bluuebunny/crossref_metadata_2025_split huggingface dataset:
Notch driven mTORC1 signaling enables rapid, division-independent plasma cell division in marginal zone B cells
Authors: Gaudette Brian T. , Roman Carly , Atria Daniela Gomez , Siebel Christian W. , Maillard Ivan , Allman David 
Published: February 2023

Abstract
Lymphocyte differentiation is often tightly linked to mitosis. Clonal bursts due to antigen- or TLR-driven responses increase numbers of responding cells and may also facilitate changes in gene expression and chromatin needed for effector cell differentiation. Alternatively, to guard against rapid infection, lymphocyte pools may also contain cells poised for effector differentiation with minimal proliferation. Since marginal zone (MZ) B cells, which have increased basal mTORC1 activity and c-Myc expression, reside in the marginal sinus of the spleen where they are positioned to respond rapidly to blood borne microbes, we compared their ability to produce plasma cells (PC) with that of follicular B cells in an ex-vivo stimulation assay. We found that MZ B cells are able to produce PCs rapidly and independently of cell division whether exposed to cell cycle inhibitors or with genetic ablation of Cdk1. Furthermore, we found that blockade of Notch signaling rapidly down-regulated c-Myc-driven gene expression and mTORC1 activity in MZ B cells and caused them to adopt differentiation kinetics similar to follicular B cells. Genetic ablation of c-Myc further emphasized the uncoupling of cell division and differentiation in MZ B cells. Whereas acute loss of c-Myc blocked all cell division in ex-vivo stimulation assays, PC differentiation was only blocked with prolonged loss of c-Myc. Finally, using genetic ablation of Tsc1 to disinhibit mTORC1 signaling, we conferred both rapid and division-independent plasma cell differentiation to follicular B cells. These data illustrate that ongoing Notch signaling through c-Myc and mTORC1 allow for rapid division-independent antibody responses in MZ B cells.
Role of the Notch-TRIB2 axis in CD8+ T cell differentiation
Authors: Le Corre Laure , Boulet Salix , De Sousa Dave Maurice , Labrecque Nathalie 
Published: February 2023

Abstract
Following activation, naïve CD8+ T cells expand and differentiate into two effector subpopulations: short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). After the effector response has taken place, SLECs undergo apoptosis, while MPECs mature into memory T cells that protect against reinfection. Notch, a highly conserved pathway, was shown to control SLEC differentiation. Our transcriptomic analysis has revealed that Notch signalling controls the transcription of a large number of genes in activated CD8+ T cells. Among them is Trib2, coding for the pseudokinase Tribbles homolog 2. TRIB2 was reported to activate AKT in some tumour cell lines while Notch-deficient CD8+ T cells show decreased AKT activation, suggesting that Notch transcriptional induction of Trib2 might be important to properly activate AKT and promote SLEC differentiation. Therefore, we hypothesize that induction of TRIB2 expression by Notch signalling promotes SLEC differentiation through AKT activation. To test this, we overexpressed TRIB2 in Notch1–2 deficient CD8+ T cells using retroviral transduction and followed their differentiation after their adoptive transfer into Listeria infected mice. Our results show that overexpression of TRIB2 partially restores SLEC generation in absence of Notch. In conclusion, we uncovered that TRIB2 promotes SLEC differentiation through the Notch pathway. These findings provide a better understanding of the molecular events controlling the differentiation of SLECs, a cell type essential for the elimination of infected cells and cancer.
Regulatory T cell suppressive capacity is governed by synergistic Foxp3 enhancers
Authors: Feng Yongqiang , Zong Xinying 
Published: February 2023

Abstract
Regulatory T (Treg) cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How robust Treg function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3 known as distinct modules promoting Treg cell induction or lineage stability. Their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms of the Foxp3 gene determining Treg suppressive capacity uncertain. Therefore, we examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction and stability through distinct modes. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers acting in a stage-specific manner, improving our understanding of the genetic determinants of Treg suppressive capacity.
Myosin specific TRM cells mediate increased severity of immune checkpoint inhibitor myocarditis
Authors: Kalinoski Hannah Maryam , Won Taejoon , Rusinkevich Vitali , Talor Monica V , Hughes David M , Wood Megan K , Hooper Jody E , Cihakova Daniela 
Published: February 2023

Abstract
Immune checkpoint blockade has revolutionized the field of cancer immunotherapy; however, it has been also associated with immune-related adverse events (IRAE). Immune checkpoint inhibitor (ICI)-myocarditis occurs in approximately 1% of patients, however, it has a high fatality rate of up to 50%. To prevent life-threatening toxicities, it is imperative to understand what predisposes patients to ICI-myocarditis. We examined if previous cardiac injury increases an individual’s susceptibility to develop ICI-myocarditis. We demonstrated that ischemic injury substantially changes the phenotype of cardiac lymphocytes, causing them to upregulate the well-characterized tissue resident markers such as CD69 and CD103. We were excited to find that these cardiac tissue resident T (TRM) cells express prominent levels of the checkpoint molecule PD-1 and have high TCR specificity for cardiac myosin. TRM cells have been described in the literature to establish residency in non-lymphoid organs where they provide a rapid functional response more efficiently than circulating memory T cells. To investigate the role that cardiac TRM cells play in the occurrence of ICI-myocarditis, we developed a novel two-hit model. In this model cardiac injury is induced through ischemic injury (first hit), mice are allowed to recover before we begin the administration of immune checkpoint antibodies (second hit). Our data suggest that after the administration of PD-1 blocking antibodies, mice with myosin specific TRM cells are more susceptible to ICI-myocarditis. Further characterization of cardiac TRM cells could provide insight into why checkpoint mediated cardiac toxicities are particularly rapid and have high fatality rates.
Non-agonist peptide-MHC engagement triggers TCR proximal signaling distinct from agonists.
Authors: Wolf Gideon S , Singh Nevil J , Douek Daniel C 
Published: February 2023

Abstract
The maintenance of naïve and memory T cell populations, is regulated by signals from cytokines including IL-7 as well as those ensuing from the tonic TCR recognition of endogenous peptide-MHC (pMHC) complexes. These TCR signals are thought to be distinct from typical agonist antigen-driven signals, but the precise biochemistry is poorly understood. In mice, the 5C.C7 TCR transgenic model has well characterized interactions with agonist and non-agonist foreign and self-peptides, respectively. Using these cells, we find that agonist pMHC engagement elicits strong phosphorylation of ERK, actin polymerization, increase of cell size as well as upregulation of surface markers such as CD69. Interestingly, co-culturing 5C.C7 T cells with both the agonist and non-agonist pMHC complexes amplifies these phenotypes of T cell activation when compared to the agonist alone. Additionally, we found that endogenous peptides alone do not directly elicit these downstream cellular responses. In contrast, examination of more TCR proximal signaling suggests that endogenous peptide engagement results in strong LAT phosphorylation comparable to levels triggered by the agonist. These non-agonist-induced phosphorylated LAT levels were present from 30 minutes until 4 hours at a relatively sustained level, compared to the synergistic effects of the downstream signaling (pERK, CD69, etc) which only began to emerge at the 2 hour time point and onwards. These data suggest that TCR signaling after engaging with endogenous self-peptides is uncoupled from agonistic signaling at the level of LAT. This bifurcation may allow T cells to use agonist vs non-agonistic signals for distinct biologic outcomes.
Moderate Malnutrition exacerbates Plasmodium chabaudi induced gut leakage and reduced mucosal Innate Immunity in mice
Authors: Murr Noah Joseph , Olender Tyler , Smith Amari , Opata Michael M. 
Published: February 2023

Abstract
Gastrointestinal problems are among the most reported symptoms in serious cases of malaria infection. While many pathophysiologies including gastric mucosal changes have been reported in serious cases of malaria infection, the influence of moderate malnutrition, common in malaria endemic areas, has not been well explored. Here, we used a rodent mouse model to investigate how moderate malnutrition affects gut integrity and mucosal innate immunity during malaria. Utilizing a well-established low protein diet that is deficient in zinc and iron to induce moderate malnutrition, we investigated mucosal tissue phenotype and integrity, and mucosal innate immunity in the gut. We observed that the infected moderate malnourished mice had lower parasite burden at the peak of infection, but high levels of FITC-Dextran concentration in the blood serum, indicating increased intestinal permeability. The small intestines in the moderate malnourished mice were also shorter after infection with malaria. This was accompanied with lower numbers of CD11b+macrophages, CD11b+CD11c+ myeloid cells, and CD11c+ dendritic cells in the small and large intestines. Despite the lower number of innate immune cells, macrophages in the malnourished mice were highly activated as determined by MHCII expression. Thus, our data suggests that malaria infection may exacerbate the deformities in the gut induced by moderate malnutrition.
Re-thinking the Plasmodium mouse model: using wild derived mice to interrogate asymptomatic malaria
Authors: Cornwall Douglas , Srey Mellina , Maloba Franklin , Evavold Birk , Olatunde Adesola , Jensen Anne , Lamb Tracey J , Evavold Brian D 
Published: February 2023

Abstract
Malaria is a major world health issue, with over 200 million clinical cases per year that lead to over 200,000 deaths. Though there have been advances in treatment and control of malaria in symptomatic patients, nearly 60–75% of Plasmodium infections are asymptomatic (no overt symptoms), leading to a large proportion of ignored infections that have a large influence on transmission. However, the term asymptomatic is misleading, as many of these individuals display evidence of mild anemia and vascular activation, leading to a higher risk for co-morbidities such as infection with typhoidal Salmonella. Unfortunately, the immunological mechanisms governing the asymptomatic phenotype are poorly understood, partially due to a lack of reliable immunologically intact asymptomatic animal models. Here, we utilize a unique genetically diverse wild-derived mouse model to address the immunological underpinnings of asymptomatic malaria. This model allows us to disentangle the relative roles of the genetics and environment in the generation of immune responses to Plasmodium infections. Results show the wild-derived mice have varying levels of anemia associated with Plasmodium yoelii XNL infection, with some mice exhibiting an asymptomatic phenotype with mild anemia independent of parasitemia. Anemia levels positively correlate with the production of TNF-a and IL-10, which is consistent with patterns seen in children in Cameroon. Furthermore, the CD4 T cells producing IL-10 and IFN-g were also correlated with the severity of anemia, also a pattern seen in human malaria. These results demonstrate that the wild-derived mice can be used to model asymptomatic malaria and allow us to interrogate the immune mechanisms leading to anemia.
Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling on intestinal epithelial cells
Authors: El-Naccache Darine W. , Chen Fei , Palma Mark J , Lemenze Alexander , Wu Wenhui , Mishra Pankaj Kumar , Eltzschig Holger , Robson Simon C. , Di Virgilio Francesco , Hasko George , Gause William C 
Published: February 2023

Abstract
Intestinal nematode infections trigger potent type 2 immune responses, although the mechanisms that initiate these host protective responses against multicellular parasites remain uncertain. We have previously reported that A2BAR deficient mice (A2BAR−/−) have an impaired type 2 immune response and delayed helminth expulsion during Heligmosomoides polygyrus bakeri (Hpb) infection. However, the cell types expressing A2BAR receptors that participate in this initiation and how the adenosine-A2BAR axis drives memory type 2 immune responses in helminth infections remains unknown. We now report that mice lacking A2BAR specifically on intestinal epithelial cells (VillinCre-A2BARfl/fl), but not on myeloid cells (LysMCre-A2BARfl/fl) show increased worm metabolism and delayed worm expulsion after Hpb secondary inoculation. We further show, the transfer of Hpb primed CD4+ T cells from WT but not from VillinCre-A2BARfl/fl can rescue the impaired immune response in recipient VillinCre-A2BARfl/fl mice. Moreover, the transfer of Hpb primed CD4+ T cells from WT but not from IL-4−/− mice into IL-4−/− mice rescued the protective memory type 2 immune response. During the primary response, type 2 immunity was dependent on epithelial A2BAR signaling as early as 24 hours after inoculation and was associated with marked increases in eATP production. Furthermore, mice lacking CD39 exhibited similarly impaired type 2 immunity to Hpb, indicating that extracellular ATP is metabolized to adenosine, which then acts as an essential endogenous danger signal. Our data thus demonstrate a key role for intestinal epithelial cell-specific A2BAR signaling in the development of host protective CD4+ IL-4 expressing memory T cells during helminth infection.
Understanding the role of peptidoglycan and associated protein NapA in Lyme disease pathogenesis
Authors: McClune Mecaila E. , Davis Mari , Jutras Brandon 
Published: February 2023

Abstract
Lyme disease is the most common vector-borne illness in the United States with 400,000 estimated new cases annually. Borrelia burgdorferi (Bb), the causative agent, causes severe clinical manifestations, but lacks classical virulence factors. The primary cause for patient symptomology is unknown. Peptidoglycan (PG) serves as both a protective barrier from osmotic pressure and a pathogen associated molecular pattern (PAMP). In diderms, this structure resides between the outer and inner membrane. Bb is an atypical Gram-negative bacterium. It contains L-ornithine in its PG peptide stem and lacks a PG recycling pathway. The collective results are an atypical pathogen that sheds unusual PG fragments into its extracellular environment.
We have recently shown that these PG fragments reside in the human host, well after acute infection in Lyme arthritis patients. Also, when injected into a mouse, Bb PG is capable of causing acute arthritis that mimics that of Lyme arthritis. Here, we probed the pathogenic properties of Bb PG chemistry. Comparative RNA-seq analysis from human PBMCs stimulated with PG fragments isolated from different bacteria demonstrate a surprising and unique immunological response that appears to be dictated by the chemical features unique to Bb PG.
We also provide evidence that Bb PG is not alone in eliciting this unique response. Our recent, unpublished studies show that NapA— Neutrophil Attracting Protein A— is physically linked to Bb PG and contributes to this atypical PG response. Using molecular and cellular studies, including a novel microfluidic chamber, we show that the unique PG-NapA linkage augments the production of IL-17 and recruits the frontline of the innate immune system in response towards this unusual PAMP.
Age-associated defects in the adaptive immune response to Clostridium difficile infection impair the development of a protective immune response in the elderly
Authors: Bell Matthew , Bernui Mariana , Shah Neev , Kutzler Michele A. 
Published: February 2023

Abstract
Clostridium difficile is the number one cause of healthcare-associated infection in the United States and the most lethal acute enteric pathogen. The elderly (≥65) have the greatest risk of C. difficile infection (CDI) and severe morbidity and mortality due to CDI. Additionally, most recurrent CDIs occur within the elderly. To better understand why the elderly are at greater risk of severe and recurrent CDI, our lab has conducted a longitudinal study of the aging immune response to primary and recurrent CDI in patients at Hahnemann University Hospital. Both elderly and young CDI patients were enrolled in the study, and stool and blood samples were collected at enrollment and 12 days after diagnosis of CDI. Analysis of the samples looking at the humoral response in elderly versus young CDI patients shows that the early humoral response in elderly patients is impaired when compared to young CDI patients. In addition, recurrent CDI patients have similarly defective humoral responses. Finally, preliminary work in an aging mouse model of CDI further supports that age-related defects within the adaptive immune response impair the development of a protective immune response. Since the adaptive immune response to CDI plays an important role in neutralizing toxins produced by C. difficile, an impaired humoral response in both aged and recurrent CDI patients may contribute to the increased risk of infection, morbidity, and mortality observed in elderly patients. Future studies will seek to further characterize the aging immune response using patient samples as well as aging mouse models of CDI.
IL-17A or IL-17F is sufficient to maintain innate response and control of H. pylori immunopathogenesis
Authors: Algood Holly Marie Scott , Dixon Beverly R.E.A. , Lee Tiffany J , Piazuelo M. Blanca 
Published: February 2023

Abstract
Interleukin-17 receptor (IL-17R) signaling is required for control of many extracellular pathogens due to its impact on neutrophil recruitment and antimicrobial responses. Infection with the extracellular pathogen Helicobacter pylori results in Th1 and Th17 cell activation and a chronic inflammatory process which can lead to adverse outcomes such as gastric cancer. Previously, we identified IL-17RA as a requirement for the recruitment of neutrophils. Surprisingly, H. pylori infected IL-17RA−/− mice had significantly more chronic inflammation than H. pylori infected WT mice. In the current study, in vitro human epithelial cell cultures and in vivo mouse models were used to investigate differential roles for IL-17A, IL-17F and IL-17A/F during H. pylori infection. The data indicate generally that epithelial cells responded to IL-17A or IL-17A/F better than IL-17F. Increased gene expression of some factors, such as Cxcl8, required a co-stimulus such as H. pylori, TNF or IL-22 in epithelial cells, but expression of Pigr and Nox1 were induced by IL-17A alone. In vivo deficiencies of IL-17A or IL-17F alone did not significantly change the immunopathological response to H. pylori, but if both cytokines were absent, a hyperinflammatory lymphocytic response developed similar to what was observed in IL-17RA−/− mice. These data imply that IL-17A and IL-17F may have some overlapping role or compensatory roles in maintenance of the gastric mucosal response to infection which is required for preventing immunopathology.
Impulse oscillometry system as a new diagnostic tool in patients with chronic obstructive pulmonary disease
Authors: Elzahapy Nehal A. , Sharshar Ragia S. , Mohamed Ahmed S. , El-Shimy Wafaa S. 
Published: February 2023

Background
Both diagnosis and assessment of chronic obstructive pulmonary disease (COPD) are based mainly on pulmonary-function tests that are of very important significance in COPD. Impulse oscillometry is a noneffort-dependent method to assess the mechanical structure of the respiratory system.

Objectives
The study aims to evaluate impulse oscillometry system (IOS) as a diagnosis tool of COPD, in a trial to clarify the sensitivity and correlations of IOS parameters with COPD severity.

Patients and methods
The study included 30 healthy volunteers, group I (control group): 15 smokers, 15 nonsmokers, and 60 patients with COPD, group II: 30 patients with mild-to-moderate COPD, and group III: 30 patients with severe COPD. All participants were sequentially assessed by IOS to detect impedance, after this, spirometry was done, and both were repeated 15–45 min after the first dose of inhalation therapy (salbutamol). IOS is more sensitive in detecting small-airway affection in mild-to-moderate COPD than spirometry.

Results
In COPD, a significant increase in IOS-resistant parameters (R5, R5–20), reactance parameter (AX), and a decrease in reactance (X5) parameter was observed in two groups of COPD (groups II and III) if compared with control group I. IOS parameters significantly correlated with spirometric parameters, particularly large-airway parameters (R5 correlated with forced expiratory volume in the first second postbronchodilator in group II and group III), small-airway parameters (R5–20, X5, and AX correlated with maximal mid-expiratory flow postbronchodilator in group III).

Conclusions
IOS is very useful in detecting small-airway affection in mild and moderate COPD and could be done as an alternative to spirometric tests in severe COPD patients with more accurate grading.