8 T cells. These mice were infected with MCMV-Δm157 strain, and the expansion and phenotype of inflationary and acute-contracting T cells was examined. The results revealed that the IE3 and M38 CD8 T cell responses do not inflate in absence of FOXO1. Furthermore, with an absence of FOXO1, there were fewer Ag-specific CD8 T cells that produced both IFNγ and TNFα. Consistent with this lack of CD8 effector cells the mice were less able to control the virus in the spleen and the liver at day 6 after infection. Moreover, we found that FOXO1 KO Ag-specific CD8 T cells fail to up-regulate the memory associated transcription factors, TCF-1 and EOMES, correlating with a lower percentage of memory precursors (KLRG1lo CD27+). Finally, we found that FOXO1 KO Ag-specific CD8 T cells cycle normally (Ki67+), but display an anergic state, as measured by calcium mobilization activation, and are prone to apoptosis. Collectively, these results demonstrate an intrinsic role for FOXO1 in establishing the inflationary memory program that is essential to forming long-lived effector memory cells
Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza
Authors: Zarnitsyna Veronika I , Ellebedy Ali H , Davis Carl , Jacob Joshy , Ahmed Rafi , Antia Rustom 
Published: January 2023

Abstract
The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza’s main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stem of HA, which are attractive targets for a ‘universal vaccine’. We develop multi-epitope models to explore how pre-existing immunity modulates the immune response to new strains following immunization. Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics of OAS and limited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for how pre-existing antibodies to an epitope on HA decrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains.
Novel antitumor complexes of bispecific antibodies using ALT-803 as a scaffold demonstrate Tetra-specific binding activities
Authors: Liu Bai , Kong Lin , Noel Terra , Han Kaiping , You Lijing , Dee Michael , Rhode Peter R , Jeng Emily K , Alter Sarah , Wong Hing C 
Published: January 2023

Abstract
IL-15 and its receptor α (IL-15Ra) are co-expressed in antigen presenting cells allowing trans-presentation of IL-15 to immune cells bearing IL-2Rβγc and stimulation of effector immune responses. We have demonstrated that an IL-15 superagonist:IL-15Rα-Fc complex (ALT-803) is capable of stimulating T cell and NK cell responses. We have reported that ALT-803 could be exploited to create a functional scaffold for the design of multivalent disease-targeted complexes (Liu et al, J. Biol. Chem. 2016 291: 23869). The lead molecule based on anti-CD20 rituximab is currently in pre-clinical development. In this study, this approach was further optimized by generating an IL-15 superagonist:IL-15Rα-Fc complex (2B8T3M) comprising two anti-human CD20 scFv domains and two anti-human CD3 scFv domains. 2B8T3M molecules exhibit CD3, CD20, Fc-receptor and IL-15Rbgc tetra-specific binding activities and IL-15 bioactivity. In contrast to 2B8T2M which redirects NK cells to lyse CD20+ B-lymphoma cells (ADCC), 2B8T3M was capable of redirecting both CD8+ T cells via the anti-CD3 scFv domains and NK cells via the Fc domain against CD20+ Daudi cells. In order to investigate antitumor activities in vivo of the tetra-specific molecules in immunocompetent mouse, we have also constructed and generated mouse CD3/CD19-binding T3M complexes. Antitumor efficacy of these molecules is being assessed in mouse A20 B cell lymphoma model. These findings suggest that tetra-specific T3M complexes may serve as novel, T-cell based targeted immunotherapeutics for treating cancer.
Protective function of Calcium permeable cation channel TRPM2 during pneumoseptic Klebsiella pneumoniae infection
Authors: Sharma Jyotika , Tripathi Jitendra , Sharma Atul , Jondle Christopher Ned , Mishra Bibhuti B. 
Published: January 2023

Abstract
Calcium influx mediated by plasma membrane calcium permeable cation channels play essential role in immune homeostasis. Transient receptor potential melastatin 2 (Trpm2) is a trp superfamily member cationic channel which is reported to shape several effector functions of myeloid cells. Because of its role in neutrophil chemotaxis, we examined a yet undetermined function of Trpm2 in pathogenesis of Klebsiella pneumoniae (KPn), a causative agent of pneumonic sepsis with a significant neutrophil component. Here we show that Trpm2−/− mice exhibit significantly increased susceptibility to pulmonary KPn infection corresponding with an increased bacterial burden and exacerbated tissue pathology. This correlated with a modulation of local and systemic inflammatory response in-vivo in KPn infected Trpm2−/− mice as well as altered calcium influx, ROS generation and MAP kinase activity in Trpm2 deficient neutrophils compared with their WT counterparts. Our data suggest that Trpm2 regulates KPn pathogenesis by controlling neutrophil mediated inflammation and oxidative stress.
Combined inhibition of JAK/STAT and BCL2 during ex vivo NK cell expansion enriches a highly cytotoxic NK cell subset
Authors: Walker Kirsti Lorraine , Gavcovich Tara B , Ea Dennis , Capitini Christian M. 
Published: January 2023

Abstract
Ex vivo expansion of human NK cells with CD137L and IL-15 is being explored both preclinically and clinically as a means of increasing the number and activation of NK cells for a variety of cancers, but results to date have not shown consistent efficacy. JAK1/2 inhibition impairs NK cell maturation, activation and cytotoxicity. However, the absence or mutation of STAT1/3 molecules which are typically phosphorylated by JAK1/2 enhance NK cytotoxicity. We hypothesize that inhibition of the JAK/STAT pathway in CD137L/IL-15 activated NK cells stimulate NK cell activation and increase more potent effectors if combined with a BCL2 inhibitor. NKs were ex vivo expanded with CD137L/IL-15 for 12 days, then exposed to increasing concentrations of Ruxolitinib (0.313 – 10μM) and/or Venetoclax (6.25 – 200nM) for 24 hours before analysis. Ruxolitinib and Venetoclax enriched a CD56dim cytotoxic subset and decreased a CD56 bright cytokine-producing subset in a dose-dependent manner. Ruxolitinib alone increased CD16 and CD69 expression which indicates NK cell activation. Importantly, both drugs did not induce markers associated with senescence (CD57) or exhaustion (PD-1/Tim-3) or decrease NK cell viability. Treatment of two human T cell acute lymphoblastic leukemia (T-ALL) cell lines with 1.25μM Ruxolitinib and 25nM Venetoclax decreased proliferation and increased apoptosis of T-ALL cells in a synergistic manner (CI&lt;1; p&lt;0.001). Usage of Ruxolitinib and Venetoclax has implications on both the biology of ex vivo activated NK cells and T-ALL, and may be a novel pharmacologic combination for improving adoptive cell therapy of leukemia.
Mouse Models for Immunology Research available from The Jackson Laboratory Repository
Authors: Valenzuela Alicia , Fancher Karen , Lutz Cat , Rockwood Stephen 
Published: January 2023

Abstract
The Jackson Laboratory Repository serves as a centralized facility for the development, distribution and cryopreservation of mouse models of human biology and disease. Hundreds of new strains are added annually to one of the largest collections of characterized mouse strains available.
Our newest strains carry genes associated with T lymphocyte regulation and development. T cells from the Fyb (ADAP) knockout (KO) exhibit impaired proliferation and TCR-mediated adhesion. T cells from the Cd27 KO have a diminished viral response and a delayed memory cell response. A conditional KO of Kdm6b (Jmjd3), a histone demethylase, results in altered T cell differentiation. Finally, conditional expression of an HA-tagged mutant human transcription factor, FOXO, is associated with regulatory T cell function.
Mice carrying the Ifnar1 (interferon αβ receptor 1) KO allele have a reduced immune response and increased susceptibility to viral infection. The Ifnar1 KO, combined with the Ifngr1 (interferon γ receptor 1) KO allele provide a model for Zika virus (and other viruses) pathogenesis.
New tool strains include two conditional GFP knockin reporters, one in Spic, a transcription factor expressed in macrophages, and the second in Ebf1, a transcription factor involved in B cell development. A knockin to Zbtb46, a zinc finger transcription factor, expresses Cre recombinase in classical dendritic cells.
Donating a strain to the Repository fulfills the NIH’s requirements for sharing mice. Researchers wishing to have strains considered for inclusion in the Repository are encouraged to submit their strains: www.jax.org/donate-a-mouse.
This work is supported by NIH, HHMI, and several private charitable foundations.
MicroRNA-155 regulates T-bet expression in anti-viral CD8+ T cells
Authors: Hope Jennifer L , Stairiker Christopher , Spantidea Panagiota , Gracias Donald Tom , Carey Alison J , van Meurs Marjan , Brouwers-Haspels Inge , Fike Adam J , Rijsbergen Laurine , Mueller Yvonne M , Fraietta Joseph A , Klop Roos , Erkeland Stefan , Katsikis Peter D 
Published: January 2023

Abstract
MicroRNAs (miRNAs) are small, single-stranded non-coding RNAs that play essential roles in regulating key cellular processes, and are highly conserved across species. miRNA are known to regulate immune cells and play an important role in effective CD8+ T cell (CTL) responses to viral infection and tumors. To understand the role of miRNA in CTL responses we performed microarray miRNA expression profiling and identified unique in vivo expression patterns of miRNAs in naïve and effector anti-viral CTL. In particular, miR-155, which we and others previously have demonstrated to regulate CTL responses, was significantly upregulated in effector CTL. We show that further increasing the levels of miR-155 by retroviral overexpression significantly augments anti-viral effector CTL and skews memory CD8+ T cells towards an effector memory phenotype. MiR-155 overexpression resulted in enhanced T-bet expression, which is known to be required for effector CTL and to promote effector memory cell formation. MiR-155 overexpression-induced T-bet expression was required for miR-155 mediated increases in effector CTL. Our studies have revealed an important and unexpected link between miR-155 and T-bet transcription factor in the context of in vivo CTL responses.
Combating Antibody-dependent Enhancement of Dengue Viral infection in Peripheral Blood Monocytes by NK Cell-mediated Antibody Dependent Cell Cytotoxicity
Authors: Sun P , Williams Maya , Nagabhushana Nishith , Morrison Brian J 
Published: January 2023

Abstract

Background
The dengue virus (DENV) group is composed of 4 serotypes, DENV-1, -2, -3 and -4. The 4 serotypes of DENV share70% sequence homology, therefore cross-reactivity among 4 serotypes is common. Cross-reactive antibodies (Ab) can cause Ab-dependent enhancement (ADE) of viral infection. ADE is thought to be an underlying mechanism of elevated immune-pathology associated with severe dengue diseases. Human monocytes and macrophages are target cells for ADE. This study investigates NK cell-mediated Ab-dependent cell cytotoxicity (ADCC) as a critical control mechanism following an established ADE intracellularly.

Methods
To model the physiological situation, whole human PBMCs were infected with DENV in the presence of autologous serially diluted sera. ADE in monocytes was detected by intracellular staining of viral antigens and by RT-PCR. NK cell activation was monitored in the same cultures by a degranulation marker CD107a. Other NK cell markers, cell proliferation and cytokine/chemokines were investigated.

Results
ADE was only detected in monocytes with the serially diluted immune sera. NK cell activation occurred concomitantly with the detection of ADE. The peak of the ADCC response was 48 hours post infection, but the response was still detectable at day 7. Minimal activation of T cells was observed. The power of ADE in monocytes ranged between 3 to 10.2 folds when NK cells were depleted as compared to 0.6 to 1.8 folds under normal condition. Activated NK cells had elevated expression of CD69, CD335, CD336, and CD96, but had downregulated CD337 and CD314.

Conclusion
ADCC is activated when DENV escapes from Ab neutralization and establishes infection in host cells, and it can act as the first line of defense to combat ADE.
Anti-spike IgG exacerbates lung injury by skewing monocyte-macrophage responses during SARS-CoV infection
Authors: Liu Li , Wang Haibo , Wei Qiang , Tang Hangying , Nishiura Kenji , Kwok Hauyee , Peng Jie , Alvarez Xavier , Lackner Andrew , Chen Zhiwei 
Published: January 2023

Abstract
Deceased SARS patients displayed severe acute lung injury (ALI) with exuberant inflammatory responses yet faster neutralizing IgG development. The mechanism underlying this discrepancy remains elusive. Here, we combine vaccination and passive immunization strategies to determine whether anti-spike (S) IgG modulates SARS-CoV-mediated lung injury in Chinese rhesus macaques. We found that macaques pre-vaccinated with MVA-S displayed more severe lung injury compared with MVA-vaccinated controls after SARS-CoV challenge. Moreover, passive immunization of purified anti-spike IgG but not control IgG resulted dose-dependently in enhanced lung infection and severer lung injury, associated with prolonged responses of pro-inflammatory alveolar MAC387+ and CD163+TGF-b− macrophages, IL-6 production and delayed wound-healing CD163+TGF-b+ macrophages response. Consistently, accumulated pro-inflammatory CD163+TGF-b− macrophages were found in lungs of deceased SARS patients. Our results demonstrated that anti-spike IgG exacerbates lung injury likely by enhancing infection and skewed alveolar monocyte-macrophage responses, which may have significant implications to CoV-mediated pathogenesis and immunotherapy.
Efficient control of chronic LCMV infection by CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model
Authors: He Ran 
Published: January 2023

Abstract
CD4+ T cells are essential for sustaining CD8+ T cell responses during chronic infection. The adoptive transfer of virus-specific CD4+ T cells has been shown to efficiently rescue exhausted CD8+ T cells. However, the question of whether endogenous virus-specific CD4+ T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8+ T cells remains unexplored. In this study, we developed a CD4+ T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We primed chronically LCMV-infected mice with the Listeria monocytogenes vector expressing the LCMV glycoprotein-specific I-Ab-restricted CD4+ T cell epitope GP61-80 (LM-GP61) and subsequently boosted the primed mice with an influenza virus A (PR8 strain) vector expressing the same CD4+ T cell epitope (IAV-GP61). This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4+ T cell responses, which further improved both the quantity and quality of the virus-specific CD8+ T cells and led to better control of viral loads. The combination of this strategy and the blockade of the programmed cell death-1 (PD-1) inhibitory pathway further enhanced anti-viral CD8+ T cell responses and viral clearance. Therefore, heterologous prime-boost immunization that selectively induces virus-specific CD4+ T cell responses in conjunction with inhibitory pathway blockade may represent a promising therapeutic approach to treating patients with chronic viral infection.
A subset of NK1.1+ follicular helper CD4+ T cells promotes early extrafollicular plasmablast production during Plasmodium yoelii infection
Authors: Stumhofer Jason Scott , Wikenheiser Daniel J 
Published: January 2023

Abstract
Early plasmablast induction is a hallmark of Plasmodium infection, including P. yoelii, and is thought to be essential for control of acute parasite burden. Although long understood to be a T-cell dependent phenomenon, control of early plasmablast differentiation in response to Plasmodium is poorly understood. Here, we identify a subset of CD4+ T cells that express the innate NK cell marker NK1.1 as being critical for early plasmablast and parasite-specific Ab production. Interestingly, NK1.1+ CD4+ T cells arise from conventional, naive NK1.1− CD4+ T cells and their induction is independent of CD1d but critically reliant on MHC-II. Early NK1.1+ CD4+ T cells express more ICOS than conventional (NK1.1−) CD4+ T cells and subsequently expand more rapidly and give rise to PD-1high follicular helper T (Tfh) cells more frequently than conventional CD4+ T cells. Further study of this population revealed that NK1.1+ Tfh cells are more likely to be complexed with plasmablasts than conventional Tfh cells. Moreover, NK1.1+ Tfh cells interact almost exclusively with PD-L1high plasmablasts and more readily express markers indicative of apoptosis than conventional Tfh cells. Ultimately, depletion of NK1.1+ cells significantly impairs class-switched parasite-specific antibody production during early P. yoelii infection. Together, these data suggest NK1.1+ Tfh cells are essential for driving early plasmablast induction during Plasmodium infection and may represent a unique Tfh cell subset whose modulation could promote effective vaccine design.
IL-15 complex-stimulated NK cells protect mice from cerebral malaria
Authors: Burrack Kristina Stoermer , Huggins Matthew A , Hart Geoffrey T , Johnson Aaron J , Jameson Stephen C , Hamilton Sara E 
Published: January 2023

Abstract
Cerebral malaria (CM) is one of the most lethal complications of Plasmodium falciparum infection, responsible for a large fraction of the nearly 500,000 malaria-related deaths annually. In the experimental mouse model of CM (ECM), mice are inoculated with red blood cells infected with Plasmodium berghei ANKA (PbA) parasites and develop a CM-like disease within 6–10 days post-infection (dpi) resulting from CD8 T cell-mediated damage to the CNS. We found that treatment of C57Bl/6 mice with interleukin (IL)-15 complexes (IL-15C; IL-15 bound to an IL-15Rα-Fc fusion protein) prevented the development of PbA-induced ECM. IL-15C treatment stimulates natural killer (NK) and CD8 T cells. Interestingly, adoptive transfer of IL-15C-stimulated NK cells, but not CD8 T cells, prevented ECM. Similar complexes formed with IL-2 (IL-2C; IL-2 bound to the anti-IL-2 S4B6 antibody) also induce robust expansion and activation of NK cells, but fail to protect against ECM. Rescue from ECM was not associated with reduced parasitemia at 6 dpi. Instead, IL-15C treatment resulted in reduced CD8 T cell activation in the brain at 6 dpi and reduced blood brain barrier breakdown. Moreover, we found that in vivo IL-15C, but not IL-2C, treatment of mice induces IL-10 expression in NK cells, and that IL-10 is required for IL-15C-mediated protection from ECM. These data indicate that NK cells – which are typically involved in promoting inflammatory responses – can also restrain damaging immune responses, and that differences between the activation of NK cells by IL-2C and IL-15C regulates their capacity to control the inflammatory response to blood stage malaria infection.