bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of IL-6 signaling by zinc leads to repression of the Th17 response (IRM11P.763)
Authors: Lee Won-Woo , Lee Hyunju , Yoon BoRuem , Hwang Yuri 
Published: January 2023

Abstract
Zinc is an essential trace element that plays pivotal roles in multiple facets of the immune system. Besides its catalytic and structural roles, zinc also functions as an intracellular signaling molecule, and changes in zinc levels can cause both direct and indirect modulation of immune responses. Further, cytoplasmic levels of bioavailable zinc in immune cells are largely influenced by many extracellular stimuli. Here we provide evidence that zinc alters the cytokine production profile of human CD4 T cells by functioning as an intracellular signaling molecule during T-cell responses. In vitro zinc treatment of T cells in the presence of activated monocytes inhibited IFN-γ and IL-17 producing cells, but not IL-4 producing cells. Of note, production of IL-17+ CD4 T cells, which is significantly upregulated by LPS-stimulated monocytes, was preferentially repressed by zinc. Increased cytoplasmic zinc in T cells suppressed IL-6 signaling via repression of phosphorylation of Stat3, thus leading to an inhibitory effect on Th17 responses facilitated by monocyte-derived IL-6 in humans. These finding suggest that therapeutic manipulation of zinc bioavailability may be a good means by which to modulate CD4 T-cell responses.
The origin of natural antibody (LYM6P.764)
Authors: Reynolds Alexander , Kuraoka Masayuki , Kelsoe Garnett 
Published: January 2023

Abstract
Natural antibody is constitutively present in the serum of all mammals. This unique IgM plays an important role in the clearance of cellular debris, the early control of viral and bacterial expansion, and the initiation of T-dependent humoral responses. Despite decades of study, the origins of natural antibody have not been precisely defined. Transfer experiments have shown a close correlation between peritoneal cells, including B1a cells, and natural antibody, but peritoneal B1 cells do not secrete adequate amounts of IgM to support the levels found in mouse serum. Here, we show that a discrete population of IgM plasmacytes in the bone marrow produces all serum IgM in resting mice. These plasmacytes originate from cells in the peritoneal cavity, but not from B1a B cells, and transfer of these progenitors completely restores serum IgM and the specific compartment of bone marrow plasmacytes in Rag1 deficient mice. This plasmacyte compartment contains a substantial fraction of non-dividing, long lived cells that do not occupy the IgG plasmacyte survival niche in the bone marrow but instead depend on IL-5. Genetic analysis of these IgM plasmacytes reveals an unmutated, clonally diverse population strongly enriched for VH11 rearrangements. We propose that these natural IgM plasmacytes represent an “innate B-cell” population descended from yolk sac progenitors, and that natural IgM plasmacytes are not the progeny of B1 B cells but instead share an earlier common ancestor.
Each naïve B cell within a polyclonal repertoire produces a different frequency and pattern of effector cells (LYM6P.769)
Authors: Taylor Justin , Pape Kathryn , Jenkins Marc 
Published: January 2023

Abstract
Following activation with antigen, naïve B cells undergo a robust proliferative expansion and differentiation that results in the production of numerous distinct cell types with different roles in protective immunity. In fact, germinal center B cells, memory B cells, plasma cells and an undifferentiated population of T/B border B cells are all detected 7 days following immunization. While some of the transcriptional regulators and extrinsic factors directing differentiation of these subtypes are known, these mechanisms cannot account for the simultaneous existence of all 4 cell subtypes. By tracking the response of a single naïve B cell within a polyclonal response we find that an individual naïve B cell usually contributes half of the subtypes found in a polyclonal response. In fact, the progeny of only 8% of cells analyzed contained all 4 subtypes while 12% of cells only generated a single subtype. One factor constraining differentiation is B cell receptor affinity for antigen, but individual cells with identical receptors do produce different patterns of progeny. Thus, the heterogeneity found within the polyclonal response is in part the result of the differential responses of individual naïve B cells.
Lig4 modulates p53-p21 checkpoints and inhibits A-EJ during end-joining repair phase of IgH class switching (LYM6P.770)
Authors: Park Jihye , Welner Robert , Tenen Daniel , Yan Catherine 
Published: January 2023

Abstract
Mutations in the non-homologous end-joining DNA repair protein DNA Ligase IV (LIG4) causes a human syndrome of immunodeficiency and radiosensitivity. We previously described knock-in mice with a homozygous R278H mutation in Lig4 (Lig4R/R) that displayed severely leaky B lymphocyte development, resulting in near lack of mature B cells yet only a partial block in IgH class switch recombination (CSR). Here we show that diminished DNA ligase 4 activity, resulting in slower kinetics of DNA double strand break (DSB) repair and attenuation of p53-dependent DNA double strand break (DSB) response, to underlie the partial CSR block in the Lig4R/R activated B cells. Analysis of p53 levels in activated Lig4R/R B cells revealed increased proteosome mediated p53 decay and p21 activation, indicative of slower repair kinetics, effects mimicked in the human Lig4 R278H 180BR cell line. Concurrent p53 inactivation had little effect on the frequency of IgH breaks; but substantially slowed the cell cycle progression of activated Lig4R/Rp53-/- B cells, and failed to promote the development of B-lymphomas that recurrently developed in murine Lig4-/-p53-/- settings. Analysis Lig4R/R CSR junctions also revealed the predominance of NHEJ instead of NHEJ-independent A-EJ in their generation. Hence NHEJ maintains genomic stability by modulating the p53 DNA damage response and inhibiting A-EJ. These findings provide an explanation for the complex B-lymphoid phenotypes of the human Lig4 Syndrome.
The Pseudomonas aeruginosa virulence factor Cif inhibits the generation of the pro-resolving lipid mediator 15-epi lipoxin A4 (MPF3P.812)
Authors: Flitter Rebecca , Ono Emiko , Hvorecny Kelli , Levy Bruce , Madden Dean , Bomberger Jennifer 
Published: January 2023

Abstract
Pseudomonas aeruginosa is an opportunistic Gram-negative bacteria that causes a wide range of severe nosocomial infections, especially in immunocompromised patients with chronic inflammatory lung disease. P. aeruginosa infections are characterized by persistent and robust neutrophilic inflammation which can cause damage to host tissue. Lipoxins, including 15-epi-lipoxin A4 (15-epi-LXA4), are lipid mediators that play a critical role in resolving inflammation and promoting tissue homeostasis. The production of 14,15-epoxy-eicosatrienoic acid (14,15-EET) by airway epithelial cells stimulates the generation of 15-epi-LXA4 by neighboring neutrophils through transcellular biosynthesis. We have identified a P. aeruginosa virulence factor with epoxide hydrolase activity called cystic fibrosis inhibitory factor (Cif), which we hypothesize disrupts the generation of 15-epi-LXA4. We show that both P. aeruginosa and recombinant Cif protein alone hydrolyzes the epoxide moiety of (14,15-EET), whereas a Cif mutant P. aeruginosa or catalytically dead D129S mutant of Cif have no effect. Furthermore, the Cif-mediated reduction of 14,15-EET inhibited the generation of 15-epi-LXA4 by activated neutrophils in vitro. The D129S mutant Cif was also incapable of reducing 15-epi-LXA4 biosynthesis. Taken together, our data suggest a novel model whereby the P. aeruginosa virulence factor Cif reduces 15-epi-LXA4 in the airways, thus promoting persistent inflammation and consequent lung damage.
NanoCurcumin inhibits TNF-α in Mycobacterium tuberculosis-infected macrophages (MPF3P.821)
Authors: Pokkali Supriya , Ordonez Alvaro , Chenna Venugopal , Maitra Anirban , Jain Sanjay 
Published: January 2023

Abstract
Background: Host response to M. tuberculosis (M.tb) infection leads to tissue destruction and impairs the ability of drugs to reach the bacteria. New anti-inflammatory adjuvant therapies could enhance bacterial clearance. Curcumin (diferuloylmethane) is a lipophilic phytochemical present in turmeric (Curcuma longa). Encapsulation of curcumin with polymers (NanoCurcuminTM) increased absorption and bioavailability of curcumin and is being investigated as host-directed therapies for the treatment various diseases. Methods and Results: We investigated the effect of free and encapsulated NanocurcuminTM on M.tb induced host inflammatory responses in M.tb infected J774 macrophages. Bacterial burden and cytokine levels were enumerated by standard microbiological and immunological methods. We utilized physiologically achievable levels of NanocurcuminTM (based on prior in vivo studies) and found a dose dependent decrease in the levels of TNF-α in M.tb infected J774 macrophages. Conclusions: NanoCurcumin™ can modulate TNF-α and could be utilized as a host-directed therapy to enhanced bacterial clearance and potentially shorten TB drug regimen.
The role of IL-23 in regulating the function of phagocytic cells during Listeria monocytogenes infection (MPF3P.822)
Authors: Indramohan Mohanalaxmi , Break Timothy , Witter Alexandra , Berg Rance 
Published: January 2023

Abstract
The IL-23/IL-17 axis contributes to autoimmune disorders, but is protective against certain pathogens, particularly extracellular bacteria. We have previously shown that IL-23 provides resistance against the intracellular bacterium, Listeria monocytogenes (LM) by mediating the recruitment of neutrophils to the liver, and inflammatory monocytes to the spleen. However, it is not known whether IL-23 can impact the function of phagocytic cells including inflammatory monocytes, neutrophils, and macrophages, during LM infection. Phagocytic cells express receptors for IL-23 and IL-17A suggesting the activity of these cells could be regulated by IL-23 or IL-17A. Surprisingly, phagocytic cells from mice lacking IL-23 (IL-23p19 knockout) had equivalent phagocytic potential and ROS production compared to C57BL/6 mice. Additionally, exogenous stimulation with rIL-23 or rIL-17A did not induce or enhance the production of pro-inflammatory mediators from splenocytes isolated from C57BL/6 mice. Therefore, IL-23 does not impact the function of phagocytic cells either by a direct or an indirect mechanism during LM infection. Collectively, our data reveal that the enhanced susceptibility of IL-23p19 knockout mice is not due to functional impairment of phagocytic cells; instead it is caused by the inefficient recruitment of neutrophils to the liver, and inflammatory monocytes to the spleen, resulting in a reduction in the overall levels of TNF-α and nitric oxide during LM infection.
Taenia crassiceps excreted/secreted products induce alternatively activated macrophages in vitro. (MPF3P.824)
Authors: Martínez-Saucedo Diana , Faz Berenice , Callejas Blanca , Ledesma-Soto Yadira , Terrazas Luis I. 
Published: January 2023

Abstract
Alternatively activated macrophages (aaMφ) are key players in the immunomodulation generated during helminth infections. Recent evidences suggest that derived molecules from helminths can directly induce aaMφ. Taenia crassiceps and its excreted/secreted products (TcES) have been demonstrated in modulate inflammatory responses. We have special interest in determine whether TcES directly are capable of generate aaMφ. On the other side, the ability of microRNAs (miRNAs) to influence cellular functions and their development have been suggested as a mechanism to develop new therapeutic applications based on differential expression of miRNAs. Because of this, is quite important to characterize the miRNAs involved in the response of Mφ to TcES as a possible mechanism to control inflammation as well as contributing to a better understanding of the mechanisms involved in macrophage polarization. We have found that macrophages derived from bone marrow (MφBM) exposed directly to TcES expressed molecules related to alternative activation such as PD-L1 and Mannose receptor, as well an downregulation in miR-155 and let-7i. Our data suggest that TcES induce aaMφ where some miRNA induction may participate.
The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections (MPF3P.805)
Authors: Bishu Shrinivas , Hernandez-Santos Nydiaris , Simpson-Abelson Michelle , Huppler Anna , Conti Heather , Ghilardi Nico , Mamo Anna , Lin Xin , Gaffen Sarah 
Published: January 2023

Abstract
Oropharyngeal candidiasis (OPC, thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, and individuals with congenital immune defects. Immunity to OPC is dependent on the IL-23/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans via signals from C-type lectin receptors, which signal through the adaptor CARD9 leading to production of Th17-inducing cytokines such as IL-6, IL-1 and IL-23. Recent data indicates that IL-17 can also be made by numerous innate cell subsets. These innate ‘Type 17’ cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and thus mice are naïve to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9-/- mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9-/- mice had preserved innate IL-17-dependent responses and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses.
Lung hydrolases modify the course of Mycobacterium tuberculosis infection in vivo (MPF3P.806)
Authors: Moliva Juan , Sasindran Smitha , Arcos Jésus , Turner Joanne , Torrelles Jordi 
Published: January 2023

Abstract
Mycobacterium tuberculosis (M.tb) kills one person every 18 seconds. Upon M.tb deposition in the airways, bacilli are bathed in alveolar lining fluid (ALF). Our published data indicate that hydrolytic enzymes present in ALF modify the cell wall of M.tb with two outcomes: cell wall modifications and release of cell wall fragments into the milieu. These modifications resulted in an altered macrophage immune response in vitro. Here we used the low dose aerosol mouse model of M.tb infection to assess if ALF/hydrolase-derived modifications of M.tb alter the immune response to infection in vivo. Our current data indicate that ALF/hydrolase-derived modifications on the M.tb cell wall led to increased CD4 and CD8 T cell numbers and activation in the lung, and altered cytokine secretion (increased TNF, IL-12 and IFN-γ), important for control of M.tb infection. These results correlated with an improvement of the M.tb burden within the lung starting on day 21 of infection. Thus, our results support the concept of human ALF hydrolases being novel immune components that can influence the generation of immune responses during M.tb infection.
Symbiotic bacterial metabolites regulate GI barrier function via PXR and TLR4 (MUC4P.852)
Authors: Khanna Kamal , Mukherjee Subhajit , Venkatesh Madhukumar , Qiu Zhijuan , Mani Sridhar 
Published: January 2023

Abstract
Intestinal microbial metabolites affect mucosal integrity through incompletely characterized mechanisms. Here we identify microbial specific indoles that regulate intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, serves as a ligand for PXR and down-regulates enterocyte TNF-α while up-regulating junctional protein-coding mRNAs. Pxr-/- mice exhibit a distinctly “leaky” gut physiology coupled with up-regulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier are corrected in Pxr-/-/Tlr4-/- double-knockout mice. To validate that IPA drives the anti-inflammatory response directly via PXR, we exposed intestinal commensal-depleted Pxr+/+ and Pxr-/- mice to live (IPA-producing) or heat-killed (non-IPA producing) C. sporogenes preceding indomethacin exposure (toxic small intestinal injury model). There was a significant reduction in histologic injury and mucosal myeloperoxidase (MPO) enzyme activity. The intestinal mucosa exposed to live (as opposed to heat-killed) C. sporogenes had significant induction of PXR target gene (Ugt1a1). These effects were absent in Pxr-/- mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway which involves luminal sensing and signaling by TLR4.
Innate lymphoid cells protect host against intestinal pathogen through Id2 dependent IL-22 production and regulation of microbiota. (MUC4P.855)
Authors: Guo Xiaohuan , Kee Barbara , Fu Yang-Xin 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) represent a novel family of immune cells that can regulate immunity, inflammation, and tissue repair in multiple barrier surfaces. While Id2 is known to be required for the development of ILCs progenitor, Id2 remains highly expressed in differentiated ILCs with unknown function. Using newly generated conditional KO mice, we demonstrated a novel role for Id2 in RORγt+ ILC3s not only in controlling the further development and maintenance of ILC3s but also regulating IL-22 production by ILC3s through IL-23R - STAT3 pathway. Id2 deficiency in ILC3s increased morbidity and mortality after Citrobacter rodentium infection. Interestingly, the mice with Id2 deficiency in ILC3s exhibited much higher fecal C. rodentium CFU even within 24 hours post inoculation, suggesting that preexisting Id2-dependent gut microenvironment mediated the early colonization resistance against C. rodentium. Furthermore, the wild type germ free mice colonized with the microbiota from the conditional Id2 deficient mice by gavage of cecal material also had higher fecal C. rodentium CFU, compared with the germ free mice that received microbiota derived from wild type mice. Cohousing partially rescued conditional Id2 deficient mice from lethal infection. Together, our data suggest that continued Id2 expression is required for the development and function of ILC3s, and ILC3s protect host against intestinal pathogen through Id2 dependent regulation of microbiota.
Goblet cell-associated antigen passages are reduced during enteric infection (MUC4P.831)
Authors: Kulkarni Devesha , McDonald Keely , Knoop Kathryn , Miller Mark , Newberry Rodney 
Published: January 2023

Abstract
The intestinal mucosa is continually exposed to foreign antigens derived from the diet, commensal bacteria, and pathogens. Regulating the exposure of the immune system to this broad array of antigens is crucial to ensure intestinal homeostasis and to respond appropriately to enteric infections. Using in vivo two-photon imaging of the intestine of live mice, we recently demonstrated that under steady state conditions a subset of small intestinal goblet cells (GCs) transport luminal antigens to CD103+ dendritic cells (DCs) by forming goblet cell-associated antigen passages (GAPs). To understand how enteric infection altered GCs and GAPs, we infected mice with wildtype fluorescently labeled Salmonella typhimurium and evaluated GCs and GAPs using fluorescence microscopy. Within hours of intraluminal exposure, Salmonella preferentially localized around and within GCs that had formed GAPs. 24 hours after oral Salmonella infection, a subset of GCs were found to be apoptotic, and 72 hours after infection, GAPs were significantly decreased beyond the level of GC apoptosis. Salmonella infection resulted in epithelial activation of the epidermal growth factor receptor (EGFR), a potential regulator of GC secretion and GAP formation. These observations indicate that GAPs may provide a portal of entry for pathogens, and that GAP formation is reduced following enteric infection potentially to avoid delivery of luminal antigen to lamina propria immune cells in a hostile environment.
Trefoil factor 2 maintains and restores pulmonary function via promoting epithelial repair and M2 activation (MUC5P.859)
Authors: Herbert De'Broski , Hung Li-Yin , Sen Debasish , Oniskey Taylor , Kim Charlie , Krummel Matthew 
Published: January 2023

Abstract
Mechanisms responsible for pulmonary tissue homeostasis and regeneration are incompletely understood. This study investigated whether Trefoil factor family (TFF) proteins, regulators of gastrointestinal restitution, served any role in the pulmonary tract under steady state conditions or pathogen infection. At baseline, TFF2 lung mRNA transcript levels were highest compared to TFF1 and TFF3. Strikingly, TFF2 deficient mice (TFF2-/-) were hypoxic by 6-8 weeks of age, with abnormal alveoli, reduced blood oxygen levels, and defective integrin expression on alveolar type 1 cells. TFF2 was essential for mucosal barrier function in tracheal epithelia and TFF2 deficiency caused multiple transcriptional defects in adhesion, motility, and wound repair. Unexpectedly, TFF2 expression in hematopoietic cells was necessary for Type 2 immunity and recovery of pulmonary function after inoculation with the hookworm Nippostrongylus brasiliensis. TFF2 served a cell-intrinsic role in promoting macrophage polarization towards the M2 subset. Thus, in addition to epithelial restitution, TFF2 derived from hematopoietic cells instructs macrophage subset differentiation, promotes host immunity, and stimulates tissue repair within the pulmonary tract.
Superior protection and distinct phenotype of pulmonary CD8+ T cells elicited by mucosal vaccination (MUC5P.863)
Authors: Gilchuk Pavlo , Hill Timothy , Guo Yan , Clark Travis , Erickson John , Lu Pengcheng , Boyd Kelli , Williams John , Shyr Yu , Joyce Sebastian 
Published: January 2023

Abstract
CD8-positive T cells (CTLs) confer protective immunity against many infectious diseases, and thus the development of safe and efficient CTL-targeted vaccination is of high clinical significance. Although many respiratory pathogens invade the host through the lung mucosa, most licensed human vaccines elicit limited and systemic T cell responses, rather than strong local pulmonary responses. We therefore wondered whether elicitation of pulmonary CTL response with microbe-free CTL-targeted subunit vaccine might benefit the host and protect against respiratory infections. We discovered superior protection of humanized mice from lethal respiratory challenge with vaccinia virus with intranasal, but not intra-peritoneal, vaccination. Critically, this superior protection did not correlate with the magnitude of the systemic CTL response but was dependent on in situ elicitation of robust pulmonary epitope-specific CTLs, which were able to limit viral replication and prevent disease. Global transcriptome analysis revealed that pulmonary CTLs elicited by vaccination possessed distinct phenotypic and functional properties when compared to CTLs that homed to the spleen. To extend this finding, we developed an approach for eliciting protective CTL responses that utilizes nanoparticle-based mucosal delivery of epitope-targeted vaccine formulated with an optimal adjuvant.