bluuebunny/crossref_metadata_2025_split huggingface dataset:
The sexually dimorphic histone demethylase promotes optimal T cell responses during infection
Authors: Krawczyk Connie , Zhai Lukai , Guak Hannah , VanderArk Alexander , Davidson Paula , Weiland Matthew , Corrado Mario 
Published: January 2023

Abstract
Females have stronger immune responses than males. This can be a protective benefit for immune responses to infection and cancer, but also a detriment for the development of autoimmune disease. The genetic contributions to sexually dimorphic immunity are not well understood. We have identified the X-linked histone demethylase KDM5C as an important regulator of T cell immunity. KDM5C escapes X inactivation so is expressed more in females than males. KDM5C demethylates H3K4, participating in gene silencing, however also has a role in promoting gene expression. Mice deficient in KDM5C in immune cells have reduced ability to control acute and chronic infection. CD8 and CD4 T cells have reduced expression of T cell effector molecules and increased expression of PD-1. We find that KDM5C promotes optimal T cell responses through epigenetic and metabolic programming. These data implicate KDM5C as an important promoter of T cell immunity and a mechanism underpinning sexual dimorphic immune responses to infection.
ERK5 and CCL19 Regulate the Secondary Immune Response in Mice.
Authors: Cervantes Jaisel A , Vines Charlotte M , Knight Colin D , Gehre Mika D , Bill Colin A 
Published: January 2023

Abstract
C-C chemokine receptor 7 (CCR7) binds to its ligand CCL19, which is expressed on the surface of activated dendritic cells, antigen activated B-cells and within lymphoid organs. Previous studies showed that homozygous deletion of CCR7 or its ligands leads to increased production of antibodies. However, it is unclear to what extent CCL19 contributes to this phenotype, since stimulation of naïve T cells with the second CCR7 ligand, CCL21, is sufficient to promote trafficking of T cells to the lymph nodes. We hypothesized that using a CCR7 antagonist during immunization would create a pseudo CCR7(−) state. Previously, we have shown that signaling via CCR7/CCL19 is mediated through ERK5. Therefore, we investigated the effect of the CCL19 antagonist CCL198-83 or blocking downstream signaling through the CCR7/CCL19 axis by using ERK5flox/flox/Lck-CRE mice, on antibody production. We found in the presence of CCL198-83 mice generated significantly higher levels of IgG1, IgG2b, and IgG3 than control mice in response to vaccination with DNP-KLH. In addition, we found that the level of affinity maturation between the mice treated with CCL198-83 was not significantly different from control mice demonstrating that in the absence of CCL19 activity, affinity maturation can occur. To assess the role of ERK5 signaling pathway, we used ERK5flox/flox/Lck-CRE mice to examine the effect of CCR7 downstream signaling on antibody production. We found that these mice produced significantly higher levels of IgG1 and IgG3 following immunization with DNP-KLH than the ERK5flox/flox control mice suggesting that the ERK5 pathway, at least in part, mediates signaling from CCR7/CCL19.
Supported by NIH-SC1GM111172 NIH-2U54MD007592 NSF-HRD-182675 NIH-5UL1GM118970
Myeloperoxidase deficiency impacts the composition of the gut microbiome: a case for variable disease penetrance?
Authors: Neu Savannah , Gurski Cody , Strzepa Anna , Dittel Bonnie N 
Published: January 2023

Abstract
The most abundant proteolytic enzyme found in neutrophilic granules, myeloperoxidase (MPO) is a heme peroxidase with microbicidal activity. While MPO inhibition has therapeutic promise for treatment of inflammatory illness, differential disease penetrance has been observed in MPO-deficient mice during various disease models. In our studies using the DSS-colitis mouse model, MPO-deficient mice under conventional specific pathogen-free (SPF) conditions experienced similar disease penetrance to co-housed, wildtype controls. In contrast, when housed in restricted SPF conditions lacking norovirus and Helicobacter species, MPO-deficient mice experienced more severe colitis while wildtype mice were unchanged. From these data, we hypothesized that an interplay between MPO (microbicidal activity) and the composition of the gut microbiome impacts disease penetrance of colitis. To investigate, we performed 16S rRNA-sequencing on the intestines of MPO-deficient and wildtype mice housed in restricted SPF conditions and found a proportionate increase in Ruminococcus gnavus, which is associated with intestinal dysbiosis. Correspondingly, we found proportionate decreases in the gut beneficial bacteria Akkermansia muciniphilia and Prevotella sp. These data show that MPO does affect the composition of the gut bacteria, and supports an interplay between inflammatory mediators, the microbiome, and altered disease penetrance.
Amniotic fluid metabolites mediate maternal high fat diet expansion of group 3 innate lymphoid cells in offspring.
Authors: Mirpuri Julie 
Published: January 2023

Abstract

Introduction
Previously, we demonstrated that maternal high fat diet (mHFD) exposure results in a unique pattern of microbial colonization in offspring, expansion of IL-17 producing group 3 innate lymphoid cells (ILC3) and increased susceptibility to a model of necrotizing enterocolitis (NEC). We hypothesized that amniotic fluid (AF) metabolites are modified by maternal diet and partially responsible for the phenotype in offspring.

Methods
To assess if AF metabolites in mHFD were unique from regular diet (RD) AF, we collected AF from E15 dams and performed non-targeted global mass spectroscopy. To determine if the mHFD AF is responsible for expansion of ILC3, we gavaged 5-day-old RD germ-free pups with mHFD and RD AF (from conventional dams) every other day and examined them at 2 weeks by flow cytometry for ILC3. mHFD mothers were supplemented with metabolites that were decreased in the mHFD AF and offspring examined for expansion of ILC3 and susceptibility to the LPS/PAF model of NEC.

Results
We identified 1069 metabolites in HFD and RD AF. Principal component analysis revealed that mHFD AF was uniquely clustered from RD AF. We specifically found decreases in indole, short chain fatty acid and furoic acid metabolites in HFD AF compared to RD AF. Gavage of germ-free neonatal pups with mHFD AF resulted in expansion of IL-17 producing ILC3 compared to RD AF at 2 weeks. Supplementation of mHFD dams prenatally with metabolites diminished in HFD AF resulted in decreased expansion of ILC3 and resistance to LPS/PAF model of NEC.

Conclusion
mHFD modifies metabolites present in AF and can expand ILC3 in germ-free offspring. Supplementation of deficient dietary metabolites in mHFD pregnant dams rescues offspring from susceptibility to NEC.
Supported by NIH R01 1K12HD068369
Gene editing at position 71 in DRB1*04:01 blocks collagen sensitization and avoids allorecognition.
Authors: Jha Vibha , Coulombe Marilyne , Rosloniec Edward F , Matsuda Jennifer , Freed Brian M , Roark Christina L 
Published: January 2023

Abstract
DRB1*04:01 is strongly associated with susceptibility to rheumatoid arthritis (RA). Our previous work demonstrated that changing lysine (K) at position 71 in DRB1*04:01 to glutamic acid (E), an amino acid found in resistant alleles, abrogated binding of the immunodominant collagen258-272 peptide. The purpose of this study was to determine if the K71E mutation in DRB1*04:01 would prevent sensitization to collagen and be tolerated by the host immune system in mice. DRB1*04:01 and DRB1*04:01K71E transgenic mice were created on the murine MHC class II knockout background (B6.129S2-H2dlAb1-Ea/J). DRB1*04:01 and DRB1*04:01K71E mice were immunized twice with bovine type II collagen in complete Freund’s adjuvant on days 0 and 21. On day 56, lymph node cells were harvested and stimulated in vitro with collagen258-272 peptide. Introduction of the K71E mutation in DRB1*04:01 resulted in a &gt;90% reduction in proliferation as compared to CD4+ cells from collagen-immunized DRB1*04:01 mice. Next, skin grafts were transplanted from DRB1*04:01K71E mice onto DRB1*04:01 recipients to test for rejection. The skin grafts from DRB1*04:01K71E mice were accepted by the recipient DRB1*04:01 mice with no signs of rejection out to day 70. Our results demonstrate that introducing the K71E mutation in DRB1*04:01 blocks collagen sensitization and avoids allorecognition suggesting that this mutation could safely halt progression of RA by blocking autoimmune T cell responses to collagen.
STAT3 degraders inhibit cellular activation, cytokine production, and Th17 development, resulting in inhibition of autoimmunity in the MOG-EAE model of CNS inflammation.
Authors: Sullivan Jeffrey , Brown Crystal , Mayo Michele , Dixit Vaishali , Enerson Bradley , Rong Haojing , Yang Bin , De Savi Chris , Gollob Jared , Mainolfi Nello , Slavin Anthony , Hubeau Cedric 
Published: January 2023

Abstract
Signal transducer and activator of transcription 3 (STAT3), an “undruggable” transcription factor activated by a variety of receptor- and non-receptor tyrosine kinases, plays a critical role in activation pathways triggered by cytokines, hormones, and growth factors, which makes it an attractive target for the treatment of autoimmune and autoinflammatory disorders. Kymera has developed heterobifunctional molecules that selectively target STAT3 for degradation by the ubiquitin-proteasome pathway. These degraders have broad and potent activity in-vitro against TLR receptor and cytokine-induced activation of immune and stromal cells and attendant mediators release such as MCP-1 (CCL2) and collagen1a1. STAT3 degradation in CD4+ T cells potently inhibited Th17 development, decreasing IL-17, IL-22, IL-8/CXCL8, and TNFa production, with concomitant increase in Treg numbers, that was superior to JAK1/2 kinase inhibition. STAT3 degradation was subsequently evaluated in-vivo in murine models of autoimmune disease. In the Th17-driven inflammatory model of MOG-induced Experimental Autoimmune Encephalomyelitis (EAE), dose-dependent decrease of incidence, disease onset, clinical scores, and histopathology were observed in comparison to a S1P1 inverse agonist or steroid treatment. Ex-vivo MOG-stimulated cytokine release by leukocytes isolated from draining lymph node was also robustly inhibited. These data demonstrate the broad activity of STAT3 degradation in alleviating autoimmune inflammation in systems relevant to human disease.
Tolerogenic Artificial Antigen Presenting Cells for Selective Tolerance in Autoimmune Disease
Authors: Raimondi Giorgio , Rhodes Kelly , Tzeng Stephany , Lozano Marcos Igleasias , VanDyke Derek , Neshat Sarah , Spangler Jamie , Green Jordan 
Published: January 2023

Abstract
Autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes develop when autoreactive immune cells attack healthy cells and tissues. Current treatments are non-curative and leave patients immunocompromised. As an alternative, therapies that expand regulatory T cells (Tregs) are being actively explored to establish antigen-specific tolerance. We recently showed that an IL-2 immunocytokine (IL-2_IC), a fusion of an antibody to IL-2, preferentially engages and expands Tregs over effector T cells. As a more targeted approach to tolerize the immune system towards a specific autoantigen, we explored the design and therapeutic efficacy of a microparticle bearing an IL-2_IC and an MHC II/peptide complex on its surface (TolAPC).
Microparticles composed of a blend of PLGA and PBAE were loaded with rapamycin, and then chemically conjugated with IL-2_IC and MHC II I-A(b) tetramers loaded with a peptide derived from myelin oligodendrocyte glycoprotein (MOG). Characterized TolAPC were tested in a mouse model of MS, Experimental Autoimmune Encephalomyelitis (EAE). When administered prophylactically, TolAPC delayed EAE development and reduced severity compared to unconjugated controls, with 36.4% of mice remaining asymptomatic for the duration of the study. When administered therapeutically, TolAPC reversed symptomatic EAE. Clinical improvements correlated with a nearly two-fold increase in Tregs in the brain and spinal cord of TolAPC-treated mice compared to controls six days after treatment. Furthermore, administration of additional booster doses led to sustained amelioration of the disease.
Overall, TolAPC can selectively expand Tregs and provide both protection and treatment in an autoimmune mouse model.
Supported by grants from DoD (W81XWH-18-1-0735; W81XWH-21-1-0892), NIH (R01EB029455), and JDRF (1-INO-2020-923-A-N)
Dysfunction of Dendritic Cells in Tumor-Draining Lymph Nodes
Authors: Bandola-Simon Joanna Marta , Roche Paul A 
Published: January 2023

Abstract
An effective anti-tumor response requires activation of both CD4 helper T cells (through MHC-II) and CD8 cytotoxic T cells (through MHC-I). Activation of tumor-specific T cells depends on tumor antigen presentation by DCs. However, it is known that the tumor microenvironment largely suppresses immune responses. The focus of our study is to characterize the functional status of DCs in tumor-draining lymph nodes (TDLN) and to identify the mechanisms that lead to defective tumor antigen presentation. We transplanted tumors into the flank of mice and analyzed DCs from TDLN and contralateral non-draining lymph nodes (NDLN). Cross-presentation of OVA to CD8 T cells was not suppressed in TDLN either in vivo or ex vivo. However, both in vivo and ex vivo CD4 T cell activation by DCs from TDLNs was defective. Subset analysis revealed that both migratory and resident DCs in TDLN show a less mature phenotype as compared to their counterparts isolated from NDLN. Functional assays revealed defects in antigen uptake by DCs from TDLN. Interestingly, DCs in TDLN also showed poor removal of the Invariant-chain CLIP peptide from the MHC-II peptide binding groove. This is likely to be due to a functional defect of the peptide-editor H2-M. Using Invariant-chain mutant mice and H2-M knock-out mice we confirmed that defective peptide exchange from MHC-II molecules hampered the anti-tumor responses and lead to enhanced tumor growth. These features of DC function, supported by RNA-Seq analysis, contribute to defective antigen presentation to CD4 T cells and may explain the dysfunction of DCs in tumor-bearing mice. Further analysis could allow us to “correct” these DC defects, thereby allowing CD4 T cell priming to provide the necessary help for antitumor CD8 T cells.
Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promotes cancer lung metastasis
Authors: Ding Chuanlin , Yan Jun 
Published: January 2023

Abstract
Lung metastasis-associated macrophages (MAMs) play a very important role in tumor metastasis. In mouse models of lung metastasis, interstitial macrophages (IMs) markedly accumulate and differentiate into MAMs. Several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis. In this study, we hypothesize that host responses to chemotherapy treatment enhance breast cancer metastasis by modulation of lung macrophage toward a pro-metastatic phenotype. Here, we show that multi-dose chemo treatment promotes breast cancer lung metastasis in the spontaneous breast cancer animal model. Pretreatment with Gemcitabine and Paclitaxel induces a significantly higher number of pulmonary metastases in the experimental metastasis model. Mechanistically, multi-dose of chemotherapy induces reactive myelopoiesis characterized by increase of BM LSK cells and multipotent progenitors in tumor-free mice, which is associated with the increase of mitochondrial ROS. Further, chemokine CCL2 expression is significantly increased in the plasma and lung tissues of chemo-treated tumor-free mice. Consequently, the percentage of BM Ly6C+ monocytes are significantly increased because of increased progenitor monocyte differentiation potential and monocyte proliferation, which results in an increase of lung monocytes and IMs with enhanced expression of coagulation factor X (FX). Inhibition of activated FX (FXa) can inhibit chemotherapy-induced lung metastasis. Together, these studies suggest a novel mechanism for chemotherapy induced metastasis via the modulation of BM-derived monocytes/macrophages and extravascular clotting in lung tissues.
Supported by grants from NIH (P20GM135004)
Determination of CD91 intracellular signaling pathway following HSP stimulation
Authors: Harkness James F , Binder Robert J 
Published: January 2023

Abstract
Cancer immunosurveillance is dependent on the heat shock protein (HSP) receptor, CD91, which is expressed on professional antigen-presenting cells (APCs). While CD91-facilitated cross-presentation of HSP-chaperoned peptides has been well studied, CD91-mediated signaling is not completely defined. The binding of CD91 by immunogenic HSPs leads to production of unique inflammatory cytokine profiles by APCs. This requires the phosphorylation of tyrosine residues on intracellular domains of CD91 and activation of NF-κB. However, adaptor proteins associated with CD91 and molecules involved in signal transmission have not been characterized and their role in cancer immunosurveillance remains untested. Our general strategy to identify adaptor proteins involves crosslinking and co-immunoprecipitation of CD91 and its associated signaling complex following stimulation of CD91 with the immunogenic HSPs gp96, calreticulin, and hsp70. Preliminary studies with gp96 have identified Shc as an adaptor protein and AXL receptor tyrosine kinase and tyrosine-protein kinase Fgr as membrane associated kinases. The impact on their inhibition on cytokine release by APCs is being tested. We have also developed a novel mouse expressing mutant, non-signaling CD91, and its impact on cancer immunosurveillance will be determined. Investigation of these complexes will aid in understanding the signaling pathway that activates production of cytokine profiles within APCs. This project will allow us understand the pathways to priming immune responses responsible for cancer immunosurveillance and also to develop better therapeutic strategies for cancer and autoimmune diseases.
Supported by grants from NIH (RO1 CA233803)
CD155 axis modulation promotes natural killer cell-mediated graft-versus-tumor effects against osteosarcoma
Authors: Cho Monica , Phillips Madison , Song Longzhen , Erbe-Gurel Amy , Capitini Christian M 
Published: January 2023

Abstract
Patients with relapsed/refractory osteosarcoma (OSA) have a poor prognosis with few treatment options. Immunotherapy with allogeneic natural killer (NK) cells after allogeneic bone marrow transplant (BMT) is an attractive approach to employ a graft-versus-tumor (GVT) effect against OSA. However, NK cells have had limited success against solid tumors in vivo. CD155 is overexpressed on OSA and interacts with DNAM-1, an activating ligand, and TIGIT, an inhibitory ligand, on NK cells. The impact of blocking CD155 after allogeneic BMT is unknown. IL-15-expanded C57BL/6 (B6, H-2b) and BALB/c (H-2d) murine NK cells were co-cultured with K7M2 murine OSA (H-2d) after CD155 and CD155 ligand blockade, and analyzed by flow cytometry and cytotoxicity assays. BALB/c mice were also transplanted with T cell depleted allogeneic B6 or syngeneic BALB/c bone marrow, challenged with K7M2 and treated with IL-15-expanded NK cells and CD155 blockade. Allogeneic NK cells showed increased degranulation, interferon-gamma production and cytotoxicity against K7M2 OSA in vitro compared to syngeneic NK cells. NK cell activation and cytotoxicity were further enhanced by CD155 and TIGIT blockade, but decreased with DNAM-1 blockade. In vivo, allogeneic NK cell infusion and anti-CD155 treatment decreased tumor growth and increased survival compared to syngeneic NK cell treatment, without induction of graft-versus-host-disease. CD155 blockade augments NK cell activation, cytotoxicity and GVT effects against OSA without toxicity, suggesting TIGIT is the dominant CD155 checkpoint during allogeneic BMT. CD155 blockade with allogeneic NK cell therapy after BMT may be an effective combination immunotherapy platform for treating relapsed/refractory OSA.
Supported by NIH grants (T32 CA009135, R01 CA215461)
Pre-treatment with a novel synthetic TLR4 agonist prior to challenge with mouse-adapted H1N1 and H2N3 influenza strains reduced morbidity and mortality in BALB/c mice
Authors: Whitacre Margaret , Ward Janine , Jackson Konner , Bess Laura , Jayah Rachel , Sands Cherrokee , Arayangkul Hathaipat , Khalaf Juhienah K , Miller Shannon M , Evans Jay T , Bazin Helene G 
Published: January 2023

Abstract
According to the World Health Organization, influenza causes 3–5 million cases of severe illness and 250,000 – 500,000 deaths annually despite the availability of a seasonal vaccine. As an alternative therapy for use in high-risk groups and environments, we evaluated the efficacy of prophylactic treatment with a novel synthetic TLR4 agonist in BALB/c mice. Animals were anesthetized and treated with a TLR4 agonist intranasally (IN) 0 to 28 days prior to a lethal challenge with either H1N1 or H3N2 mouse-adapted human influenza. Animals were monitored daily for weight loss, decreased body temperature, body score, and mortality. Initial dose-response experiments demonstrated that mice treated with 50 μg or 10 μg of our novel TLR4 agonist in an aqueous formulation were similarly protected from H3N2 influenza challenge with respect to weight loss and survival. However, initial weight loss data demonstrated that 50 μg was not as well tolerated as 10 μg. The 10 μg dose was therefore selected as the lead dose in subsequent experiments. In a series of formulation comparison experiments, the lead formulation resulted in marked improvement in both percent weight loss and survival compared to initial TLR4 agonist formulations. Animals treated with all formulations of our novel synthetic TLR4 agonist 0, 7, or 14 days prior to infection resulted in 80–90% survival. The lead formulation also resulted 80–90% survival when given prophylactically 21 or 28 days prior to infection compared to 0–20% survival in untreated mice. Overall, our results show that pre-treatment with our novel synthetic TLR4 agonist prior to exposure to mouse-adapted H1N1 and H2N3 influenza strains reduced morbidity and mortality in infected mice for up to 28 days after treatment.
This work was supported by NIH grant 5R44AI136081-03