bluuebunny/crossref_metadata_2025_split huggingface dataset:
T lymphocytes characterization and systemic inflammation after hypoxic ischemia in naturel-resuscitation newborn rats
Authors: Shen Chao-Bin , Gu Yan-Ni , Yu Lan , Wang Li-Min 
Published: January 2023

Abstract

Background
Perinatal hypoxia-ischemia (HI) remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as cerebral palsy of children. In this study we performed investigations of systemic inflammatory cytokines from peripheral blood and T lymphocytes and CD11b+ cells from spleen tissue at acute stage after self-recovery neonatal HI brain injury in rats.

Methods
HI was induced in 4-day old rat and specimen was collected up to 14 days natural resuscitation to investigate expression of immune associated with cell-markers, CD3, CD4, CD8 and CD11b, and multiple inflammation cytokines (IL-1β, IL-6, TNF-α, L-8 and IL-10). We assessed quantity changes of T cell populations and CD11b from the spleen by flow cytometry. We measured cytokines concentration from peripheral blood by ELISA after recovery HI rats.

Results
At 14d after recovery HI rats, FACS analysis showed a marked decrease in the number of CD3, CD4 and CD8 (p&lt;0.001), CD11b+ cells was no relative increase of (p = 0.14). IL-1β, IL-6 and TNF-α was higher than control group in peripheral blood (p=0.0012, 0.001 and 0.003 respectively) and IL-8 and IL-10 were lower than control group (p=0.0042 and 0.018 respectively).

CONCLUSIONS/SIGNIFICANCE
Our findings demonstrate inhibition of systemic immune responses is changes in self-recovery stage after hypoxic ischemic neonatal. The short term immune inhibition observed is of general importance for future studies of the immune response after hypoxic-ischemia as most previous studies have focused on the first few days after damage, while the effects of the late immunocompromise may be remain existed.
Homeostatic maintenance of human T cells in bioengineered secondary lymphoid organoids – a model for studying age-related immune decline
Authors: Gustafson Claire Ellen , Lambert Simon , Weyand Cornelia M , Goronzy Jorg J 
Published: January 2023

Abstract
During aging, homeostatic maintenance of naïve T cells in secondary lymphoid tissues (SLT) is lost, leading to reduced cell numbers, a loss of stem-like properties and partial differentiation. The underlying mechanisms that drive these changes are unclear. Moreover, mechanistic studies in humans are currently limited by poor T cell homeostasis in standard in vitro culture and in humanized mice. Thus, we sought to develop a robust culture system mimicking SLT that maintains human T cell survival and homeostasis. In our system, we encapsulate human T cells into a bioengineered matrix containing primary fibroblastic reticular cells (FRC), which are stromal cells that support T cell homeostasis within SLT in vivo. Within these SLT-like organoids, resting naïve T cells from young donors exhibited significantly higher viability and dramatically longer survival times (&gt; 3 weeks) compared with two-dimensional (2D) T cell-FRC cultures. Survival was not driven by T cell receptor activation or proliferation. Moreover, naïve T cells maintained a quiescent-like phenotype (CD45RAhighCD27high), which is a phenotype preferentially lost by naïve T cells in 2D culture as well as during aging. Using small molecule screening, we found that inhibition of adenosine receptor signaling caused naïve T cells to break quiescence and acquire a partially differentiated phenotype (CD45RAlow) similar to that of naïve T cells from older individuals. As old naïve T cells expressed similar levels of adenosine receptors as young, these data suggest that the loss of adenosine within SLT may contribute to immune aging. Thus, we have developed a new, malleable model system that allows for mechanistic investigation into human T cell homeostasis and the effects of aging.
The role of ERK2 in regulating germinal center B cell fate decisions
Authors: Negron Austin Joseph , Jeffreys Sean , Abdul-Baki Nawal , Perez Rebecca , Perez Christina , Forsthuber Thomas G 
Published: January 2023

Abstract
The regulation of B cell activation, differentiation, and survival is a crucial control point for the maintenance of B cell tolerance in the germinal center (GC) and involves the precise coordination of several complex intracellular signaling pathways. Dysregulation of these pathways can lead to the generation and persistence of autoreactive memory B cells and antibody-secreting cells (ASCs), resulting in autoimmune disease. The mitogen-activated protein kinase (MAPK) pathway is central to signals required for GC B cell selection and differentiation, such as those received through the B cell receptor (BCR) and C-X-C chemokine receptor type 4 (CXCR4), respectively. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), important effectors of this pathway, play a major role in B cell activation and differentiation. Though ERK2 specifically regulates the pro-apoptotic protein, Bmf, its role in regulating GC B cell fate is unknown. Our lab has developed a mouse model in which the deletion of Erk2 is accompanied by the expression of the fluorescent reporter protein, eYFP, allowing us to identify and isolate viable Erk2Δ B cells using flow cytometry. Preliminary data using this model has shown that peripheral Erk2Δ B cells express DEC205, which is associated with follicular T helper cell interactions and CD80, which is involved in co-stimulation and immunoglobulin class switching. Thus, we hypothesize that ERK2 regulates several aspects of GC B cell selection. Our results will help elucidate the molecular mechanisms underlying B cell differentiation, potentially offering new approaches to treating B cell-driven autoimmune diseases.
Utilization of Stable Isotope Tail-Vein Infusion to Assess Glutamine Utilization by Physiologically Activated CD8+ T cells in vivo
Authors: Ma Eric H , Verway Mark J , Roy Dominic G , Steadman Mya , Griss Takla , Sambroska Bozena , Chubukov Victor , Roddy Thomas P , Jones Russell G 
Published: January 2023

Abstract
Metabolic reprogramming is an essential part of the T cell activation program. Upon activation, T cells undergo dramatic rewiring of their metabolic pathways to promote ATP production and biosynthesis sufficient to support the rapid exponential growth of antigen-specific T cells. The metabolic profile of T cells is shaped by both cell-intrinsic factors, such as genetics and receptor-mediated signaling, and environmental conditions, such as nutrient availability. However, our understanding of T cell metabolism has largely been shaped by studies in vitro, where oxygen and nutrients are in excess. Here, we combined bioenergetic profiling and 13C-glutamine infusion techniques to investigate the metabolism of CD8+ T cells responding to Listeria infection. Similar to in vitro-activated T cells, glutamine is a prominent source of fuel for the TCA cycle during early expansion (3 dpi). However, at later timepoints of infection (6 dpi), the use of glutamine is substantially decreased by Teff cells. Similar to the observation of decreased glucose usage by T cells over the course of infection (Ma et al Immunity 2019). Our data suggests a dynamic flexibly in nutrient usage by T cells in vivo to fuel the different phases of T cell functions, from the early T cell response (3 dpi) to the late (6 dpi). Our work highlights the differences in T cell metabolism in vivo compared to in vitro cultures and a new method to study T cell nutrient utilization in vivo.
Integrative characterization of the coding and non-coding transcriptome in human memory B cells
Authors: Moroney Justin B , Vasudev Anusha , Pertsemlidis Alexander , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
An effective response against a previously experienced pathogen is contingent upon the generation of memory B cells. These display intrinsic differences over naïve B cells, including extended lifespan and rapid response to antigen, with production of high-affinity class-switched antibodies. However, the transcriptional and regulatory programs that underpin the unique features of memory B cells remain unexplored. Here, we have developed an integrated analysis of differentially expressed (DE) mRNAs, miRNAs, lncRNAs and chromatin profiles to determine how gene expression intersects with epigenetic regulatory elements to shape the identity and functions of human memory B cells. DE analysis revealed an exclusive gene signature shared by CD27+IgG+ and CD27+IgA+ B cells that segregates these memory B cells from CD27−IgD+ naïve B cells – “unswitched” CD27+IgD+memory B cells displayed a transcriptional signature of transition between naïve and switched memory B cells. While changes in DNA accessibility typically predicted changes in mRNA expression, some genes of the “memory” signature deviated from this, suggesting a layer of post-transcriptional regulation mediated by ncRNAs. Indeed, probing the miRNAome revealed downregulation of miR-181 and concomitant upregulation of five target genes (RASSF6, TOX, TRERF1, TRPV3, RORA) in switched memory B cells. In these B cells, select DE lncRNAs clustered proximal to the IgH gene locus on chr 14, suggesting a role in their regulation of BCR expression. Thus, we have identified a set of genes characteristic of memory B cells and have provided evidence these genes are subject to integrated regulation by chromatin remodeling, cis-regulatory elements and distinct sets of miRNAs and lncRNAs.
Bnip3/Nix-mediated mitophagy protects memory B cells by restricting de novo fatty acid synthesis
Authors: Kodali Srikanth 
Published: January 2023

Abstract
Immunological memory preserved by long-lived memory cells forms the basis for long-term protection by the adaptive immune system against repeat infections. Autophagy is crucial for the longevity of memory cells, though the molecular mechanisms for this phenomenon remain unclear. Bnip3 and its homolog Nix are Bcl-2 family proteins that localize to the outer mitochondrial membrane. Here, we show that autophagic clearance of mitochondria mediated by Bnip3 and Nix is critical to maintain mitochondrial homeostasis and prolong memory B cell survival. In mice with deletion of Nix and Bnip3 in B cells, memory B cells formed normally, but declined in numbers thereafter. Nix- and Bnip3-deficient memory B cells had impaired mitophagy and accumulated both total and functional mitochondria. Interestingly, Nix- and Bnip3-deficient memory B cells also had increased lipid droplets and elevated expression of genes required for de novo fatty acid synthesis. Inhibition of the fatty acid synthesis enzyme acetyl-CoA carboxylase 1 (ACC1) prevented lipid accumulation and rescued Nix- and Bnip3-deficient memory B cell numbers in vivo. Our results suggest that Nix and Bnip3 mediate the autophagy of excess functional mitochondria in memory B cells to limit de novo fatty acid synthesis and protect against steatosis-related cell death.
Candida tropicalis infection dramatically affects the gut microbiome in DSS-induced colitis
Authors: Di Martino Luca , Buttò Ludovica , Ghannoum Mahmoud , Hager Cristopher , Osme Abdullah , Buela Kristine-Ann , De Salvo Carlo , Pizarro Theresa , Cominelli Fabio 
Published: January 2023

Abstract
Candidiasis caused by Candida (C.) tropicalis has dramatically increased worldwide. The role of C. tropicalis in the pathogenesis of intestinal inflammation in Crohn’s disease patients has not been fully elucidated. We have previously reported that C57BL/6 mice infected with C. tropicalis show significantly increased severity of intestinal inflammation following induction of colitis by administration of dextran sodium sulfate (DSS) in drinking water. These effects were associated with increased gene expression of Tnfa and Ifng, and decreased expression of Th2-associated genes, such as Il4 and Il13. In the present study, we investigated the effects of C. tropicalis infection on the composition and function of the gut microbiome in this model. Analysis of 16s rRNA in fecal samples of infected mice showed that C. tropicalis significantly altered the gut microbiome composition, affecting, in particular, the abundance of mucin-degrading bacteria, such as Akkermansia Muciniphila and Ruminococcus Gnavus (β diversity analysis: P&lt;.05). Alcian Blue staining showed a significant decrease of mucus-producing goblet cells in infected mice before and after DSS-induced colitis (number of goblet cells per power field: 50.3±9.1 vs. 21.4±5.4; P&lt;.05). Flow cytometry analysis showed that in lymph nodes of infected mice, there was a higher percentage of group 2 innate lymphoid cells (% ILC2: 10.28±2.28 vs. 2.08±0.34, P&lt;.05). Our data demonstrate that C. tropicalis may play a pro-inflammatory role in intestinal injury by altering the gut microbiome community and affecting the abundance of specific mucin-degrading bacteria. Therefore, the resulting dysbiosis may affect the susceptibility of the host to develop inflammatory bowel disease.
Proteomic analysis of exosomes released from Leishmania infected macrophages
Authors: Keller M Murphy , Kelly Patrick H , Pope R Marshall , Thery Fabien , Wilson Mary E 
Published: January 2023

Abstract
Visceral leishmaniasis (VL) is a potentially fatal disease caused by Leishmania donovani or L. infantum. Parasites reside quiescently in macrophages (Mϕ) but dramatically affect systemic immune responses. These Mϕs, like most eukaryotic cells, release small, protein- and RNA-laden extracellular vesicles called exosomes, which facilitate intercellular communication. We hypothesized exosomes released from infected Mϕs mediate some systemic immune changes in VL. If correct, exoproteomes of infected Mϕs must differ from uninfected Mϕs.
Monocyte derived Mϕs (MDMs) from 4 healthy human donors were infected with L. infantum and extracellular parasites removed. Exosomes were collected and exoproteomes were isotope labeled and identified by LC-MS/MS. Data were exported in MaxQuant 1.6.3.3, and analyzed with Perseus 1.6.2.3.
After filtering for quality and for proteins found in all 5 technical replicates of at least one group, 244 proteins were quantified. Pairwise comparison revealed significant differences between donors (FDR 0.05, S0=1), and between infected and uninfected states. 2-way ANOVA (p&lt;0.05) revealed 100 proteins differed significantly by infection status, including histone proteins, HSP-70, Prosaposin, Lipoprotein lipase, CD36, Galectin-9 and several histocompatibility regions and antibody constant chains. The data are reflective of dysregulated lipid metabolism known to occur in visceral leishmaniasis.
These findings highlight a need to investigate Heat Shock proteins, lipid metabolic pathway proteins, histocompatibility antigens, and histones in extracellular vesicles as potential contributors to the immune dysregulation observed during leishmaniasis.
Mice infected with the hypervirulent Mycobacterium tuberculosis HN878 strain develop lung lesions resembling human tubercle granulomas
Authors: Bobba Suhas , Choreño-Parra José Alberto , Rangel-Moreno Javier , Ahmed Mushtaq , Mehra Smriti , Rosa Bruce , Martin John , Mitreva Makedonka , Kaushal Deepak , Zúñiga Joaquin , Khader Shabaana A 
Published: January 2023

Abstract
The aerosol infection of mice with lab-adapted Mycobacterium tuberculosis (Mtb) strains in not an ideal model to study the immune parameters crucial for structural organization of protective human tuberculosis (TB) granulomas. Since experimentation in larger animals that mimic human lung granulomatous responses is expensive, a cost-effective animal model recapitulating morphological aspects of human granulomas is needed. Here, we addressed whether the use of hypervirulent Mtb strains could be a better strategy to improve the mouse model of TB. Hence, we infected C57BL/6 mice with a low dose of aerosolized Mtb HN878 and histologically analyzed infected lung tissues at different time points after infection. We found that granulomas that developed early after Mtb HN878 infection resemble human and NHPs granulomas, except for the lack of multinucleated giant cells. These structures displayed a central core of macrophages surrounded by a lymphocyte cuff. Immunofluorescence analysis showed that the presence of Mtb within mouse human-like granulomas was restricted to the central core area where some macrophages also expressed iNOS. Furthermore, increased formation of B cell lymphoid follicles expressing CXCL13 and germinal center markers was observed at the peripheral lymphocyte cuffs of human-like granulomas. As B cell follicles are indicators of protective immunity in humans, we addressed whether their formation was crucial for Mtb control. In Ighm−/− B cell deficient mice, we found an increased susceptibility to Mtb HN878 infection and enhanced lung inflammation at 50 days post-infection as compared to wild-type mice. Thus, our data supports the use of Mtb HN878 infection to model human TB granuloma formation in mice.
Host resistance to pulmonary cryptococcal infection requires CX3CR1 expression
Authors: Strickland Ashley , Chen Yanli , Shi Meiqing 
Published: January 2023

Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen, and a leading cause of death among HIV-infected individuals. These encapsulated yeast fungi are believed to enter the body through the respiratory tract and initially cause pulmonary infection. If the host immune system fails to contain the fungal cells within the lung, the organism will disseminate to the brain via the bloodstream, consequently resulting in fatal meningoencephalitis. As such, the early interactions between immune cells and C. neoformans in the lung are critical for determining the progression of the disease. CX3CR1 is a chemokine receptor commonly expressed by most myeloid lineage cells. Despite its prevalence though, the role of CX3CR1 during cryptococcal infection has not been fully examined. Here we report that pulmonary infection with C. neoformans enhanced CX3CR1 expression in the lung. Following infection, mice lacking CX3CR1 had significantly higher pulmonary fungal burdens, as well as decreased survival times compared to wild type mice. These infected CX3CR1 knockout mice also displayed higher expression of pro-inflammatory cytokines including MIP-2, MCP-1 and CCL7, but lower expression of anti-inflammatory cytokines such as IL-10. In addition, CX3CR1 deficiency resulted in mice having dramatically enhanced neutrophil accumulation in the lungs following infection. Interestingly, depletion of neutrophils drastically improved lung CFU in infected knockout mice, indicating that excessive inflammation drove fungal growth. Taken together, these data indicate that CX3CR1 expression is essential for host resistance to pulmonary cryptococcal infection by inhibiting excessive lung inflammation.
Subchronic inhalation of Aspergillus versicolor conidia leads to sustained innate immune responses and is associated with irreversible remodeling of pulmonary arterial tissue following recovery
Authors: Barnes Mark A , Croston Tara L. , Lemons Angela R. , Rush Rachael E. , Beezhold Donald H , Green Brett J. 
Published: January 2023

Abstract
Aspergillus versicolor is an environmentally ubiquitous fungal species that is particularly abundant in environments with water infiltration. Respiration of fungal products, including conidia, hyphal fragments, mycotoxins, and other secondary metabolites may cause adverse pulmonary health effects including asthma and allergy. In the present study, pulmonary immune responses in B6C3F1 mice were examined following 1, 2, 4, 8, and 13 weeks of repeated respiratory challenge to 3×105A. versicolor conidia. Increased alveolar macrophages, inflammatory monocytes, neutrophils, and eosinophils, which peaked between 4 and 8 weeks, were detected in the lungs of mice exposed to viable conidia. Type 2 innate lymphoid cells (ILC2s) peaked between 8 and 13 weeks compared to total T cells which increased between 2 and 8 weeks and decreased at 13 weeks. Protein concentrations of the Th2 cytokines IL4, IL5, and IL13 were highest in bronchoaveolar lavage fluid of exposed mice following 4 weeks and exhibited a time-dependent reduction at 8 and 13 weeks. Inhalation of conidia for 13 weeks led to goblet cell hyperplasia, vascular wall thickening, and perivascular inflammation. Finally, mixed perivascular inflammation and smooth muscle hypertrophy were sustained at 4 weeks post-exposure. These data indicate that exposure to A. versicolor elicits a Th2-biased immune response that is driven by innate cell populations and is associated with the induction of remodeling of the pulmonary vasculature.
Neonatal Tregs Suppress the Development of a Stromal Niche for Th2 Cells in Skin
Authors: Boothby Ian C , Habrylo Ireneusz , Boda Devi P , Rosenblum Michael D 
Published: January 2023

Abstract
Many allergic diseases originate during early life and cause chronic inflammation that persists into adulthood. Immune dysregulation during the “critical window” of postnatal development has been hypothesized to establish lifelong susceptibility to inflammation; however, mechanistic evidence is lacking. Regulatory T cells (Tregs) are critical suppressors of inflammation and autoimmunity that are functionally unique during early life. We have found that neonatal Tregs (neoTregs) suppress profound dysfunction of skin immunity and stromal architecture in neonates but not adults. Transient depletion of neoTregs results in the aberrant outgrowth of fibrous bands in the skin subcutis. Single cell RNA sequencing and subsequent validation studies revealed that these fibrous bands are composed of a novel “type 2” fibroblast celltype that localizes to the subcutis and expresses the alarmins IL-18 and IL-33. Concurrently, Th2 cells accumulate in neoTreg-depleted skin and persist through adulthood. These Th2 cells reside near type 2 fibroblasts in the subcutis, and genetic ablation of IL-18 or IL-33 reduces their accumulation. Collectively, these data suggest that neonatal Tregs suppress the formation of a sustained stromal niche that supports pathogenic skin-resident Th2 cells and may predispose to disease later in life. These findings advance our understanding of how pathogenic immune cells arrive and persist in peripheral tissues and may be relevant to human allergic disease.