bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hvem expression in innate lymphoid cells mediates host defense against intestinal infection
Authors: Seo Goo-Young , Shui Jr-Wen , Takahashi Daisuke , Kim Pyeung-Hyeun , Kronenberg Mitchell 
Published: January 2023

Abstract
The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor super family (TNFRSF14), has diverse functions in augmenting or inhibiting the immune response. We previously reported that epithelial HVEM signaling at mucosal barriers provides host defense against pathogenic bacteria, but the role of HVEM expression in innate lymphoid cells (ILC) in the mucosal immune system was unknown. To address this issue, we exposed RORgt-Cre × Hvemfl/fl mice with Yersinia enterocolitica (Y. enterocolitica), a small intestine infection model. We found increased bacterial translocation and decreased survival at an early time point. In these mice, Hvem is deleted in NK cells, ILC3 and in all T lymphocytes. Ifng−/− mice also showed reduced survival and increased bacterial translocation early after infection with Y. enterocolitica, demonstrating the importance of this cytokine for host defense. Interestingly, ILC from infected RORgt-Cre × Hvemfl/fl mice produced less IFNg after infection, but IFNg production by CD4+ T cells was not affected. Furthermore, in CD4-Cre × Hvemfl/fl mice, which deleted HVEM only in CD4+ T cells but not in ILCs, were not more susceptible to Y. enterocolitica. Additionally, we found that depletion of ILC from Rag1-deficient mice resulted in increased bacterial translocation and decreased body weight at an early time point. Taken together, our data indicate first, that IFNg production by ILCs, such as NK cells and ILC3, is important for host defense during Y. enterocolitica infection. Second, although the activation of ILCs is regulated by cytokines, our data show that HVEM, a member of the TNF super family, also is required for their ability to respond by producing IFNg early after infection.
Electronic sorting of immune cell subpopulations based on highly plastic genes
Authors: Wang Pingzhang , Han Wenling , Ma Dalong 
Published: January 2023

Abstract
The publicly available omic big data provide a great and valuable resource to drive big-data-based discoveries. Previously, we used immunologically relevant transcriptome data from microarrays to analyze gene co-expression, gene plasticity (GPL) and biomarker evaluation for human and mouse immune cells, and have built two immunological databases, ImmuCo (http://immuco.bjmu.edu.cn/) and ImmuSort (http://immusort.bjmu.edu.cn/), for gene co-expression and gene plasticity analyses, respectively.
In the current study, we addressed a brand new method for the first time, electronic sorting, which surveys big data samples to do virtual analysis and to sort immune cell subpopulations based on highly plastic genes at mRNA level. We also called this process either ‘virtual sorting’ or ‘in silico sorting’, because no actual immune cells were sorted as they are in the fluorescence-activated cell sorting (FACS) process. Through virtual sorting of human Tregs and cytokine-producing T helper cells, our results strongly supported the feasibility, effectiveness and predictability of this method. For example, we found that human CD4+FOXP3hi T cells were highly expressive of certain known molecules such as CD25 and CTLA4, and that this process of investigation did not require isolating or inducing these immune cells in vitro.
We made a systematic virtual analysis of all of the potential human CD4+ T cell subpopulations, and potential signature genes or marker molecules for these subpopulations were identified. Besides CD4+ T cells, the methods in this study are also suitable for other immune cells, non-immune cells and even for cancers for studies on gene expression and regulation.
Kinetic study of B cell-depletion with a novel mAb anti-mouse CD20, clone SA271G2.
Authors: Moyron-Quiroz Juan Enrique , Lin Leo , Oida Takatoku , Garcia-Mojica Salvador , Yang Xifeng 
Published: January 2023

Abstract
CD20 is a member of the membrane-spanning 4A family (MS4A), involved on the transmembrane calcium-influx, activation and proliferation of B cells. CD20 is first expressed on Pre-B cells and its expression is sustained throughout the different stages of the B cell differentiation, with the exception of plasma cells. CD20 is also expressed by many malignant cells from the B cell-lineage, making it an important target for immunotherapy.
We developed a novel antibody anti-mouse CD20 (clone SA271G2, rat IgG2b, κ), useful to deplete B cells in vivo. A single intravenous dose of antibody (0.25mg) depleted more than 90% of the B cells from peripheral blood, spleen and lymph nodes; while in the bone marrow, only mature B cells (CD19hi B220hi IgD+ IgMhi IL-7Ra−), but not immature B cells (CD19int B220lo IgD− IgM−/int IL-7Ra+), were eliminated.
The B cell depletion was sustained for over 20 days; then a gradual return of the B cell population was observed, and was fully recovered around day 40. During this time, no noticeable effect of this antibody on CD20− cells was observed.
SA271G2 is a novel and useful tool to study the role of B cells on in vivo models of disease, mechanisms of the immune response and immunotherapy; with the advantages of allowing the use of only wild type mice, eliminating the need of genetically modified animals, and of having a fully reversible effect on B cell depletion.
Immunomodulatory effects of repository corticotropin injection (H.P. Acthar® gel) on the MRL/lpr model of lupus
Authors: Higgins Paul , Decker Dima , Becker Patrice 
Published: January 2023

Abstract
Repository corticotropin injection (RCI) is indicated during exacerbations or as maintenance therapy for systemic lupus erythematosus (SLE), yet studies on the mechanisms of action have been limited. This study was performed to evaluate the effects of RCI on the MRL/lpr mouse model of lupus. Mice were administered RCI at 160, 400, and 800 U/kg s.c. every other day beginning on week 13 (after onset of clinical symptoms) until week 23. Urine and blood were collected for analysis of proteinuria and anti-dsDNA IgG antibody. In-life assessments were made weekly for lymphadenopathy and skin lesions. Kidneys and spleens were harvested for assessment of histopathology and leukocyte phenotyping performed by FACS. The results demonstrate that RCI at 400 and 800 U/kg significantly inhibited the development of proteinuria compared to placebo (p &lt; 0.01, Friedman test). Development of lymphadenopathy (at 400 and 800 U/kg, p &lt; 0.0001 and p &lt; 0.001 Friedman test, respectively) and skin lesions (at 160 and 400 U/kg, p &lt; 0.0001 and p &lt; 0.05 Friedman test) were both reduced by drug treatment. RCI also significantly inhibited the generation of anti-dsDNA IgG antibodies at week 22 by 74%, 85%, and 90% at 160, 400 and 800 U/kg, respectively. Summed kidney histopathology scores were significantly reduced 67% and 74% at the 400 U/kg and 800 U/kg doses, respectively. Frequencies of specific spleen cell phenotypes were affected by RCI treatment. Immature B cells increased whereas transitional, marginal zone and germinal center B cells decreased. B220+ double negative T cell effector cells were also decreased. These results demonstrate the efficacy of RCI in the MRL/lpr lupus model and describe its immunomodulatory activity against specific lymphocyte subsets.
Kallikrein-Kinin System suppresses Type I Interferon (IFN) responses: a novel mechanism of IFN regulation.
Authors: Sriram Uma , Fernandes Nicole C. , Lee Michael Hweemoon , Didukh Marta , Zuluaga-Ramirez Viviana , Potula Raghava , Gallucci Stefania 
Published: January 2023

Abstract
Kallikrein-Kinin System (KKS) that comprises of kallikreins (klks), bradykinins (bk), angiotensin converting enzyme (ACE), and many other molecules, have classically known to be involved in a variety of physiological processes, including coagulation, angiogenesis and control of blood pressure. The role of KKS in regulating immune responses has come to light recently. Recent reports indicate that KKS is involved in lupus and giving exogenous klks can ameliorate lupus in mice. We have reported earlier the expression of a Type I IFN signature by dendritic cells (DCs) from the B6.Sle1, 2, 3 congenic model of lupus-prone mice. In this study, we directly asked the question if exogenous KKS regulates IFN induced responses. We used Flt3L induced bone-marrow-derived DCs from normal C57BL/6 (B6) mice and PBMC from normal human donors for in vitro studies. We stimulated the cells with recombinant IFN-α, IFN-β, CpG (TLR9 ligand), or R848 (TLR7 ligand) to induce IFN responses, and further treated with KKS candidates [Lys-bk, Hyp-bk, klk]. We analyzed the IFN induced responses by Interferon Stimulated Gene (ISG) expression and cytokine production. KKS candidates suppressed IFN or TLR induced IRF7 gene expression and CXCL10 production in both mouse DCs and human PBMCs. KKS candidates also suppressed IFN or TLR induced IL-6. We also used HOE140, a bk receptor 2 antagonist, and observed that blocking bk signaling increased the IFN responses in vitro. In vivo administration of Hyp-bk after IFN induction with CpG strongly decreased IRF7 and CXCL10 gene expression in B6 splenocytes, confirming our in vitro observations. Our results suggest a novel pathway of Type I IFN regulation by the KKS and opens up a new direction for designing drug targets for lupus.
Increases in the numbers of cells with the phenotype of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia
Authors: SALEM MOHAMED LABIB , Abdou Said , El-Shanshory Mohamed , Attia Mohamed , Zidan Abdel-Aziz , Sobhy Shymaa , Zidan Mona 
Published: January 2023

Abstract

Background
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanisms behind the relapse in this disease are not clearly known. One possible mechanism could be the accumulation of regulatory cells including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) which we and others have reported to mediate suppression of anti-tumor immune responses. Few previous studies investigated the roles of Treg cells in ALL, while no studies reported the emergence of MDSCs in ALL.

Aim
Therefore, we aimed to analyze the frequencies and phenotype of these cells in a group of Egyptian B-ALL pediatric patients (n=45).

Materials and methods
MDSCs were identified as Lin− HLA-DR− CD33+CD11b+; and Treg cells as CD4+CD25+CD127−/low using multiparametric flow cytometer.

Results
We found significant increases in the numbers of MDSCs and Treg cells in B-ALL patients as compared to healthy control volunteers. B-ALL patients showed significant increased numbers of MDSCs and Tregs before chemotherapy when compared to healthy volunteers. The numbers of MDSCs were more increased while the numbers of Treg cells were more decreased in patients during induction of chemotherapy. The highest increase in the numbers of MDSCs was observed in patients after induction of chemotherapy, while Treg cells showed the most significant decreased numbers after induction of chemotherapy.

Conclusion
Our results indicate that B-ALL patients harbor both MDSCs and Treg cells, opening a new avenue to investigate the mechanism mediating the emergence of these cells in larger numbers of patients at different treatment stages.
Ovarian cancer ascites-activated neutrophils suppress T cell proliferation in a contact-dependent mechanism
Authors: Singel Kelly L , Khan ANM Nazmul H , Emmons Tiffany R , Mayor Paul C , Moysich Kirsten B , Odunsi Kunle , Segal Brahm H 
Published: January 2023

Abstract
Ovarian cancer (OC) is often diagnosed at advanced stages. Necrosis is a hallmark of advanced cancer and releases DAMPs that activate innate immune responses. It is well known that CD8+ T cells mediate antitumor immunity and immunosuppressive myeloid cells can impair T cell responses. In contrast, there is limited knowledge on the role of activated neutrophils in the tumor microenvironment. In patients with newly diagnosed OC, ~90% of ascites cells were inflammatory (CD45+) with varying proportions of neutrophils, monocytes and lymphocytes. Although patient variability existed, neutrophils comprised ~15% of CD45+ cells and the neutrophil:CD8+ T cell ratio was 1:1. In ex vivo studies, cell-free ascites (CFA) attracted normal donor neutrophils (NDN). Neutrophil extracellular traps (NETs) are a distinct mode of death, and characterized by extracellular release of DNA, histones, and granular products. We found that CFA induced NDN to generate NETs ex vivo. In co-culture studies, CD3/CD28-stimulated normal donor T cells were incubated with media; purified NDN 1:1; CFA; or NDN + CFA. After 72h, T cell proliferation was measured by [3H] thymidine incorporation. While CFA or NDN alone did not suppress T cell proliferation, CFA-activated NDN completely suppressed proliferation. Suppression did not affect T cell viability or induce apoptosis, and was not reversed by the addition of arginine, N-acetyl-L-cysteine or IL-2. Suppression required T cell contact with NDN. These results support a model in which ascites-activated neutrophils suppress T cell responses, thereby abrogating antitumor immunity. Further studies will identify ascites constituents that activate neutrophils and mechanisms for neutrophil-mediated T cell suppression.
Regulatory T cells modulate tumor progression and clearance
Authors: Kumar Sanjay , Stokes James A , Gunn Karyn Scissum , Singh Udai P , Manne Upender , Ponnazhagan Selvarangan , Mishra Manoj K 
Published: January 2023

Abstract
Regulatory T (Treg) cells, a distinct lineage of T cells, are required to maintain immunological tolerance. However, the molecular mechanism(s) by which Treg cells modulate tumor growth and clearance needs further investigation. Thus, the goal of this study is to analyze the absolute number and role of Treg cells during tumorigenesis. To achieve this goal, tumor induction studies were performed on C57/B6 mice using transgenic adenocarcinoma mouse prostate (TRAMP) cell lines C1, C2 and C3. Interestingly, TRAMP C1 and C2 are tumorigenic while TRAMP C3 fail to form tumor. C57/B6 mice treated with different tumorigenic concentrations of TRAMP (C1, C2, and C3) cells. The experimental design also included appropriate controls. Developing tumors, spleen and draining lymph nodes were dissected out and single cell suspensions were prepared. Cells were stained with the specific antibodies such as NK cells, NKT cells, CD4, CD8, macrophages, B cells and Treg cells and analyzed using a 13-color flowcytometer. Preliminary data revealed that development of tumors by TRAMP C1 and TRAMP C2 cells and non-tumorigenesis by TRAMP C3 cells was dependent on number of Treg cells in tumor microenvironment. Therefore, the data suggest that the number of Treg cells present in tumor microenvironment may have a direct impact on tumor progression and clearance. Thus, modulating the number of Treg cells in tumor microenvironment may be a successful therapeutic strategy to control tumor progression
CD45 phosphatase regulates the fate of myeloid cells in tumor microenvironment by inhibiting STAT3 activity
Authors: Kumar Vinit , Cheng Pingyan , Condamine Thomas , Mony Sridevi , Languino Lucia , McCaffrey Judith , Hockstein Neil , Guarino Michael , Masters Gregory , Penman Emily , Denstman Fred , Xu George , Altieri Dario , Du Hong , Yan Cong , Gabrilovich Dmitry I. 
Published: January 2023

Abstract
The abnormal differentiation of myeloid cells is one of the key features of altered immune response in cancer. Myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) are the major components of immune suppressive network. MDSC accumulate in large numbers in peripheral lymphoid organs and inside tumors. However, in contrast to peripheral lymphoid organs such as spleen, inside tumors, monocytic MDSC rapidly differentiate to TAM with potent immune suppressive activity. We have demonstrated that this phenomenon is mediated by dramatic down-regulation of STAT3 activity in MDSC in tumor site. In cancer patients, MDSC in tumor site also had substantially lower level of pSTAT3 than MDSC in peripheral blood. These results were unexpected, since high level of STAT3 activity is a hallmark of MDSC present in blood and lymphoid organs. The mice with constitutively active STAT3 had shown the expansion of MDSC and down-regulation of macrophage population in tumor microenvironment, emphasizing the crucial role of STAT3 in myeloid cell differentiation. Hypoxia is an intricate part of tumor microenvironment. The decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. We further demonstrate that the up-regulation of CD45 tyrosine phosphatase activity in MDSC exposed to hypoxia in tumor site was responsible for down-regulation of STAT3 activity. Moreover, the positive regulation of CD45 activity in hypoxia was mediated by the disruption of CD45 protein dimerization via sialylation. This suggests a novel role of STAT3 in the regulation of myeloid cells in tumors with potential implications for therapeutic targeting.
The transcription factor GLI2 modulates CD40L expression in the tumor microenvironment
Authors: Han Weiguo , Jackson David A , Matissek Stephan , Misurelli Jason , Elsawa Sherine F 
Published: January 2023

Abstract
The interaction between tumor cells and the tumor microenvironment (TME) is essential for cancer cell growth and survival. Cytokines play an important role in mediating this crosstalk. Although this interaction is clearly established, the molecular mechanisms mediating this remain elusive. In previous work, we have shown that the transcription factor GLI2 modulates the expression and secretion of IL-6 in the TME. In this study, we screened for novel cytokine targets for GLI2 in bone marrow stromal cells and identified CD40L as a novel target of GLI2. GLI2 overexpression in HS-5, L87, L88 and Saka cells increased CD40L expression by real-time PCR. Conversely, GLI2 knockdown resulted in reduced CD40L expression. Similar results were obtained when screening for protein levels by western blotting. Using a mutant of GLI2 that lacks an N-terminal transcriptional repressor domain, we found an increase in CD40L beyond that observed with full-length GLI2. Bioinformatics analysis of a 2000 bp CD40L promoter region identified 2 candidate GLI binding sites in the CD40L promoter region. Using expression, luciferase and chromatin immunoprecipitation assays, we demonstrate that GLI2 binds to CD40L promoter. Furthermore, GLI2 modulates CD40L promoter activity. We were able to rescue the effect of GLI2 knockdown using an RNAi resistant GLI2 cDNA. Finally, we found that signaling through the CCR3-PI3K-AKT mediates GLI2-CD40L. Taken together, our data identify a novel mechanism regulating CD40L in stromal cells in the TME. Because of the importance of CD40L in malignant B cells, understanding the mechanism of its regulation is of great importance for the development of novel therapies aimed at targeting the malignant bone marrow TME.
Absence of Grail in CD8+ T cells confers spontaneous tumor regression.
Authors: Nurieva Roza I , Wang Junmei , Haymaker Cara , Alekseev Andrei , Bernatchez Chantale , Neelapu Sattva S. 
Published: January 2023

Abstract
T cell tolerance is the main obstacle to successful cancer immunotherapy; thus, it is of high priority to develop strategies to break immune tolerance to malignancy. Here we report that expression of the E3 ubiquitin ligase Grail is significantly upregulated in CD8+T cells infiltrated into lymphoma tumors and Grail-deficiency confers tumor rejection. Importantly, therapeutic transfer of Grail-deficient CD8+ T cells was sufficient to reject established tumors. Mechanistically, loss of Grail enhanced anti-tumor reactivity and survival of CD8+ T cells. Unexpectedly, Grail ablation was associated with ability of CD8+ T cells to evade regulatory T cell-mediated suppression. In addition, Grail deficient CD8+ T cells exhibited increased IL-21R expression and subsequently are hyper-responsive to IL-21 treatment. Finally, CD8+ T cells isolated from human lymphoma patients expressed high levels of Grail and lower levels of IL-21R compared with normal donors. Altogether, our data demonstrate that Grail is a crucial factor that controls CD8+ T cell anti-tumor activity.
Lymphoma Galectin-1 Expression Drives CD20 Immunotherapy Resistance
Authors: Lykken Jacquelyn M , Horikawa Mayuka , Minard-Colin Veronique , Kamata Masahiro , Miyagaki Tomomitsu , Poe Jonathan C , Tedder Thomas F 
Published: January 2023

Abstract
Non-Hodgkin’s lymphoma is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (Rituximab) is widely used to treat Non-Hodgkin’s lymphoma, even though the initial effectiveness of Rituximab varies widely amongst patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well-established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The collection of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, nor serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma galectin-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated galectin-1 compared with non-malignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy.