bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secretory IgA responses induced by rice-based oral cholera toxin B subunit vaccine are solely responsible for antibody-mediated long-standing cross-protection against Vibrio cholerae - and enterotoxigenic Escherichia coli -induced diarrhea (46.3)
Authors: Tokuhara Daisuke , Yuki Yoshikazu , Nochi Tomonori , Kodama Toshio , Mejima Mio , Kurokawa Shiho , Takahashi Yuko , Nanno Masanobu , Takaiwa Fumio , Honda Takeshi , Kiyono Hiroshi 
Published: January 2023

Abstract
Introduction: We investigated whether the cholera toxin B subunit (CTB)-specific secretory IgA (SIgA) induced by rice-based oral vaccine expressing CTB (MucoRice-CTB) gives long-term protection against V. cholerae - and enterotoxigenic Escherichia coli (ETEC)-induced diarrhea. Methods: Mice were orally immunized with MucoRice-CTB, which stored at room temperature for 3 years, and then evaluated for induction of SIgA-mediated protective immunity against CT or heat-labile enterotoxin (LT). The role of CTB-specific SIgA was also examined in polyimmunoglobulin receptor (pIgR)-deficient mice. Long-term immune memory was evaluated 6 months after final primary immunization. In vivo V. cholerae (El Tor O1 Inaba) and ETEC challenge was performed in the intestinal loops of immunized mice. Results: Oral MucoRice-CTB immunization provided SIgA-mediated protection against LT- or CT-induced diarrhea. This protection was impaired in pIgR-deficient mice. The vaccine offered long-lasting protection against toxin-induced diarrhea (for at least 6 months after primary immunization), and a single booster immunization extended the length of protective immunity for at least 4 more months. In the intestinal loop assay, MucoRice-CTB vaccination inhibited diarrhea in the face of V. cholerae and ETEC challenge. Conclusion: MucoRice-CTB is an effective cold-chain-free oral vaccine inducing CTB-specific SIgA-mediated long-term protection against V. cholerae - or ETEC-induced diarrhea.
Mucosal S-IgA Abs is required for complete immunity to Streptococcus pneumoniae (46.6)
Authors: Fukuyama Yoshiko , King Janice , Kobayashi Ryoki , Gilbert Rebekah , Hollingshead Susan , Briles David , Fujihashi Kohtaro 
Published: January 2023

Abstract
We investigate whether pneumococcal surface protein A (PspA)-specific secretory (S)-IgA antibodies (Abs) induced by nasal vaccine is necessary for the prevention of streptococcal colonization and their clearance. IgA deficient (IgA-/-) and control mice were nasally immunized four times at weekly intervals with PspA plus flt3 ligand plasmid (pFL). One week after the last immunization, PspA-specific S-IgA and IgG Ab as well as Th1- and Th2-type cytokine responses by CD4+ T cells were determined. Further, mice were challenged with Streptococcus pneumoniae (EF3030) via the nasal route. Five days after challenge, nasal washes (NWs) and nasal passages (NPs) were collected and the numbers of bacterial colonies were determined. Mice nasally immunized with PspA plus pFL showed significantly increased levels of Th2 cell-mediated PspA-specific S-IgA and IgG Ab responses in NWs and plasma when compared with naïve mice. Thus, these vaccinated wild type mice showed essentially no bacteria in the nasal cavity. Although IgA-/- mice given nasal PspA plus pFL had significantly high levels of PspA-specific IgG Abs, high numbers of bacteria were detected in NWs and NPs. Further, nasal PspA plus pFL effectively reduced pre-existing S. pneumoniae in the nasal cavity of wild-type, but not IgA-/- mice. These results show that PspA-specific S-IgA Abs play important roles in the prevention of S. pneumoniae colonization and clearance. Supported by NIH grants AG025873 and DE12242.
TLR2 Regulation of Oral Keratinocyte Driven Mucosal Homeostasis in the Context of Diabetes Mellitus (47.11)
Authors: Wallet Shannon 
Published: January 2023

Abstract
Oral epithelium contributes to innate immunity and plays an important role in immune tolerance/homeostasis. Disruption of this homeostasis can result in initiation and/or exacerbation of localized inflammation that secondarily causes/worsens systemic diseases. Toll-like receptor 2 (TLR2) is one molecular pattern receptor that under cell- and/or environment-specific conditions can induce either inflammatory or regulatory immune responses. Hyperglycemia, a sequela of diabetes mellitus, has multiple profound effects on the local innate responses, which drives cyclical pathogenesis where elevated glucose disrupts mucosal homeostasis, exacerbating oral inflammation that in turn compounds systemic manifestations of diabetes. We evaluated the innate immune responses of oral keratinocytes (HOK) under homeostatic and hyperglycemic conditions. Our results demonstrated that TLR2 homo-dimerization resulted in an immunoregulatory response, and that this maintenance of tolerance is interrupted under hyperglycemic conditions. We have also demonstrated that regulation of this immunoregulatory response involves expression and phosphorylation of TLR signaling intermediates regulated by multiple miRNA. We propose that HOK regulation is multi-factorial and our model will facilitate development of therapies designed at restoring oral homeostasis to stop the vicious cycle linking systemic diseases such as diabetes with disruption of mucosal homeostasis and exacerbation of the systemic disease.
Exacerbation of DSS induced colitis by localized delivery of IFN-β secreted by Lactobacillus acidpohilus (47.6)
Authors: McFarland Adelle , Savan Ram , Wagage Sagie , Addison Augustina , Young Howard 
Published: January 2023

Abstract
There have been conflicting reports of the role of Type I interferons in gut inflammation and inflammatory bowel diseases. While in some patients with active ulcerative colitis (UC), treatment with Type I interferons induced remission of symptoms, other reports have documented the spontaneous occurrence of UC in multiple sclerosis and chronic hepatitis C patients receiving IFN-β therapy. In order to evaluate the potential for IFN-β as a therapeutic for IBD, we developed a delivery system involving probiotic bacteria. Treatment of healthy mice with Lactobacilli secreting IFN-β results in increased IFN-γ positive cells within the gut as well as a reduction in the percentage of T-regulatory cells. When mice were pretreated with Lactobacilli secreting IFN-β prior to induction of acute DSS colitis, we observed more weight loss and a worsening of intestinal thickening/shortening. In addition, there was an increase in the percentage of Th17 cells, as well as an increase in the production of TNF-α by colonic tissue. This study demonstrates that localized delivery of IFN-β by probiotic bacteria results in an exacerbation of DSS induced colitis in a preventative model.
Critical role for the NLRP3 inflammasome in colitis and colitis associated colorectal cancer (47.9)
Authors: Zaki Mohammad , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Mutations in NOD-like receptor (NLR) Nlrp3 cause a variety of rare autoinflammatory disorders. Decreased expression of the Nlrp3 was recently associated with susceptibility to Crohn's disease. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in the inflammasome, a protein complex responsible for the maturation and secretion of IL-1β and IL-18. However, the role of Nlrp3 in colitis has not been characterized. Here, we show that mice deficient for Nlrp3 or the inflammasome effectors ASC and caspase-1 are highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation leads to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration and increased chemokine production in the colon. To explore the possibility that increased inflammation in inflammasome-deficient mice may lead to tumorigenesis, we developed colorectal tumor model using azoxymethane followed by DSS-induced chronic colitis. Nlrp3- and caspase-1-deficinet mice showed an increased incidence and multiplicity of tumors compared to those of wild-type. Antibiotics treatment ameliorated clinical readouts of colitis and tumorigenesis in Nlrp3-deficient mice, demonstrating the role of commensal microflora in aggravating colitis severity. Therefore, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis and colorectal tumorigenesis.
B cells in chronically inflamed skin. (48.10)
Authors: Geherin Skye , Fintushel Sarah , Hay John , Gudrun Debes 
Published: January 2023

Abstract
B cells infiltrate extralymphoid tissues in many chronic inflammatory diseases, including cutaneous manifestations of autoimmunity as well as infection. However, the phenotype and function of B cells in the skin remains poorly understood. In a granuloma model of cutaneous inflammation in sheep and mice, B cells increase during the chronic phase of inflammation in both percentage and absolute number in the skin and skin-draining afferent lymph. B cells in the skin and skin-draining lymph are a heterogeneous population that is phenotypically distinct from B cell populations in the spleen and lymph nodes. Many skin B cells exhibit an ‘innate-like’ phenotype co-expressing IgM and CD11b. Furthermore, skin B cells have increased MHCII and CD80/86 expression compared to lymph node or splenic B cells, suggesting that they are well-suited for T cell activation at the site of inflammation. Additionally, skin B cells are not responsive to ligands of chemokine receptors typically associated with skin homing. The data support a model in which innate-like B cells use alternative chemokine receptors to migrate to the skin where they support inflammatory or protective immune responses.
Lung CD4+ T cell receptor AV2S3+ T cells in sarcoidosis respond to the mycobacterial protein mKatG (48.6)
Authors: Wikén Maria , Ostadkarampour Mahyar , Willett Matthew , Chen Edward , Eklund Anders , Moller David , Grunewald Johan , Wahlström Jan 
Published: January 2023

Abstract
Background Sarcoidosis is an inflammatory disease in which T cell responses have been found against the mycobacterial protein mKatG. Our aim was to study the ability of lung and blood CD4+ or CD8+ T cells, and in particular T cell receptor (TCR) AV2S3+ CD4+ T cells, to respond with cytokine production to mKatG. Methods Bronchoalveolar lavage (BAL) fluid and peripheral blood were obtained from 13 HLA-DRB1*0301+ patients, who recover spontaneously, all with lung-accumulation (&gt;10.5% of CD4+) of AV2S3+ T cells. Using flow cytometry and intracellular cytokine staining lung and blood T cells were studied with regard to IFNγ, TNF and IL-2 production, after mKatG or purified protein derivate (PPD) stimulation. Results Lung CD4+ T cells responded with IFNγ, TNF and IL-2 production after mKatG or PPD stimulation, whereas CD8+ T cells responded with IFNγ production, and only to mKatG. AV2S3+ T cells responded with IFNγ secretion to mKatG to a significantly higher extent than AV2S3- T cells, whereas the opposite was seen for PPD. Blood CD4+ T cells responded with IFNγ and TNF production after mKatG or PPD stimulation. Stimulation with mKatG generated a large fraction of single IFNγ-producing cells, whereas PPD stimulated to a more pronounced multifunctional profile with IFNγ/TNF or IFNγ/IL-2 secretion. Conclusion A specific mycobacterial antigen, mKatG, triggers a subset of the AV2S3+ T cells, indicating a possible role for these cells in eliminating an offending antigen in sarcoidosis.
IL-6 and IL-1α together, but not alone, are key modulators of regulatory T cell suppressive function: insights from computational and in vitro studies. (49.11)
Authors: Raimondi Giorgio , Ziraldo Cordelia , Pillai Mahesh , Manzoni Giulia , Kowalkowski Frank , Vodovotz Yoram , Thomson Angus 
Published: January 2023

Abstract
Modulation of the susceptibility of effector T cells to suppression by naturally-arising regulatory T cells (Treg) influences the development of autoimmune diseases, cancer, and transplant outcome. However, our understanding of the factors that underlie this modulation is limited. We aimed to identify the inflammatory mediators that are released by innate immune cells following their exposure to danger signals, and that reduce T cell susceptibility to suppression. A CFSE-based, in vitro mouse T cell activation system was employed to quantify Treg function and to measure the influence of the supernatant of dendritic cells sampled at multiple times after stimulation with the TLR4 ligand LPS. In parallel, 24 cytokines were quantified using Luminex™ in each sample tested. ‘Principal Component Analysis’ was utilized to assess the likely role of these cytokines with the extent of Treg suppression. This analysis suggested that IL-6, IL-1α, and TNFα were possible inhibitory mediators working in synergy. Using the CFSE dilution assay, we found that no single cytokine was capable of reducing Treg suppression. However, combinations of cytokines, in particular IL-6 and IL-1α, resulted in pronounced modulation of suppression. Our results suggest that combining computation with experimentation may help to dissect the complex milieu that determines T cell susceptibility to suppression, and specifically to identify the synergy between IL-6 and IL-1α as target for immunomodulatory therapies.
CD200Fc(Gly)6TGFβ suppresses transplant rejection and MLCs in vitro (49.15)
Authors: Gorczynski Reginald , Chen Zhiqi , Shivagnahnam Saaiis , Taseva Adriana , Wong Karrie , Yu Kai , Khatri Ismat 
Published: January 2023

Abstract
CD200 suppresses graft rejection after engagement of receptors (CD200R), via induction of Treg and production of TGFβ. We asked if a hybrid molecule linking a soluble form of CD200, CD200Fc, to murine TGFβ through a (Gly)6 linker would produce superior suppression to either CD200FC or TGFβ alone, or in combination. MLC cultures used BL/6 responder cells and irradiated BALB/c DCs, in the presence/absence of varying doses of CD200Fc or TGFβ, alone or in combination, or CD200Fc(Gly)6TGFβ. CD200Fc(Gly)6TGFβ produced suppression at 20-100-fold lower concentrations than all other reagents tested alone or together. When used in vivo to suppress rejection of BALB/c skin grafts in C57BL/6 mice, CD200Fc(Gly)6TGFβ also produced immunosuppression at 100-fold lower concentrations. Further studies suggest the mechanism(s) by which this novel molecule produces suppression involves increased numbers of (inducible) Foxp3+ Treg which cause antigen-specific suppression in MLCs in vitro. Using cells with targeted deletion of the main receptor for CD200 (CD200R1), and/or treated with lentiviral particles encoding shRNAs specific for TGFβRII, we showed that suppression depended on responder T cells with a functional TGFβRII, and DCs expressing CD200R1. Augmented inhibition of suppression by CD200Fc(Gly)6TGFβ using anti-CD200R2 in cultures from CD200R1 knockout mice confirmed a role for CD200R2 in suppression. We conclude that CD200Fc(Gly)6TGFβ may have clinical utility in vivo, or ex vivo.
1,25-dihyroxyvitamin D3 enhances the activity of the FOXP3 gene in human CD4+ T cells through directly binding to putative VDRE sites in the FOXP3 gene (49.2)
Authors: Kang Insoo , Kim Sang Hyun , Lee Won-woo , Kang Seong Wook , Lee Jin Soo 
Published: January 2023

Abstract
1,25-dihyroxyvitamin D3 (1,25(OH)2VD3) is known to have immune regulatory effects on T cells. However, it is unknown whether 1,25(OH)2VD3 can directly regulate the expression of the FOXP3 gene in human CD4+ T cells. We thus searched and found putative response elements for vitamin D receptor (VDR) in a highly conserved non-coding sequence (CNS) region of the human FOXP3 gene that encompassed +1,722 to +2,562 using NUBIscan algorithm. The presence of VDR and retinoid X receptor (RXR), which heterodimerizes with VDR, in the nucleus of human CD4+ T cells was detected by co-immunoprecipitation using biotinylated fragments of the CNS region that contained the putative vitamin D response elements (VDRE) sites. We next performed a chromatin immunoprecipitation (ChiP) assay to determine whether VDR directly bound to the sites. The results of this assay showed the binding of VDR to the putative VDREs of the CNS but not to the promoter of the FOXP3 gene. To test whether 1,25(OH)2VD3 could directly enhance the FOXP3 promoter activity, we conducted a reporter assay using a PGL3 vector containing the FOXP3 gene promoter with or without VDREs in the CNS of the FOXP3 gene. Indeed, 1,25(OH)2VD3 enhanced the promoter activity of the FOXP3 gene in the presence of VDREs. Our findings indicate that 1,25(OH)2VD3 up-regulate the FOXP3 gene expression in human CD4+ T cells through directly binding to VDREs in the CNS region of the FOXP3 gene that encompasses +1,722 to +2,562.
SPPL3 regulation of Ca2+ homeostasis modulates NFAT activation during antigen-receptor stimulation in lymphocytes (50.11)
Authors: Lew Stefanie , Pomerantz Joel 
Published: January 2023

Abstract
During T cell receptor signaling, activation of several transcription factors initiates new gene expression, leading to the generation of specific T cell responses. One important event in this pathway involves store-operated calcium entry (SOCE) through Ca2+-release-activated-Ca2+ (CRAC) channels, which activates the key transcription factor NFAT. Induction of this Ca2+-dependent signaling necessitates tight regulation of intracellular Ca2+ levels, and while the identification of STIM1 and CRACM1 has significantly helped elucidate how SOCE is achieved, other players in this pathway and alternative unknown pathways also controlling Ca2+ levels are not well understood. Here, we have used an expression cloning screen to identify signal peptide peptidase like 3 (SPPL3) as a novel activator of NFAT. Interestingly, SPPL3 is a polytopic membrane protein which localizes to the ER or Golgi compartment. Using Ca2+-sensitive dyes, we determined that SPPL3 overexpression elevated basal intracellular Ca2+ levels, dampened the thapsigargin-stimulated release of ER Ca2+ stores, and enhanced Ca2+ influx. SPPL3-mediated NFAT activation was blocked by the SOCE inhibitor SKF 96365 and a dominant negative CRACM1. By influencing intracellular Ca2+ levels, SPPL3 appears to be a novel regulator of calcium homeostasis that can positively modulate antigen receptor-mediated activation of NFAT.
The role of β2 integrins in host responses to intracellular bacterial infection in mice (50.27)
Authors: Bose Tina , Khanna Dr. Kamal , Lefrancois Dr. Leo 
Published: January 2023

Abstract
β2 (CD18) integrins (CD11a,b,c,d) are important adhesion molecules necessary for leukocyte migration, homing, and cell to cell interactions. CD18-deficiency in humans is characterized by recurrent bacterial infections and poor wound healing, due to defects in leukocyte activation and migration. However, the in vivo role of each of the individual β2 family members is poorly understood. CD11a, CD11b and CD11c are all upregulated on activated CD8 T cells. In order to study the potential role for β2 integrins in host defense, CD11a, CD11b and CD11c deficient and wildtype mice were infected with Listeria monocytogenes (LM). Surprisingly, the absence of the integrins had no effect on the expansion of antigen specific CD8 T cells in response to infection with LM. Although CD11b-/- and CD11c-/- exhibited normal effector functions, granzyme levels and effector cytokines were reduced in CD11a-/- CD8 T cells as compared to WT CD8 T cells post LM infection. CD11b and CD11c are also highly expressed by important antigen presenting cells such as macrophages and dendritic cells (DC). Therefore, we tested whether the absence of CD11c or CD11b compromised DC function. However, preliminary experiments indicated that upon infection, CD11b-/- and CD11c-/- DCs are capable of normal activation and migration. Overall, these results suggested that unlike CD11b and CD11c, CD11a may play an integral role in induction of optimal effector functions in CD8 T cells.
ICAM-1 expression on CD8+ T cells negatively regulates IFN-γ production. (50.28)
Authors: Zumwalde Nicholas , Shimizu Yoji 
Published: January 2023

Abstract
The factors that regulate the production of effector cytokines following antigen stimulation of naïve CD8+ T-cells are incompletely characterized. We utilized ICAM-1-/- mice to determine if the expression of ICAM-1 on naïve CD8+ T-cells modulates CD8+ T-cell activation and differentiation. Stimulation of purified wild-type OT-I CD8+ T-cells with purified MHC/Antigen, B7-1, and the inflammatory cytokine IL-12 results in robust proliferation and differentiation into CD8+ effector T-cells producing IFN-γ. This activation is associated with prominent T-cell:T-cell clusters and increased expression of ICAM-1. The presence of IL-12 sustains elevated levels of ICAM-1 on activated CD8+ T-cells and enhances T-cell:T-cell clusters. Activation of ICAM-1-/- OT-I T-cells results in comparable levels of proliferation as wild-type OT-I T-cells. However, ICAM-1-/- CD8+ T-cells fail to form significant homotypic clusters upon activation in this system. In addition, when compared to wild-type OT-I T-cells, antigen-specific activation of ICAM-1-/- OT-I T-cells results in a higher percentage of effector T-cells producing IFN-γ. These results suggest that inflammatory cytokines such as IL-12 may attenuate the generation of IFN-γ+ CD8+ effector T-cells via modulation of ICAM-1 expression following antigen stimulation of naïve CD8+ T-cells.
Inflammatory responses elicited by ocular herpes simplex virus type 1 infection are inhibited by upregulation of programmed cell death ligand 1 on trigeminal ganglionic neurons (50.29)
Authors: Cherpes Thomas , Jeon Sohyun , Vicetti Miguel Rodolfo , Phillips Jaclyn , Hendricks Robert 
Published: January 2023

Abstract
T cell effector responses are required for clearance of viral infection. In locations such as the central and peripheral nervous systems, where cell types lack regenerative ability, it is also critical that protective T cell responses produce minimal collateral damage. Using a murine model of ocular herpes simplex virus type 1 (HSV-1) infection, we report that programmed cell death ligand 1 (PD-L1) expression by trigeminal ganglia (TG) neurons is dramatically upregulated during acute infection, and that this increased PD-L1 expression is regulated by local expression of gamma-interferon. We further observed that treatment with anti-PD-L1 antibody significantly increased the overall number of CD4+ and CD8+ T cells as well as the number of HSV-specific CD8+ T cells present in the TG during acute infection. Anti-PD-L1 antibody treatment also affected T cell activation status as increased granzyme B expression was detected in all three of these T cell populations. Although control of viral replication in the TG appeared to be unaffected by treatment, during acute infection TG neurons from mice treated with anti-PD-L1 antibody became susceptible to perforin-mediated killing. Together, our data demonstrate a novel neuroprotective role for PD-L1 during acute viral infection, and may also suggest avenues for development of therapies capable of inhibiting the neuronal damage associated with many inflammatory conditions.