bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered inactivation of commensal LPS due to acyloxyacyl hydrolase deficiency in colonic dendritic cells impairs mucosal Th17 immunity (MUC4P.825)
Authors: Janelsins Brian , Datta Sandip 
Published: January 2023

Abstract
Interleukin 17 (IL-17)-secreting CD4+ helper T (Th17) cells are essential for host defense at mucosal surfaces, and dysregulation can result in autoimmunity. Exposure to microbial products such as lipopolysaccharide (LPS) can affect the ability of dendritic cells (DC) to polarize Th17 cells. Acyloxyacyl hydrolase (AOAH) is a mammalian enzyme expressed by antigen (Ag)-presenting cells that inactivates LPS in host tissues. We hypothesized that inactivation of intestinal-derived LPS by AOAH influences the ability of DC to prime Th17 cells. We found that LPS-containing microbiota augmented the polarization of Ag-specific Th17 cells, and identified CD103+CD11b+ colonic DC with the unique capacity to express AOAH and bias Th17 cells. Compared to wild-type, these Aoah-/- colonic DC produced less IL-6, which resulted in diminished Ag-specific Th17 polarization and increased regulatory T cell induction in vitro. Oral administration of LPS led to reduced IL-6 production from CD103+CD11b+ colonic DC in Aoah-/- mice in comparison to Aoah+/+ mice, resulting in an abrogated Ag-specific Th17 response in the gut after mucosal immunization that could be rescued by systemic delivery of recombinant IL-6. These data identify the ability of AOAH to modulate microbiota signals that drive mucosal Th17 polarization, and suggest that host pathways to handle microbiota-derived products may be targeted to modulate Th17 responses in the context of inflammatory disorders or infection at mucosal surfaces.
Neutrophils negatively regulate induction of mucosal IgA antibody responses to sublingual immunization (MUC4P.835)
Authors: Jee Junbae , Kim Eunsoo , Bonnegarde-Bernard Astrid , Iwakura Yoichiro , Cormet-Boyaka Estelle , Boyaka Prosper 
Published: January 2023

Abstract
Secretory IgA antibody plays an important role in the protection of mucosal surfaces against microbial pathogens. Induction of the IgA antibody has been known to be largely dependent upon the cytokine milieu. However, the importance of innate immune cell subsets for IgA responses has not been fully appreciated yet. We investigated the role of myeloid cell-subsets on IgA responses to sublingual immunization. In contrast with cholera toxin as an adjuvant which promotes IgA responses, sublingual application of the Bacillus anthracis edema toxin (EdTx) to C57BL/6 mice transiently increased the frequencies of neutrophils in sublingual tissue and cervical lymph nodes (CLNs), and promoted antigen-specific serum IgG, but not serum or mucosal IgA responses. However, EdTx as an adjuvant failed to increase frequencies of neutrophils in sublingual tissue and CLNs of mice lacking IKKβ in myeloid cells (IKKβΔMye), and these mice developed antigen-specific mucosal IgA responses. Interestingly, depletion of neutrophils in C57BL/6 mice promoted antigen-specific fecal and serum IgA responses, similar to those of IKKβΔMye mice, and this effect was associated with increased frequencies of surface IgA expressing plasma cells, α4β7+CCR9+ B cells in lamina propria and number of Peyer’s patch. Our results show that the presence of neutrophils at mucosal inductive sites negatively influences induction of IgA responses and underlying mechanisms are under investigations.
Commensal microbiota and food antigens are important factors in the regulation of IgE production in mice (MUC4P.848)
Authors: Hong Sung-Wook , Kim Kwang-Soon , Surh Charles 
Published: January 2023

Abstract
IgE is one of key modulators in the pathogenesis of allergy by inducing FcR-mediated activation of mast cells and basophils. Production of IgE is regulated by commensal microbiota, as it is normally undetectable in conventional mice, but highly elevated in germ-free mice shortly after weaning into solid food. The mechanism behind IgE production in germ-free mice is poorly understood, but could be a consequence of dysregulated immune responses to Ags in the food. To address this idea, germ-free mouse pups were weaned into an antigen-free elemental diet comprised of essential amino acids, vitamins and minerals. Strikingly, neither these mice nor their offsprings, designated as antigen-free mice, possessed detectable levels of serum IgE. Moreover, feeding adult germ-free mice with antigen-free diet reduced the serum IgE level, indicating continued presence of food is required to sustain high amount of IgE production. As expected, antigen-free mice weaned into normal solid food diet produced high levels of IgE. To determine the age-dependency of commensal microbiota in IgE production, germ-free mice were conventionalized at various ages, starting from 4 wks. Colonization of commensal microbiota at 4 wks of age prevented high levels of serum IgE, but not for older mice. These results suggest that food Ags by default induce a strong IgE response that is suppressed by the commensal microbiota.
Metabolites from commensal microbes are closely associated with maintaining mucosal homeostasis through modulation of innate lymphoid cells in Peyer’s patch (MUC4P.849)
Authors: Jang Yong-Suk , Kim Sae-Hae , Lee Ha-Yan 
Published: January 2023

Abstract
It was characterized that the innate lymphoid cells (ILCs) are a group of immune cells closely associated with immune functions such as lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation through cytokine-mediated cell regulation. ILC subsets can be categorized into three groups based on cytokine-secreting patterns. Group 1 ILCs secrete IFN-γ. Group 2 produces type 2 cytokines dependent on GATA-3. Group 3 represents all RORγt+ ILC subtypes secreting IL-17 and/or IL-22. In mucosal immunity, RORγt+ ILCs play an essential role in early protection against enteric pathogen infections, although its regulation by mucosal environment is unknown. In this study, we suggest that butyrate, one of commensal microbe-derived metabolites, as a modulator of PP ILCs, because it is known that butyrate treatment closely associated with the protection of bacterial infection or DSS-induced colitis. In order to understand the mechanism underlying the proposed role of butyrate, we monitored the expression pattern of each transcription factors and cytokines in PP ILCs after oral administration of sodium butyrate in SPF and antibiotics-treated mice. To understand the regulating activity of PP ILCs induced by butyrate in mucosal immunity, we try to understand the regulation of DSS colitis in the same mice. Collectively, this study suggests that regulation of ILCs by butyrate in gastrointestinal tract was closely associated with maintaining mucosal homeostasis.
Microbial driven TLR5-dependent signaling modulates distal malignant progression through tumor-promoting inflammation (MUC4P.828)
Authors: Rutkowski Melanie , Stephen Tom , Allegrezza Michael , Svoronos Nikolaos , Perales-Puchalt Alfredo , Tesone Amelia , Nguyen Jenny , Tchou Julia , Conejo-Garcia Jose 
Published: January 2023

Abstract
The dominant R392X TLR5 polymorphism abrogates flagellin responses in &gt;7% of humans. We report that TLR5 recognition of commensal bacteria at intestinal surfaces influences malignant progression at distal (extra-mucosal) locations through the initiation of tumor-promoting inflammation. In TLR5-responsive mice, IL-6 is up-regulated through an autocrine loop in IL-6 reactive tumor cells, resulting in increased mobilization of MDSC and augmented tumor growth, compared to TLR5-deficient controls. In contrast, TLR5-deficient mice systemically up-regulate IL-17, which augments tumor growth only in the presence of IL-6 unresponsive tumors. Notably, differences in tumor growth are completely abrogated following depletion of commensal bacteria. Most importantly, similar differences in inflammation and malignant progression are recapitulated in TLR5-responsive/unresponsive patients with extra-mucosal tumors. Our results demonstrate that TLR5 signaling at mucosal surfaces, which is dependent upon commensal microbiota, significantly influences tumor progression at extra-mucosal locations through systemic tumor-promoting inflammation. These results have implications for the large proportion of individuals that harbor the common genetic polymorphism in TLR5 and demonstrate that the systemic response to tumors outside of the intestines is in part mediated through TLR5-signaling.
Resident memory γδ T cells orchestrate response to secondary oral Lm infection (MUC4P.829)
Authors: Romagnoli Pablo , Sheridan Brian , Pham Quynh-Mai , Khanna Kamal , Lefrançois Leo 
Published: January 2023

Abstract
Intestinal mucosa shapes the immune system by interacting with commensal bacteria while preventing the invasion of bacterial pathogens. In a physiological model of oral Listeria monocytogenes (Lm) infection, we have previously reported the generation of Lm-elicited protective memory Vγ4 Vδ1 T cells that reside in lamina propria and mesenteric lymph nodes (mln). Here we tested the hypothesis that Lm-elicited γδ T cells drive the accelerated secondary immune response to oral Lm infection in the mln. We show that memory γδ T cells secreted IL-17A and IFNγ in vivo and formed clusters with neutrophils that surrounded Lm aggregates in the mln 1 day after secondary oral Lm infection (d.p.r.). Neutralizing IL-17A disrupted cluster formation and neutrophil recruitment leading to delayed bacterial clearance. Cluster formation was also abrogated by forced gamma delta TCR downregulation. Together, these observations demonstrate that IL-17A, secreted by Lm-elicited memory γδ T cells, was essential for both recruitment of neutrophils to the mln, and for cluster formation to contain Lm during a secondary oral infection. In addition, we observed the induction of CXCL9 in areas surrounding the clusters, which has been shown to mediate rapid mobilization of memory αβ T cells to prevent further spread of bacterial infection. We believe these observations support an exciting new role for memory gamma delta T cells in the containment of intestinal pathogens.
Proliferation, cytokine secretion, and immunosuppressive activity of YFAK-specific regulatory T cells. (THER3P.885)
Authors: Ng Sze-Ling , Strominger Jack 
Published: January 2023

Abstract
Autoimmune diseases occur when there is misregulation within the immune system. Regulatory T cells (Tregs) are critical for the regulation of this immune response, however, little is known about their own regulation. The induction and activation of Tregs have been shown to alleviate symptoms of autoimmune disease such as human multiple sclerosis (MS). Our lab has identified Tregs that are activated by the random amino acid copolymer YFAK. These YFAK-specific Tregs can reduce the symptoms of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, more effectively than YEAK (Copaxone), a drug currently used in MS therapy. We have generated both YFAK-specific T cell lines as well as retrogenic mice expressing YFAK-specific T cell receptors (TCR) in order to study the regulation and activation of these beneficial Tregs. We find that these YFAK-specific Tregs will proliferate upon stimulation with glucococorticoid-induced TNF receptor ligand (GITRL). In addition, these Tregs can be activated to produce high levels of anti-inflammatory cytokines, and are immunosuppressive against conventional T cells. We plan to further characterize these YFAK-specific Tregs, as well as to utilize the TCR retrogenic mice in in vivo functional experiments. These studies will help to further explore the use of YFAK-specific Tregs in the prevention of autoimmune diseases such as multiple sclerosis.
GM-CSF-neuroantigen fusion proteins inhibit experimental autoimmune encephalomyelitis upon injection into lymphatics primed by encephalitogenic peptide and complete Freund’s adjuvant. (THER3P.878)
Authors: Curtis Alan , Islam Touhidul , Wilkinson Daniel , Mannie Mark 
Published: January 2023

Abstract
Single-chain fusion proteins comprised of GM-CSF and a myelin neuroantigen (NAg) epitope are potent, NAg-specific inhibitors of rat and mouse models of experimental autoimmune encephalomyelitis (EAE). This study provided evidence that GMCSF-MOG (myelin oligodendrocyte glycoprotein 35-55 peptide) inhibited EAE when co-injected adjacent to the encephalitogenic MOG35-55/ complete Freund’s adjuvant (CFA) emulsion. Furthermore, GMCSF-MOG had tolerogenic activity in the C57BL/6 model of chronic EAE when directly incorporated with MOG35-55 in the CFA emulsion. Likewise, GMCSF-PLP (proteolipid protein 139-151 peptide) inhibited relapsing-remitting EAE in SJL mice when mixed with PLP139-151 in the CFA emulsion. In vitro studies revealed that GMCSF-MOG stimulated the growth and differentiation of inflammatory dendritic cells (DC) and targeted the MOG35-55 domain for potentiated antigen presentation. However, presentation of MOG35-55 by these inflammatory DC was inhibitory, and the inhibitory mechanism in part depended upon the elaboration of nitric oxide. In conclusion, GMCSF-NAg was tolerogenic in CFA-primed lymphatics by a mechanism associated with inflammatory DC, targeted NAg presentation, and nitric oxide production. The inhibitory activity of GMCSF-NAg in CFA-primed lymphatics distinguished GMCSF-NAg fusion proteins as inflammation-dependent tolerogens mechanistically distinct from peptide or protein-based tolerogens.
Effects of hormone receptor activation on tumor associated dendritic cell signaling (TUM4P.921)
Authors: Watkins Stephanie , Thompson Matthew 
Published: January 2023

Abstract
Gender disparity has been observed in cancer in relation to incidence, disease aggressiveness and prognosis. However, the role of the immune system and the activation of an anti-tumor immune response based on gender is unclear. Some of the most successful cancer therapies to date have focused on hormone receptor blockade in tumor cells. Immune suppression is a major hurdle to overcome in the effort to find an effective and durable treatment against cancer. The underlying causes of immune suppression are complex and not completely understood. Hormones, including androgen and estradiol, are also known to dampen immune responses, but immune suppression or activation has not been studied during hormone deprivation therapy. Many studies indicate that tumor-associated dendritic cells within the tumor microenvironment are key regulators of cytotoxic T cell function and may serve as a critical target for immunotherapy. Therefore, in the current study, we demonstrate that hormone receptor signaling, androgen receptor and estrogen receptor in dendritic cells has a critical impact on the transcriptional regulation of factors known to induce immune suppression and may be a key factor to consider when designing immune therapies. Furthermore, the data may also implicate the patient’s gender as an important consideration in boosting anti-tumor immune responses.
Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in the HLA-DR mouse model of prostate cancer (TUM4P.923)
Authors: Klyushnenkova Elena , Kim David , Alexander Richard , Riabov Vladimir 
Published: January 2023

Abstract
Tumor-associated macrophages (TAM) were shown to support progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer displaying striking differences in the tumor growth outcome. Mice expressing Prostate-Specific Antigen as a self-antigen in the prostate (PSA tg mice) rejected PSA-expressing TRAMP tumors with high frequency. However, introduction of HLA-DRB1*1501(DR2b) transgene aggravated the growth of TRAMP-PSA tumors in DR2bxPSA F1 mice. Despite the difference in the tumor growth outcome, tumors in both strains were equally and intensively infiltrated by TAM at the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization characterized by the production of pro-inflammatory (TNFα, IL1β) and anti-inflammatory (IL10) cytokines. They also secreted T cell/NK cell-recruiting chemokines (CXCL10, CCL2, CCL3, CCL4, CCL5) and expressed high levels of MHC class II and co-stimulatory molecules. Functionally, TAM demonstrated pronounced immunostimulatory activity in a mixed leukocyte reaction and induced apoptosis of tumor cells. We conclude that during early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in our model. Furthermore, we demonstrate that at this stage TAM have a potential to activate T cell immunity and mediate anti-tumor effects.
MicroRNA-9 modulates the maturation and function of myeloid-derived suppressor cells by targeting Runx1 (TUM4P.902)
Authors: Tian Jie , Rui Ke , Zhang Yue , Tian Xinyu , Wang Shengjun 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a major role in tumor-induced immunosuppression, which hampers effective immunotherapeutic approaches. Our previous study showed that β-glucans could differentiate monocytic MDSCs (M-MDSCs) into mature myeloid cells and impair the suppressive function of MDSCs. However, the molecular networks are largely unknown. MicroRNAs (miRNAs) are involved in the regulation of immunity, including the immune cell development and differentiation. In this study, we identified that the expression of microRNA-9 (miR-9) was dramatically reduced after β-glucan stimulation, which was considered an essential player in modulating the maturation and function of MDSCs. Overexpressing miR-9 could significantly enhance the activity of MDSCs and reverse β-glucan induced maturation by targeting runt related transcription factor 1 (Runx1) while down-regulating miR-9 remarkably enhanced the maturation of MDSCs and impaired the suppressive effect of the cells. In addition, down-regulation of Runx1 resulted in increased suppressive effect of MDSCs and inhibited the maturation process. Furthermore, knockdown of miR-9 significantly impaired the activity of MDSCs and inhibited the tumor growth in vivo. Collectively, our findings reveal that miR-9 expression in MDSCs plays a critical role in the molecular events governing the maturation and function of MDSCs and might be identified as a potential target in cancer therapy.
Particulate beta-glucan modulates myeloid-derived suppressor cells (MDSC) activity in tumor-bearing mice and lung cancer patients (TUM4P.931)
Authors: Albeituni Sabrin , Ding Chuanlin , Liu Min , Hu Xiaoling , Luo Fengling , Yan Jun 
Published: January 2023

Abstract
Whole glucan particles (WGP) are microparticles of 1,3-beta glucan with 1,6-branches purified from the yeast Saccharamyces cerevisiae. Previous studies have reported its therapeutic efficacy in different tumor models through the activation of dendritic cells and macrophages via the c-type lectin receptor dectin-1. In this study, we investigated the effect of WGP treatment on myeloid-derived suppressor cells (MDSC) in mouse tumor models and in patients with non-small cell lung cancer (NSCLC). MDSC are a heterogeneous population of immature myeloid cells with suppressive activity that accumulate in cancer. Here we found that tumor-bearing mice treated orally with WGP have a significantly lower tumor weight with a significant decrease in the percentage of MDSC in the spleen compared to untreated animals in vivo. Patients with NSCLC treated with WGP prior to surgery have a decreased trend in MDSC percentage and increased respiratory burst of neutrophils in the peripheral blood. In addition, in vitro stimulation of MDSC subsets with WGP abrogates STAT3 phosphorylation in polymorphonuclear MDSC and enhances STAT3 phosphorylation in monocytic MDSC, with the activation of Erk1/2 phosphorylation in both subsets, suggesting that WGP differently modulates MDSC subsets. Moreover, MDSC treated with WGP have a decreased suppressive activity when cocultured with OVA-specific OTI and OTII splenocytes. Overall, these data indicate that WGP might be a new modulator of MDSC function in cancer.
ER stress response regulates the fate of myeloid-derived suppressor cells through TRAIL receptors mediated apoptosis (TUM4P.907)
Authors: Condamine Thomas , Kumar Vinit , Ramachandran Indu , Youn Je-In , Celis Esteban , Finnberg Niklas , El-Deiry Wafik , Winograd Rafael , Vonderheide Robert , English Nickolas , Knight Stella , Yagita Hideo , Mccaffrey Judith , Antonia Scott , Hockstein Neil , Witt Robert , Masters Gregory , Bauer Thomas , Gabrilovich Dmitry 
Published: January 2023

Abstract
We studied the fate of myeloid-derived suppressor cells (MDSC) in cancer. Unexpectedly, MDSC had lower viability and a shorter half-life than their control counterparts neutrophils and monocytes. This effect was due to increased apoptosis mediated by the changes in TRAIL receptors (TRAIL-R) expression. Targeting TRAIL-R did not affect myeloid cells from naïve mice, but dramatically reduced the presence of MDSC and improved the immune responses in tumor-bearing mice. Pro-inflammatory cytokines did not affect TRAIL-R expression. However, induction of ER stress recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. ER stress response was detected in MDSC isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes. Block of ER stress abrogated changes in TRAIL-R. Thus, MDSC pathophysiology is linked to ER stress, which shortens their lifespan in the periphery and promotes their expansion in bone marrow. In conclusion, TRAIL-R can be considered for selective targeting of MDSC.
Vaccine self-assembling immune matrix (VacSIM) is a non-viral delivery platform that augments responses to recombinant protein vaccines (VAC6P.940)
Authors: Shollenberger Lisa , Grenfell Rafaella , Samli E. Farah , Harn Donald 
Published: January 2023

Abstract
Vaccination remains the most effective public health tool to prevent infectious disease. However, many vaccines remain marginally effective, especially for immune-compromised populations. To enhance vaccine immunogenicity, we exploited the biphasic property of certain synthetic oligopeptides to create a new vaccine delivery method, VacSIM (vaccine self-assembling immune matrix). Vaccine components are easily mixed with the VacSIM solution for injection, after which the peptides self-assemble into hydrated nanofiber gel-matrices, forming a vaccine depot. Thus, we have a non-viral, inert, biodegradable delivery system, not requiring formulation, which we can use to deliver a multitude of vaccines. Analogous to a treat-dispensing dog toy, VacSIM is a carrier for vaccine components, allowing for gradual release, rather than immediate administration. We believe this depot attracts antigen presenting cells, driving enhanced vaccine-specific responses that improve both the quantity and quality of the response. We have tested this delivery platform with live bacterial vectors, inactivated virus and multiple recombinant protein vaccines. Shown here, VacSIM augments vaccine responses to the recombinant Hepatitis B surface antigen and recombinant HIV Envelope in 2 strains of mice. Enhancement of vaccine responses by VacSIM administration could represent a fundamental paradigm shift in how vaccines are delivered.