bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic and Epigenomic Regulation of Leukocytes by the Polyamine Pathway
Authors: Wang Chao , Wagner Allon , Yosef Nir , Kuchroo Vijay 
Published: January 2023

Abstract
Cellular metabolism can orchestrate immune cell function. We previously demonstrated that lipid biosynthesis represents one such gatekeeper to Th17 cell functional state, promoting autoimmune responses in the experimental autoimmune encephalomyelitis model. Utilizing a transcriptome-based insilico fluxomics tool, we investigated ancillary metabolic pathways associated with Th17 cell function and studied in detail the relevance of the polyamine pathway as modulators of autoimmune inflammation. We investigated this pathway using carbon-tracing fluxomics, transcriptomics, epigenomics (ATACseq) and functionally validated their relevance in autoimmune disease models using small molecule inhibitors and knockout animals.
Drak2 contributes to autoimmunity by negatively regulating IL-2 signaling and altering regulatory T cell development
Authors: Mandarano Alexandra H , Harris Tarsha L , Creasy Blaine M , Wehenkel Marie , McGargill Maureen A 
Published: January 2023

Abstract
Drak2, a serine/threonine kinase expressed highest in B and T cells, negatively regulates T cell activation. Previously, we showed that Drak2-deficient mice were resistant to disease in models of multiple sclerosis and type I diabetes. Interestingly, these mice were not more susceptible to infection compared to wildtype mice. While this makes Drak2 an ideal protein to target to treat autoimmune disorders without compromising immunity to infectious pathogens, it is still not clear how Drak2 functions to specifically inhibit autoreactive T cells. Here, we report a novel mechanism by which Drak2 impacts autoimmunity. We found that the resistance to type 1 diabetes was due to the absence of Drak2 in the T cells rather than the pancreatic beta cells or other immune cells. Moreover, resistance to disease was dependent on the presence of regulatory T cells (Tregs). Unexpectedly, we found that the development of thymic Tregs was increased in Drak2-deficient mice due to augmented IL-2 signaling, which led to increased proportions of peripheral Tregs compared to wildtype mice. Drak2 limits IL-2 signaling in developing T cells via interaction with Stat5. These data provide important insight into the etiology of autoimmunity by demonstrating that Drak2 not only regulates T cell activation, but also impacts the development of Tregs by regulating IL-2 signaling.
Self-originating CTL peptides induce the cross-activation of Treg cells to suppress the proliferation of self-reactive CD8+ T cells
Authors: Han Seongeun , Park Bomi , Han Chungyong , Choi Beom K. 
Published: January 2023

Abstract
Most of self-reactive T cells are eliminated by the central tolerance in thymus, but some of T cells with low TCR affinity survived from the central tolerance are controlled by peripheral tolerance. Although multiple factors are involved in the peripheral tolerance, the balance between Treg and effector T cells seems to be a key player in maintaining the peripheral tolerance. Here we found that cytotoxic CD8+ T cell-restricted (CTL) peptides originating from self-tumor antigens including hTERT, WT-1 and Malan-A not only induced the proliferation of CD8+ T cells, but also induced the activation and division of Foxp3+ Treg cells with a delayed kinetics. Proliferation of self-reactive CD8+ T cells were swiftly induced by the CTL peptides during the initial phase of culture, but suppressed by the expanded Treg cells in the latter phase. Cross-activation of Tregs by CTL peptides originating self Ags is not found when the CD8+ T cells specific to cytomegalovirus (CMV) antigen. These finding indicate that CTL peptides originating self Ags have a potential to activate both CD8+ T cells and Treg cells and thus, limit the T cell-mediated autoimmune responses.
Novel role for T-helper 17 signature cytokine, IL-17, in inducing CD4 effector resistance to immune suppression
Authors: Crawford Michael Patrick , Sinha Sushmita , Renavikar Pranav S , Borcherding Nicholas , Brate Ashley , Karandikar Nitin 
Published: January 2023

Abstract
Important immune regulatory mechanisms mediated by CD4+ and CD8+ T-cells keep destructive CD4+ T-cell responses in check. CD4+ T-helper 17 (Th17) cells, characterized by IL-17 production, play critical roles in the body’s response to infections and cancer and in the pathogenesis of autoimmune diseases such as multiple sclerosis, psoriasis, arthritis, IBD, among others. Here, we demonstrate that human CD4+ T-cells exposed to a Th17-differentiating milieu are highly resistant to immune suppression by CD8+ T-cells, compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T-cells themselves, but not through their action on CD8+ T-cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T-cells to induce suppressive resistance through the induction of IL-1b and IL-6/STAT3 pathways, indicating a novel feedback loop. These studies reveal a novel function for IL-17 cytokines in a CD4-intrinsic mechanism of immune resistance. The pathways induced in this process may serve as a critical target for intensive investigation and therapeutic intervention.
Lactoferrin modulates BMDCs to be tolerogenic leading to enhancement of Foxp3+iTreg differentiation as well as suppression of T cell proliferation
Authors: Jang Young-Saeng , Park Hui-Won , Park Sun-Hee , Jo Hyeon-Ju , Kim Tae-Gyu , Kim Pyeung-Hyeun 
Published: January 2023

Abstract
DCs are professional APCs for initiating both immune response and immune tolerance. Tolerogenic DCs are generally known as regulatory DCs that suppress immune responses through regulation of T cells such as induction of T cell anergy/apoptosis and Treg. Since we have demonstrated that lactoferrin (LF) induces functional Tregs and has a protective effect against IBD, we explored the tolerogenic effect of LF on mouse bone marrow-derived DC (BMDC) and its underlying mechanisms. LF enabled BMDCs to suppress the proliferation of allogenic CD4+ T cells, and elevated levels of Arg-1, IDO-1, and CD39/73 (known as key T cell suppressor molecules). Consistently, the suppressive activity of LF-treated DCs (LF-DCs) was disappeared by inhibitors of Arg-1 and CD39. Finally, LF-DCs enhanced TGFβ1-induced OVA-specific Foxp3+ T cell population.
Collectively, these results suggest that lactoferrin effectively causes DCs to be tolerogenic by both direct suppression of T cell proliferation and indirect enhancement of Treg differentiation.
A specific microbial metabolite influences the development of peripheral intraepithelial lymphocytes
Authors: Soderholm Amelia T , Beresford-Jones Benjamin , Clare Simon , Pedicord Virginia Ahn 
Published: January 2023

Abstract
Peripheral CD4+CD8αα+TCRαβ+ intraepithelial lymphocytes (pIELs) are a specialised T cell population that are reduced in germ-free (GF) C57BL/6 mice and vary in frequency between SPF mice from different sources, indicating their development is dependent on the presence of intestinal microbes. The microbes and factors required for pIEL development, however, are not fully characterised. pIELs are closely associated with intestinal epithelial cells (IECs) that line the gastrointestinal tract, however the contribution of IECs in shaping pIEL development is not well defined. We investigated if microbial metabolites influence pIEL development, and whether this is mediated by microbe-IEC-pIEL interactions.
In this study we used flow cytometry to characterise pIEL frequencies in GF mice administered different microbial metabolites, and in SPF mice from different colonies and animal facilities. qPCR of IEC RNA isolated from these mice and of metabolite-treated enteroids and MODE-K cells was performed to identify candidate genes expressed by IECs that may influence pIEL development.
We identified a common bacterial metabolite that partially restores pIEL development in GF mice. pIEL frequency of SPF mice varied between different sources, and qPCR identified IEC expression of several T-cell-influencing cytokines that correlated with pIEL frequency in vivo.
Our results indicate that a common microbial metabolite contributes to pIEL development, corresponding to metabolite-induced IEC expression of T-cell-influencing cytokines. Our work further elucidates the mechanisms of commensal microbe modulation of host tolerance, which may enable better strategies to prevent and treat intestinal infections and inflammation.
IRF8 regulated interferon beta production drives Gram-negative bacteria-mediated NLRP3 inflammasome activation
Authors: Sharma Bhesh Raj , Karki Rajendra , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Inflammasomes are multimeric protein complexes that orchestrate into the cytoplasm to exhibit different immune outcomes in response to microbial pathogens. Lipopolysaccharides (LPS) present in Gram-negative bacteria induces non-canonical NLRP3 inflammasome activation. We have recently found that interferon regulatory factor 8 (IRF8) was not required for caspase-11–mediated NLRP3 inflammasome activation during LPS transfection. Nonetheless, the role of IRF8 in Gram-negative bacteria mediated NLRP3 inflammasome activation has been unknown. In this study, we discovered that IRF8 promotes NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) infected with Gram-negative bacteria such as E. coli and C. rodentium. Furthermore, IRF8 deficient BMDMS showed reduced caspase-11 activation and gasdermin-D cleavage. Mechanistically, IRF8-mediates the activation of IRF3 for the transcription of interferon beta—which is required for caspase-11–dependent NLRP3 inflammasome activation in the infected BMDMs. Overall, we found that IRF8 regulated interferon beta production in response to Gram-negative bacteria is a driving factor for the activation of NLRP3 inflammasome.
Differential dynamics of the Jersey ruminal microbiome and immune response in the heat stress environment
Authors: Kim Euntae , Kim Myunghoo , Son Junkyu , Lee Jihwan , Kim Donghyeon , Ha Seungmin 
Published: January 2023

Abstract
The rumen microbiome and immune cell play important roles in metabolism and immune responses of dairy cows. Accumulation data suggesting that different species of dairy cow have differential heat stress resistance, however underlying mechanism by which non-host factors contribute heat stress responses. Thus, our study was designed to understand the changes of rumen microbiome and immune cell function to heat stress response in Holstein and Jersey cows. Respiration rate and rectal temperature were measured and rumen fluid and blood were collected for microbiome analysis and immune cell analysis under normal or heat-stressed environment from eight Holstein and Jersey cows. The rumen bacteria diversity and microbial gene enrichment was analyzed by using the Illumina HiSeq™ 4000 platform. The blood of dairy cows was collected for peripheral blood mononuclear cells (PBMCs) isolation and PBMCs were analyzed by RNA sequencing (Marcrogen, Korea) under the same environmental condition. Holstein had significantly higher respiration rate compared to that of Jersey in heat stress environment. We also find that gene transcription patterns associated with functional activities in PBMCs are differ between Holstein and Jersey. Distinct and more prominent changes of rumen bacteria taxa and functional gene abundance in Jersey cows may be associated with better adaption ability to heat stress. These data suggest that different species of dairy cows had different metabolic and immunological system to adapt heat stress responses.
Molecular Mechanisms of Immune Dysregulation during Acute Orientia tsutsugamushi Infection in Mice
Authors: Soong Lynn , Trent Brandon , Liang Yuejin , Fisher James , Card Galen E. , Walker David H. , Sun Jiaren 
Published: January 2023

Abstract
Orientia tsutsugamushi is a Gram- and LPS-negative bacterium that can cause severe scrub typhus in the Asia-Pacific region. While bacteria replicate freely in endothelial cell (EC) and phagocyte cytosol, little is known regarding pathogen recognition and cellular responses. Our newly developed O. tsutsugamushi infection mouse models are valuable for mechanistic studies. Here, we show that a hallmark of lethal infection is Th1-skewed, but Th2-impaired, immune responses, accompanied by severe endothelial damage and acute tissue injury. While tissue bacteria peak at disease onset (D6), neutrophil and CD8 T cell influx/activation reach peaks around D10 (prior to mouse death). We further show the pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1, VEGFR2, and angiopoietin-2 proteins in infected tissues and lung-derived ECs, 2) a loss of endothelial quiescent/junction proteins (angiopoietin-1, VE-cadherin), and 3) a functional loss of Tie2 receptor. Pulmonary macrophages predominantly display an M1-like (CD80+CD64+CD11b+) phenotype at D6 and D9, which correlated with the significant loss of CD31+CD45− ECs and M2-like (CD206+CD64+CD11b+−) cells. NanoString analyses of infected lung and spleen tissues and in vitro studies suggested a role for Clec4e in pathogen recognition and the IL-12/IL-27 axis in driving proinflammatory immune responses and cellular injury. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease.
Antibiotic resistant Pseudomonas aeruginosa upregulate iron piracy genes during macrophage infection and evade killing
Authors: Jorth Peter Allan , Vaillancourt Mylene , Nadeau Samantha , Caldera Juan Raphael 
Published: January 2023

Abstract
Antibiotic resistant bacterial lung infections are the primary cause of morbidity and mortality in people with cystic fibrosis (CF). Recently, we showed that aztreonam resistant P. aeruginosa with a mutated nalD gene were more virulent than wild type (WT), even in the absence of antibiotic treatment. Yet, the mechanisms underlying the increased virulence were unknown. Because nalD− mutants increased antibiotic efflux pump expression, we hypothesized that their hypervirulence was dependent on the efflux pump. Surprisingly, deletion of the efflux pump did not affect nalD− virulence in an acute lung infection. To determine other potential mechanisms underlying the enhanced virulence, we performed RNA-seq on WT and nalD− grown in vitro and found that nalD− increased efflux pump expression relative to WT, as expected, but also differentially regulated hundreds of genes. Exopolysaccharide genes involved in biofilm formation were among the most highly upregulated genes. Consistent with this differential gene expression, the nalD− mutant exhibited increased biofilm formation, reduced C3 complement opsonization, and also replicated better than WT in the presence of macrophages. Subsequent RNA-seq analyses of infected macrophages revealed that nalD− upregulated iron siderophore systems relative to WT. We predict that this increased iron piracy facilitates subversion of nutritional immunity during infection. Because individuals with CF frequently experience anemia, antibiotic resistance mutations that increase iron piracy could promote bacterial growth during these periods of iron limitation.
Sensory afferent neurons coordinate in host immune responses to Citrobacter rodentium
Authors: Reardon Colin , Ramirez Valerie T , Sladek Jessica 
Published: January 2023

Abstract

Background
Neuro-immune communication is a vital component of regulating host immune responses to pathogens. Specialized sensory neurons have recently been described to detect bacterial pathogens in the skin, lung, and small intestine, inducing either maladaptive or host-protective responses. Here we assessed the role of sensory nociceptive neurons in the host response to the enteric pathogen Citrobacter rodentium.

Methods
Selective ablation of nociceptive neurons was accomplished using the Trpv1 agonist Resiniferatoxin (RTX) 10 days prior to C. rodentium infection of mice (C57BL/6).

Results
RTX-treated mice exhibited significantly increased bacterial burden 10 days post infection and delayed pathogen clearance compared to vehicle control mice. This reduced host-protective immune response was due to significantly reduced expression of IL-22, and recruitment of CD3+ T-cells into the colonic mucosa. This process appears to be TRPV1 dependent as TRPV1 KO mice experienced a similar delay in T-cell recruitment. Expression of pro-inflammatory cytokines in RTX-treated mice was significantly enhanced, and was associated with increased numbers of colonic T-cells 29 days p.i.. As previous studies identified the sensory neuropeptide CGRP as a regulator of host immune responses, we assessed the role of CGRP receptor signaling during C. rodentium infection. Antagonism of the CGRP receptor reduced expression of Il6, and Ifng, while bacterial burden and Il22 expression was not reduced compared to C. rodentium-infected vehicle-treated control mice.

Conclusions
Our data indicate that sensory nociceptive neurons exert a significant host protective role during C. rodentium infection that is independent of CGRP.
Maternal EGF protects offspring from enterally acquired bloodstream infections by limiting bacterial translocation in the neonatal intestine
Authors: Knoop Kathryn A , Floyd Alex , Warner Barbara , Tarr Phillip , Newberry Rodney D 
Published: January 2023

Abstract
Late-onset neonatal sepsis (LOS), a significant cause of morbidity and mortality in prematurely born infants, results from a bloodstream infection of gut-originating bacteria. It remains unclear how such bacteria translocate from the intestine, though it has been repeatedly observed that breastfed infants, particularly those fed mother’s own milk (MOM), have reduced risk of LOS compared to formula fed infants. Epidermal growth factor (EGF) promotes intestinal barrier function in infants and is present at high concentrations in breast milk post-partum and decreases throughout lactation. We found reduced concentrations of EGF in the stool of premature formula-fed infants compared to MOM-fed infants, and observed a similar decrease in EGF concentrations of stool of neonatal mice asynchronously cross-fostered (ACF) to dams that had delivered two weeks prior. LOS bloodstream isolates of E. coli colonized the tracts of all pups but translocated and disseminated systemically only in ACF mice resulting in bacteremia and rapid death. Goblet cell intrinsic sensing of EGF via the epidermal growth factor receptor (EGFR) limited bacterial translocation from the colon. Oral gavage of recombinant EGF reduced bacteria translocation and prevented the development of systemic disease in ACF mice. Thus, disruption of maternally delivered EGF in ACF mice results in translocation of pathogens from the gut, and a sepsis-like disease. In conclusion we have identified a mechanism whereby a gut-residing pathogen gains systemic access and have developed a novel animal model replicating this mechanism to explore the protective effect of breastmilk and EGF in LOS.
Diverse dendritic cell subsets promote infection and induction of CD8 T cell responses after foodborne Listeria monocytogenes infection
Authors: Imperato Jessica Nancy , Xu Daqi , Romagnoli Pablo A , Qiu Zhijuan , Perez Pedro , Khairallah Camille F , Pham Quynh-Mai , Milling Simon W.F. , Lefrancois Leo , Khanna Kamal M , Puddington Lynn , Sheridan Brian S 
Published: January 2023

Abstract
Listeria monocytogenes (Lm) is a common foodborne pathogen which causes mild gastrointestinal distress in healthy hosts, and systemic listeriosis in immunocompromised individuals. While immune responses have been rigorously examined after intravenous Lm infection, less is understood about Lm dissemination from the intestines or the induction of adaptive immune responses after physiologic infection through the consumption of contaminated food. Consequently, this study focused on the cells involved in early immune responses in the intestinal mucosa using foodborne Lm infection in mice. After foodborne infection, Lm trafficked intracellularly from the intestines to the mesenteric lymph nodes (MLN) and were associated with Batf3-independent dendritic cells (DC) in the lymphatics. Consistent with this observation, dissemination of Lm from the gut to the MLN occurred normally in Batf3−/− mice. Activated migratory DC accumulated in the MLN by 3 days post-infection (dpi) where they surrounded Lm foci. At this time, Lm burden in the MLN was reduced in Batf3−/− mice implicating Batf3-DC in the maximal accumulation of Lm. While both conventional type 1 DC (cDC1) and type 2 DC in the MLN contained Lm by 3 dpi, Batf3−/− mice exhibited a profound defect in the induction and gut homing of Lm-specific CD8 T cells. Surprisingly, restoration of pathogen burden was unable to restore CD8 T cell responses in Batf3−/− mice. Thus, cDC1 play a critical role in the generation of potent anti-Lm immunity following foodborne infection. Collectively, these data demonstrate that DC play diverse and dynamic roles in the early events that follow foodborne Lm infection, and in the establishment of protective, anti-Lm intestinal immunity.
The inflammatory response after an intestinal inflammatory challenge affects in an opposite manner to the female and male offspring gestated in hypothyroxinemia
Authors: Rivera Juan Carlos , Gutiérrez Barbara , Díaz Máximo , Chamorro Linda , Estrella Matías , Guajardo Reynaldo , Díaz Ignacio , Opazo María Cecilia , Boudin Helene , Neunlist Michel , Bueno Susan M , González Pablo , Kalergis Alexis M , Riedel Claudia 
Published: January 2023

Abstract
Ulcerative colitis (UC) is a highly frequent inflammatory bowel disease (IBD), which causes are unknown. We have shown that the offspring gestated under thyroxine (T4) deficiency, condition named hypothyroxinemia (HTX), shows inflammatory features at the intestine. Moreover, the offspring gestated under HTX (HTX-offspring) suffers strong experimental autoimmune disease. Suggesting that gestational HTX could imprint their offspring with a high immune response after an inflammatory challenge. Thus, we think that the HTX-offspring will be more prone to suffer IBD. To analyze this hypothesis C57BL6 pregnant mice were induced with gestational HTX during E10 to E15 by giving them methimazole in the tap-drinking water. Then, UC was induced to the HTX-offspring or control at postnatal P55 by giving them dextran sodium sulphate (DSS) in the tap-drinking water for six days. Body weight, pathological score of IBD and hidden blood in stool were analyzed daily. Then, mice were sacrificed at day 10 to evaluate their inflammatory response. For that histological analysis were performed in the intestine; the content of cytokines in serum and intestine by ELISA and the populations of innate and adaptive immune cells at the intestine and spleen by flow cytometry. Our results shown that the male and female offspring developed an opposite immune response to UC. The female HTX-offspring were more resistant and the male HTX-offspring were more sensitive to UC compared to their respective female and male control groups. Thus, our results suggest that the immune response of an individual can be set up during gestation and that the normal level of maternal T4 during gestation is fundamental for the proper function of the offspring immune system.