bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bordetella pertussis vaccine composition drives hematopoietic stem and progenitor cell expansion and immune response during vaccination and subsequent challenge.
Authors: Varney Melinda , Boehm Dylan , DeRoos Katherine , Wong Ting , Kilic Emel Sen , Bradford Shelby , Elkins Cody , Epperly Matthew , Witt William , Barbier Mariette , Damron Fredrick H 
Published: January 2023

Abstract
Pertussis is a re-emerging infectious disease world-wide. It is hypothesized that current acellular vaccines (ACVs) wane in efficacy each year after immunization. We hypothesized that whole cell vaccines (WCVs) induce hematopoietic stem and progenitor cell (HSPC) expansion and differentiation processes necessary for life-long protection. While HSPC innate immune signaling and expansion play a critical role in directing immune response to infection, their role in vaccine efficacy is unclear. To test our hypothesis, we assessed bone marrow (BM) HSPC frequency, peripheral blood composition, and immune cell proportions in the spleen and thymus upon vaccination. We find that the BM Lineage-Sca1+cKit+ (LSK) cell population undergoes progressive expansion in WCV mice when compared to ACV and PBS-injected control mice. Additionally, peripheral white blood cells and spleen size increase in WCV mice, suggesting that BM cells mobilize to the blood and spleen, where extramedullary hematopoiesis can occur. Upon infection, myeloid cells have been demonstrated to leave the spleen, enter infected tissues, and produce cytokines that favor the generation of Th1 cells. Occurring more rapidly in WCV mice, LSK cell frequency increases and spleen size decreases upon B. pertussis challenge in both WCV and PBS-injected mice when compared to ACV mice. WCV mice exhibit increased peripheral blood monocytes, neutrophils, and lymphocytes when compared to other groups. Taken together, our data suggest that HSPC expansion, differentiation, and mobilization upon WCV immunization may prime the host to better respond to pathogen, and that ACVs formulated with adjuvants that stimulate HSPC expansion, such as TLR4 agonists, may enhance vaccine efficacy.
Characterization of pathways involved in the suppression of T follicular helper cells in newborns
Authors: Yang Ji Yeon , Siddiqui Shafiuddin , Uslu Kadriye , Lee Robert C , Ireland Derek DC , Allman Windy R , Verthelyi Daniela , Akkoyunlu Mustafa 
Published: January 2023

Abstract
The immature immune system of newborns renders poor vaccine response. However, mechanisms of limited T follicular helper (Tfh)-mediated antibody production in newborns are largely unknown.
We found significantly more expression of the Tfh inhibitory genes associated with regulatory T cell (Treg) cells and IL-2 signaling in immunized newborn mice CD4+CXCR5+PD-1+Tfh cells than in adult mice. The IL-2-STAT5 signaling in CD4+CXCR5+PD-1+Foxp3+T follicular regulatory cells (Tfr) was hyperactive in newborns as compared to adults. Also, in newborns IL-6-STAT3 signaling was lower in Tfh cells but higher in Tfr cells compared to adult mice. Immunization did not elicit IL-21 expressing Tfh cells but when provided sufficient IL-21, in vitro cultured newborn T cells differentiated into Tfh-like cells. These data indicate that in newborns, dendritic cell-derived IL-6 signaling preferentially induces Treg cells to differentiate into Tfr cells, which in turn suppresses Tfh generation. Supporting this hypothesis, co-injection of newborn mice with conjugate type 14 pneumococcal polysaccharide vaccine together with IL-21 or anti-CD25 blocking antibody reduced Tfr/Tfh ratio and enhanced Tfh formation. While IL-21 elicited both IgG and IgA antibodies against vaccine, anti-CD25 antibody only improved IgA production, due in part to the elevated APRIL and TGF-β expression in T cells and fibroblast reticular cells. Since IL-21 acts both on T cells and B cells, improved IgG response in IL-21 injected mice is likely due to its direct effect on B cells.
These findings highlight the differences in the programming of IL-2 and IL-6 signaling in newborn and adult Tfh cells. These differences may be exploited in devising improved vaccines for infants.
MHC class II tetramers identify apolipoprotein B-specific CD4 T cells in mice and humans
Authors: Kimura Takayuki , Tse Kevin , Miller Jacqueline , McArdle Sara , Vassallo Melanie , Wolf Dennis , Baas Livia , Kobiyama Koji , Jenkins Marc K , James Eddie A , Kwok William , Hanna David B , Kaplan Robert C , Strickler Howard , Sidney John , Sette Alessandro , Ley Klaus 
Published: January 2023

Abstract
Immunization with atherosclerotic plaque antigens including MHC-II-restricted peptides from apolipoprotein B (ApoB, core protein of low density lipoprotein, LDL) is known to be atheroprotective in animal models. Herein we report a human ApoB peptide whose sequence is identical to mouse ApoB and which binds to both mouse (I-Ab) and human MHC class II. Immunization with this peptide reduced atherosclerotic plaque in the aortas of Apoe−/− mice fed with a Western diet and induced IL-10 producing CD25+FoxP3+ regulatory T cells (Tregs). After peptide restimulation in vivo, responding CD4+ T cells (by Nur77-GFP) were highly enriched in CD25+FoxP3+ Tregs. Using a novel I-Ab tetramer reagent, we further showed that peptide-specific CD4+ T cells expand upon vaccination, ~50% express FoxP3, and were 10-fold enriched for IL-10 producers. In human peripheral blood mononuclear cells (PBMCs) from individuals assessed for subclinical cardiovascular disease, ApoB-specific CD4+ T cells were detected using novel HLA-DR1/ApoB peptide tetramers. Peptide-specific CD4+ T cells from donors with carotid artery plaques showed more RORγt expression and less FoxP3 expression compared to those without. This is the first demonstration of ApoB-specific CD4+ T cells by tetramer in humans and the first animal model evidence of atheroprotective vaccination with a human ApoB peptide.
Chlamydia Nanovaccine Formulated with Recombinant MOMP Encapsulated in PLGA 85/15 Nanoparticles Enhances IFN-γ Production with Activation of Effector (CD44+/CD62L−) and Memory (CD44+/CD62L+) CD4+ T Cells in Balb/c Mice
Authors: Sahu Rajnish , Dixit Saurabh , Duncan Skyla , Singh Shree R , Dennis Vida 
Published: January 2023

Abstract
Chlamydia trachomatis remains the most commonly reported bacterial sexually-transmitted diseases, causing considerable morbidity and socioeconomic burden worldwide. To reduce its occurrence and global economic burden, vaccine development to provide protective immunity against the pathogen has been ineffective for many years due to its complex immunological mechanisms. Modern methods to develop vaccines by combining antigens with biocompatible and biodegradable polymers have emerged as attractive therapeutics. In the present study, we formulated a nanovaccine employing PLGA [poly (D, L-lactic-co-glycolic acid) 85/15 nanoparticles encapsulated with recombinant MOMP (major outer membrane protein) of Chlamydia, and investigated its immunogenicity in Balb/c mice. Mice were immunized via the intranasal and subcutaneous routes three times at two-week intervals. Immunomagnetic purified T cells from spleens were co-cultured with mitomycin-C treated splenocytes as antigen presenting cells to assess T-cell activation and proliferation, effector and memory T cells, and cytokines production. Our flow cytometry data showed an increase in effector (CD44+/CD62L−) and memory (CD44+/CD62L+) T cells specific to the CD4+ subset. T-cells re-stimulated with rMOMP produced enhanced IFN-g, which is required for protection against Chlamydia. IL-2 production was increased and correlated with a CFSE+ proliferating CD4+ T-cell population. Our data suggests that mice immunized with our Chlamydia nanovaccine triggers T-cell activation, antigen-specific effector and memory CD4+ T cells and IFN-γ production, which are required for protection against this mucosal pathogen.
A FUNCTIONAL METAGENOMIC APPROACH OF HUMAN MICROBIOTA IDENTIFIES A BACTERIAL STRAIN THAT CONFERS PROTECTION DURING INTESTINAL INFLAMMATION VIA IL-22
Authors: Guglietta Silvia , Nepelska Malgorzata , Lapaque Nicolas , Bardeli Glenda , Cultrone Annalisa , Doré Joel , Blottière Hervé , Rescigno Maria 
Published: January 2023

Abstract
The gastrointestinal microbiota has been shown to play an important role in resistance to pathogen invasion and in the regulation of the host metabolism. Further, it is widely recognized that the microbiota also influences the development and homeostasis of the immune system. Alteration in the microbial flora, so called dysbiosis, has been linked to many human diseases, including autoimmune and/or autoinflammatory disorders and allergies. Despite the advances in the DNA sequencing technology, a deeper understanding of the gut microbiota is still hindered by the inability to culture most of the bacterial species.
In this study, we used a high throughput cell-based functional metagenomic approach to identify several bioactive bacterial clones in the human fecal microbiota. In subsequent co-culture experiments we selected one clone, related to the phylum of Firmicutes, which indirectly activated dendritic cells through the stimulation of intestinal epithelial cells and subsequently modulated T cell functions. This effect was associated to an ABC transporter. In ex-vivo human organ culture experiments we found that this clone prevented Salmonella-induced destruction of the intestinal mucosa by stimulating the production of IL-22 in the CD4+ T cells. These results were confirmed in vivo by using a mouse model of DSS-induced colitis. Here pre-treatment of the mice with the identified clone was able to significantly reduce intestinal inflammation. This protective effect was abrogated by the administration of anti-IL22 antibody or the use of AHR antagonist.
Altogether, our functional metagenomic approach allowed the identification of bacteria and bacteria-induced genes modulating the immune system.
PGE2 controls Th17 and regulatory T cell function during intestinal immune responses
Authors: Maseda Damian , Johnson Elizabeth M , Kirk Leslie , Aronoff David M , Crofford Leslie J 
Published: January 2023

Abstract
Eicosanoids, particularly prostaglandin E2 (PGE2), are critical molecules in the initiation and resolution of inflammation during immune responses. PGE2 is associated with modulating autoimmunity through altering the IL-23/IL-17 axis and regulatory T cells, whose balance is critical for controlling pathogenic T cells. The inducible microsomal prostaglandin E synthase 1 (mPGES1) is a membrane enzyme that regulates local PGE2 levels and is highly expressed at sites of inflammation. Hematopoietic and stromal cells express mPGES1, but its role in T cell function and intestinal biology remains underappreciated. Th17 polarized cells produce 10-fold more PGE2 than Th1 polarized cells, and this PGE2 production is mPGES1-dependent. Interestingly, high concentrations of PGE2 can shift the production from IL-17A to IFNg during Th17 polarization, and PGE2 promotes more cell proliferation and cytokine production in Th1 than in Th17 cells. Sensing of PGE2 at physiological concentrations through its EP4 receptor proved to be critical to inhibit the generation of iTregs but not Th1 or Th17 cells. In the colon, we observed that different inflammatory insults induce different PGE2 production levels, with concomitant modulation of T cell responses in the mesenteric lymph nodes. Furthermore, mPGES1 displayed opposite effects on pathogenic and regulatory T cells in the T-cell transfer colitis model, with mPGES1 deficiency limiting intestinal damage driven by effector T cells, but enhancing de novo generation of Tregs and increasing colonic lamina propria homing of CD4+FoxP3+ cells. Taken together, these data demonstrate the pleiotropic and context-dependent actions of mPGES1 and PGE2 in intestinal inflammation and immunity.
Microbiota-dependent IL-21 signaling regulates intestinal immune cell homeostasis and immunopathology to infection
Authors: Cho Hyeseon , Spolski Rosanne , Kang Byunghyun , Leonard Warren J , Kelsall Brian L 
Published: January 2023

Abstract
Despite studies indicating a role for IL-21 in intestinal inflammation, how it precisely affects intestinal homeostasis and immunity to infection is not yet clear. In this study, we report a potent effect of commensal microbiota on the phenotypic manifestations of IL-21 receptor deficiency. IL-21 is expressed highly by CD4 T cells of Peyer’s patches (PPs) and small intestine lamina propria (LP) and strongly induced by co-housing with SFB-positive mice. Mice deficient in IL-21 receptor exhibit reduced numbers of GC B cells, B cell expression of AID, and IgA+ B cell populations in PPs, consistent with the known roles for IL-21 in B cell function. Consequently, IL-21R KO mice show a significant reduction in IgA+ plasmablasts and plasma cells in the small intestine LP. Interestingly, microbiota-dependent increases in RORgt+ T cells and Treg cells are observed in the small intestine of IL21-R KO mice. Neither the Th1 nor RORgt+ ILC populations are altered in the KO mice intestine compared to WT mice. Demonstrating a critical role of IL-21 signaling in immunopathology during Citrobacter rodentium infection, IL-21 receptor deficiency leads to strikingly reduced tissue pathology without affecting bacterial clearance. This reduced immunopathology likely results from dampened production of IFNg, IL-12, and IL-1b that promote severe immunopathology/lethality. Taken together, we demonstrate the regional and pleotropic effects of IL-21 signaling that fine-tunes intestinal mucosal immunity in a microbiota-dependent manner, which has significant implication for anti-IL-21 therapy to treat inflammatory bowel disease.
Innate lymphoid cells and colitis in leukocyte adhesion deficiency
Authors: Wang Baomei , Li Xiaofei , Kajikawa Tetsuhiro , Moutsopoulos Niki M , Chavakis Triantafyllos , Hajishengallis George 
Published: January 2023

Abstract
Leukocyte Adhesion Deficiency type I (LAD-I) is a primary immune deficiency caused by mutations in the CD18 subunit of β2 integrins. Affected individuals suffer from recurrent mucocutaneous infections and pathologic inflammation in certain mucosal barriers, including the periodontium, skin and the colon. Our laboratory has recently dissected the mechanistic basis of LAD-I–associated periodontitis but the mechanisms underlying LAD-I– associated colitis are yet to be defined. To answer this question, we utilized as model the CD18−/− mice after demonstrated that CD18 deficiency renders mice highly susceptible to Citrobacter rodentium-induced colitis, a widely used model of human colitis caused by enteropathogenic and enterohaemorrhagic Escherichia coli. Strikingly, we found that CD18−/− mice displayed significantly reduced IL-22 production and IL-22 producing Group 3 innate lymphoid cells (ILC3s). Therapeutic delivery of recombinant IL-22 (rIL-22) protected CD18−/− mice from C. rodentium–induced mortality. Furthermore, adoptive transfer of CD18+/+ monocytes partially restored IL-22 production from ILC3s and extended the survival of CD18−/− mice post C. rodentium infection. This is the first demonstration that ILC3-dependent expression of IL-22 is under β2 integrin regulation. In conclusion, these data not only identified a novel role of β2 integrin in mediating the crosstalk between intestinal macrophage and ILC3 but also can potentially lead to novel treatment of LAD-associated colitis.
The relationship between the cytokines TNF and TL1A in rheumatoid arthritis
Authors: Farley Taylor K , Richoz Nathan , Lamberth Sarah , Gregersen Peter , Cominelli Fabio , Meylan Francoise , Siegel Richard M. 
Published: January 2023

Abstract
The TNF-family cytokine TL1A (TNF-like ligand 1A) signaling through its receptor DR3 (Death Receptor 3) promotes immunopathology in diverse autoimmune disease models by facilitating T cell accumulation and Innate Lymphoid Cell activation at the site of inflammation while leaving systemic immune responses unaffected. TNF, a close homolog of TL1A, is a successful therapeutic in autoimmune diseases including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, a significant fraction of patients do not adequately respond to TNF blockade and are in need of alternative therapies. Previous studies have reported elevated TL1A levels in serum and synovial fluid of patients with RA. Yet, how TL1A expression may be influenced by TNF, and whether blocking TL1A/DR3 interactions would be a viable treatment for RA is unknown. We found that soluble TL1A levels are specifically elevated in synovial fluid and serum from RA patients, and that TNF blockade reduces serum TL1A levels in both responders and non-responders. Additionally, in a murine model of collagen-induced arthritis, antibody blockade of TL1A reduced both clinical disease and bone destruction. To further understand the relationship between TL1A and TNF we are now utilizing the TNFDARE mouse model of spontaneous TNF driven arthritis crossed to DR3 deficient mice. By 3D micro CT imaging and cytokine analysis of the joints we will determine if the blockade of TL1A/DR3 interactions alleviates arthritis driven by excess TNF. Taken together, these studies support an investigation into TL1A blockade as a potential therapy for patients with rheumatoid arthritis.
Inhibition of BAFF binding to its receptor, BR3, by low molecular weight compounds results in suppression of activation of monocytes and B cells in vitro and in vivo model of autoimmune diseases.
Authors: Yoshimoto Keiko , Suzuki Katsuya , Sugahara Kunio , Takeuchi Tsutomu 
Published: January 2023

Abstract

Background and Purpose
We have demonstrated that the elevated expression of BAFF receptor (BR3) on monocytes is involved in the pathogenesis of primary Sjogren’s syndrome and BR3 is a therapeutic target to treat pSS. In our previous study, we have discovered two pyrrolopryimidine derivatives, BIK12 and BIK13, which inhibit binding of BAFF to BR3, using our original high-throughput screening system. In this study, we investigated inhibitory effects of these compounds on BAFF signaling pathways in monocytes and B cells in vitro. In addition, we analyzed the effects of the compounds on serum level of an anti-dsDNA antibody in autoimmune disease model mice.

Methods
Peripheral monocytes were stimulated with soluble BAFF (sBAFF) and cultured in vitro with or without peripheral B cells in the presence of BIK-12 or BIK-13. IL-6 production by monocytes and IgG production by B cells were measured by ELISA. MRL/lpr and NZBWF1 mice were treated with these compounds three times a week at a dose of 1.0 or 0.2 mg/kg for 6 months. The titer of an anti-ds DNA antibody was measured by ELISA.

Results and Discussion
sBAFF-induced IL-6 production by peripheral monocytes and IgG production by B cells co-cultured with sBAFF-stimulated peripheral monocytes were significantly suppressed by BIK12 and BIK13 in a dose dependent manner. Interestingly, the titer of an anti-dsDNA antibody in both MRL/lpr and NZBWF1 mice received BIK13 was significantly lower than control mice after 16 weeks’ treatment, indicating that the compound was also efficacious in vivo.
Difference between Immature Dendritic Cells (imDCs) and Mature Dendritic Cells (mDCs) Derived from Human Monocytes
Authors: Nagai Taro 
Published: January 2023

Abstract
We induced imDCs and mDCs from human monocytes. Then we examined their surface markers and cytokine secretion to compare with their functions.

Surface Markers
Monocytes marker CD14 still expressed on imDCs and disappeared on mDCs. However, DC marker CD209 expressed on both imDCs and mDCs as same amount. Co-stimulatory molecules, such as CD40, CD80, CD86, and HLA Class II, expressed on mDCs more than imDCs.
So, we expected that imDCs cannot induce T cell proliferation and differentiation because

Cytokine Secretion
We stimulated imDCs and mDCs by CD40L transfected L cells with or without several kinds of cytokine for 2days and measured cytokine secretion from them by ELISA.
mDCs secreted more IL-27 than imDCs, however IL-6, IL-12p70, and IL-23 secretion from them were almost same. Effects of adding cytokines on stimulation were almost same as on imDCs and mDCs. IFN-γ enhanced IL-12p70 secretion, however almost no effects against IL-6, IL-23, and IL-27 secretion. IL-4 and IL-13, which induce Th2 differentiation, had almost no effect against IL-6 and IL-27 secretion and suppressed secretions of IL-23 which induce Th17 differentiation, however enhanced secretion of IL-12 p70 which induce Th1 differentiation.
These results suggest that even though imDC may be able to induce T cell proliferation and differentiation because they secrete enough amount of cytokines for it.
Next, we would like to co-culture DCs and naive Th cells to confirm whether imDCs can induce T cell proliferation and differentiation or not.
RUNX1 regulates KIT expression and is a novel therapeutic target in human mast-cell diseases.
Authors: TOKUMASU MAYU , KATAOKA TATSUKI R. , NOGUCHI YUKI , MORITA KEN , SUGIYAMA HIROSHI , KAMIKUBO YASUHIKO , ADACHI SOUICHI 
Published: January 2023

Abstract
Mast cells develop from hematopoietic progenitors under SCF-dependent activation of KIT encoding a type III receptor tyrosine kinase. In addition, KIT signaling also enhances release of chemical mediators from stimulated mast cells. KIT D816V mutation, a gain-of-function mutation which is often found in mastocytosis, causes SCF-independent activation of KIT, leading to autonomous mast cell survival and proliferation. ChIP-seq analysis of mouse bone marrow-derived mast cells showed that hematopoietic transcription factor RUNX1 bound to several genomic regions between KIT exon 1 and intron 1. We therefore investigated an association between RUNX1 and the transcriptional regulation of KIT in the human mast cell lines. The global gene expression profile revealed that KIT gene expression in the cells was positively linked to RUNX1 gene expression. Using ChIP assay coupled to PCR, we found RUNX1 binding at KIT intron 1 in the cells with KIT D816V mutation. RUNX1 knockdown reduced KIT expression in both cell lines with and without KIT D816V mutation, and led to a significant decrease in cell growth of those with D816V mutation. In the RUNX1-knockdown cells, PI3K-Akt pathway of KIT downstream signaling was suppressed, and G0/G1 cell-cycle arrest occurred, which was followed by apoptosis. The chlorambucil-conjugated compound that we developed to inhibit RUNX1 binding to its DNA targets successfully and effectively decreased the KIT expression of the mast cells with KIT D816V mutation, which resulted in the cell growth suppression. These findings suggested that RUNX1 upregulates KIT expression and may be a potential therapeutic target in mast-cell diseases.