bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multipotent Vδ2-negative γδT-cells after CMV-reactivation in allogeneic stem cell transplantation (162.36)
Authors: Kuball Jürgen , Scheper Wouter , van Dorp Suzanne , Kersting Sabina , Pietersma Floor , Hol Samantha , Marcu-Malina Victoria , Becke Sabine , Plachter Bodo , van Baarle Debbie 
Published: January 2023

Abstract
Human cytomegalovirus (CMV) infections and relapse of disease remain major problems after allogeneic stem cell transplantation (allo-SCT). Great promise as an alternative strategy, with a potential use for very broad patient population, arises from the non-MHC-restricted target-recognition of cancer cells and virally-infected cells by γδT-cells. Therefore, we investigated the role of γδT-cells after allo-SCT and CMV infection. An increase in selectively Vδ1-positive γδT-cells was observed in CMV-reactivating patients from CMV-positive conventional donors. Even more important, γδT-cell expansions were also observed after CMV-negative cordblood transplantation. However, in contrast to expansions from CMV-positive donors, γδT-cells from cordblood donors did not only include Vδ1-positive but also Vδ3-positive cells. Expanded Vδ2-negative γδT-cells were not only able to lyse CMV-infected fibroblasts, but also to partially mature dendritic cells (DCs) and to kill primary leukemic blasts. CMV- and leukemia-reactivity were restricted to the same clonal population and separated from DC-maturation capacities of Vδ2-negative T-cells. Vδ2-negative γδTCRs selectively mediated anti-leukemia-reactivity. This makes CMV-reactive γδT-cells e.g. from cordblood donors as well as individual Vδ2-negative γδTCRs interesting candidates for adoptive immunotherapy strategies
The role of regulatory B cells during the progression of human hepatocellular carcinoma (162.39)
Authors: Shao Yan , Li Chang Xian , Ma Yuen Yuen , Liu Xiao bing , Chu Chi Yuen , Ling Chang Chun , Yeung Wai Ho , Lee Kin Wah , Fan Sheung Tat , Lo Chung Mau , Man Kwan 
Published: January 2023

Abstract
Y SHAO1, CX LI1, YY MA1, XB LIU1, CY CHU2, CC LING1, WH Yeung1, KW Lee3, ST FAN1,2, CM LO1,2, K MAN1,2 1.Department of Surgery 2.Centre for Cancer Research 3. Department of Pathology, The University of Hong Kong, Hong Kong Human regulatory B cells (hBregs) have been shown to play an important role in autoimmune diseases, but their function during human cancer progression remains elusive. In this study, we aim to unveil the underlying mechanism of hBregs regulating human hepatocellular carcinoma (HCC) growth. B cells in HCC liver tumor were examined by immunohistochemistry. We found a tendency that the amount of B cells increased with HCC progression (p=0.001), and it’s in the marginal region of HCC increased (P&lt;0.001) more dramatically. In vitro, human HCC cell line MHCC-97L cells were cocultured with hBregs. hBregs promoted HCC cells proliferation (P=0.011) and migration (p=0.006) and decreased HCC cells apoptosis (p=0.078). HCC cells also promoted hBregs proliferation and migration (p=0.003). hBregs could interact with HCC cells directly through CD40-CD154 signaling. Tail vein injection of hBreg cells into SCID mice increased the size of HCC xenograft tumor (4 weeks, p=0.0221). In vivo imagining showed that hBreg cells could migrate into tumor. Our findings indicate that hBregs could promote HCC progression.
Role of resveratrol and nitric oxide in the modulation of murine prostate cancer cells (162.9)
Authors: Mishra Manoj , Eroglu Erdal , Singh Udai , Nyairo Elijah , Singh Shree 
Published: January 2023

Abstract
Resveratrol (RES), a polyphenolic compound found in the skin of red fruits, exhibits anti-inflammatory, anti-oxidative, anti-cancer, and anti-proliferative characteristics. RES is known to affect nitric oxide (NO) production. NO is produced by nitric oxide synthase, a regulator of innate and adaptive immunity and displays cytostatic and cytotoxic activity against pathogens and cancer cells. Prior reports suggest that RES and NO mediate the killing of cancer cells in vivo as well as in vitro. In this study, we hypothesized that the RES and NO, either alone or synergistically, modulates the molecular mechanisms in murine prostate cancer (PCa) cells. This hypothesis has been tested on mouse PCa cell lines, derived from transgenic adenocarcinoma of mouse prostate (TRAMP), in C57/B6 mice. Interestingly, TRAMP-C1 and TRAMP-C2 are tumorigenic while TRAMP-C3 is non-tumorigenic. TRAMP cells were treated with different concentrations of RES/NO at different time points and analyzed for cell viability/proliferation, cytokines and growth factors production. The results show that the RES/NO-induced molecular mechanisms in TRAMP-C1 and C2 are significantly different while compared to TRAMP-C3 suggesting that TRAMP-C3 cells may use distinct pathways that regulate “eat me” signal in comparison to TRAMP-C1 and C2. This data also demonstrates that RES/NO mode of action is very distinct and exclusive for each TRAMP cell lines in the modulation of molecular pathways.
Foxp4 is dispensable for T cell development, but required for Interferon gamma recall responses during chronic Toxoplasmosis (163.12)
Authors: Wiehagen Karla , Corbo-Rodgers Evann , Li Shanru , Staub Elizabeth , Hunter Christopher , Morrisey Edward , Maltzman Jonathan 
Published: January 2023

Abstract
Transcription factors regulate T cell fates at every stage of development and differentiation. Members of the Foxp family of forkhead transcription factors are fundamental for normal T lineage development; Foxp3 is required for T regulatory cell generation and function, and Foxp1 is necessary for generation and maintenance of naïve T cells. Foxp4, another member of the Foxp family, is highly homologous to Foxp1 and has been shown to dimerize with Foxp proteins. We report the initial characterization of Foxp4 in T lymphocytes. Foxp4 is expressed in both thymocytes and peripheral CD4+ and CD8+ T cells. We used a CD4Cre mediated approach to evaluate the cell autonomous role for Foxp4 in T lymphocytes. T cell development, peripheral cellularity and cell surface phenotype are normal in the absence of Foxp4. Furthermore Foxp3+ T regulatory cells develop normally in Foxp4 deficient animals, and naïve Foxp4 deficient CD4 T cells can differentiate to inducible T regulatory cells in vitro. In wild-type T cells, expression of Foxp4 increases following activation, but deletion of Foxp4 does not affect T cell proliferative responses or in vitro effector T cell differentiation. In vivo, despite effective control of Toxoplasma gondii infection, IFNγ production during an antigen specific recall response is reduced in the absence of Foxp4. We conclude that Foxp4 is dispensable for T cell development, but necessary for T cell cytokine recall responses to antigen in chronically infected mice.
PPARγ activation drives Th17 cells into a Treg phenotype (163.7)
Authors: Carbo Adria , Hontecillas Raquel , Hoops Stefan , Kronsteiner-Dobramysl Barbara , Lu Pinyi , Wendelsdorf Katherine , Mei Yongguo , Eubank Stephen , Marathe Madhav , Bassaganya-Riera Josep 
Published: January 2023

Abstract
Th17 cells mediate inflammatory and effector responses during infectious and immune-mediated diseases. However, the mechanisms of action modulating the plasticity between Th17 and Treg are incompletely understood. To gain a better understanding of the differentiation process we have constructed a computational and mathematical model in COPASI that mimics CD4+ T cell differentiation and contemplates the plasticity between effector Th17 and Treg. Our computer simulations predicted that activation of peroxisome proliferator activated receptor gamma (PPARγ) induces a switch from already differentiated Th17 into Treg. Conducted experimental validation approaches support in silico experimentation. Naive CD4+ T cells obtained from spleens of T cell-specific PPARγ null, RORcGFP+/+ or wild-type donor mice, all in a C57BL6 background, were transferred to SCID and RAG2-/- recipients to induce CD4+ T cell-driven colitis. Our data demonstrate a significant decrease in the expression of FOXP3 and increase of IL-17A and RORγt in recipients of PPARγ null naïve CD4+ T cells when compared to recipients of naïve CD4+ T cells from wild-type mice. Furthermore, administration of PPARγ agonists to recipient mice with colitis decreased the percentages of GFP+ Th17 cells at the gut mucosa. In conclusion, PPARγ promotes differentiation of naïve CD4+ T cells into Treg, downregulates Th17 differentiation and favors phenotype switch from Th17 into Treg CD4+ T cells.
Signals through GITR program CD4+ T cells to induce interleukin-9 (163.9)
Authors: Kim Il-Kyu , Seok Jae-Won , Kim Byung-Seok , Lee Ka-Eun , Choi Gye-Young , Kang Chang-Yuil 
Published: January 2023

Abstract
Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on various immune cells and well known as one of the co-stimulatory molecules to promote T helper (Th) type 2 responses. In this study, we show that an agonistic anti-GITR mAb (clone DTA-1) induced IL-9 production on the committing Th2 and regulatory T (Treg) cells, as well as enhanced IL-9 production from naive CD4+ T cells under Th9 skewing condition. Whereas, DTA-1 did not induce IFN-γ or IL-17A, lineage-specific cytokines of Th1 or Th17, respectively and was resistant to produce IL-9 from naive CD4 T cells under Th1 or Th17 polarizing conditions. Furthermore, GITR stimulation promoted reprogramming of regulatory T cells to produce IL-9+Foxp3+ Treg and effector Th9 cells. We found transcription factor Interferon-regulatory factor4 (IRF4) was up-regulated by GITR ligation at the early stage of Th9 differentiation and contributed to enhance IL-9 production. Also, when GITR signaling was activated, p65, activated by NFκB signaling pathways, directly interacted with Il9 locus including promoter region at the later stage of Th9 differentiation. Consistent with in vitro study, in vivo administration of DTA-1 enhanced IL-9 at the transcript level and the roles of IL-9 induced by GITR ligation in vivo are remained to be investigated for further studies.
The negative impact of helminth infection on CD8+ T cell immunity (164.11)
Authors: Marple Andrew , Wu Wenhui , Grotenbreg Gijsbert , Gause William , Yap George 
Published: January 2023

Abstract
Upon infection the protozoan parasite Toxoplasma gondii induces a strongly polarized Th1 cytokine response, necessary for effector differentiation of CD8 lymphocytes. Conversely, pre-infection with an intestinal nematode, such as Heligmosomoides polygyrus has been shown to attenuate immune responses to intracellular pathogens and inhibit the development of Th1 responses. Previous studies have shown that mice co-infected with H. polygyrus and T. gondii exhibit suppressed CD8+ T cell responses against T. gondii, however the precise mechanism by which co-infection impinges upon the priming and differentiation of antigen-specific T cells remains to be determined. Using a novel Kb-peptide tetramer-binding assay for Tgd057-reactive CD8+ T cells, we show that co-infected mice develop a diminished antigen-specific response to T. gondii. Co-infected mice develop fewer antigen-specific CD8+ T cells, a decreased fraction of terminally differentiated effector cells, and reduced effector IFN-γ production. Furthermore, terminally differentiated antigen-specific effector T cells (CD62Llo, KLRG1+) from co-infected mice retain an intrinsic defect in cytokine production. Helminth infection blocked IL-12 responses of CD8α+ dendritic cells to T. gondii, indicating that rather than inhibiting CD8+ T cell priming itself, the principal effect of helminth infection is to attenuate the differentiation of effector lymphocytes by inhibiting critical innate cytokine responses.
Vitamin D regulation of Th2 Immune responses to Aspergillus fumigatus in mice and humans: role of OX40L (164.19)
Authors: Nguyen Nikki , Chen Kong , Alcorn John , Kolls Jay 
Published: January 2023

Abstract
4-15% of cystic fibrosis (CF) patients develop Allergic Bronchopulmonary Aspergillosis (ABPA) characterized by heightened Th2 responses to Aspergillus fumigatus (Af). Colonization rates with Af in CF can approach 40-50% suggesting immune tolerance may prevent ABPA. We have previously shown that CD11c dendritic cells (DCs), OX40 Ligand, Vitamin D play a role in sensitization versus tolerance to Af in CF patients. We have set up an animal model to further explore the roles of CD11c DCs, OX40L, and Vitamin D in response to Af. Vitamin D deficient mice (by nutritional diet) and Vitamin D normal mice where sensitized and challenged with Af. In addition, mice were given anti-OX40L or PBS control 4 hours prior to Af challenge. Lung, lymph nodes (LN), and bronchoalveolar lavage (BAL) fluid where analyzed for Th2 cytokine production. Vitamin D deficient mice have significantly increased Th2 cytokine response to Af in lung, BAL, and LN. In addition, OX40L mRNA levels are increased in Vitamin D deficient mice compared to Vitamin D normal mice. When given anti-OX40L prior to Af challenge, Th2 response in both Vitamin D deficient and Vitamin D normal mice are attenuated confirming the critical role of OX40L driven Th2 response in Af sensitization. This suggests a critical role of OX40L in Vitamin D mediated Th2 suppression. These results support therapeutic trial of Vitamin D and/or anti-OX40L to treat ABPA in CF and suggest Vitamin D plays a role in immune tolerance to Af.
Novel gene expression profile in blood cells from cattle experimentally exposed to Mycobacterium avium subsp. paratuberculosis (164.24)
Authors: Thirunavukkarasu Shyamala , Purdie Auriol , Plain Karren , de Silva Kumudika , Whittington Richard 
Published: January 2023

Abstract
Mycobacterium avium subspecies paratuberculosis (Mptb) is the causative agent of the chronic debilitating condition called Johne’s (JD) disease that affects ruminants and is a suspected causative agent in Crohn’s disease in humans. Identifying and characterising the different strategies employed by Mptb to alter the host immune system in its favour and thereby persist intracellularly could hold the key to fighting this disease. Affymetrix Genechip Bovine Gene microarrays were performed using the RNA prepared from blood samples collected from exposed and non-exposed control cattle from the controlled experimental model of bovine JD. Bio-informatics tools and data mining were applied to identify relationships between genes and physiological functions. Genes related to lipid pathways and anti-bacterial defence mechanisms were identified and validated in a larger cohort at different time-points post-infection by quantitative polymerase chain reaction. Several novel gene pathways were shown to be differentially regulated in bovine JD linking lipid pathways and anti-bacterial defence mechanisms. Downregulation of the cellular cholesterol homeostasis mechanism could act as a countermeasure to infection. A novel model was developed that explores how these could impact the host immune response in a double edged sword manner that leads to the progression of pathogenesis.
Reprogrammed Foxp3+ regulatory T cells provide essential CD40L- mediated help that is synergistic with blockade of indoleamine 2,3-dioxygenase . (165.1)
Authors: Sharma Madhav , Munn David 
Published: January 2023

Abstract
We have previously shown that large numbers of FoxP3+ Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells provided essential help during initial priming of CD8+ T cells to a new cross-presented antigen. We now show that help from Treg cells is delivered via CD40L, and (unlike help from conventional non-Treg CD4+ cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg reprogramming was suppressed by tumor-induced IDO. Therapeutically, there was fundamental synergy between blocking IDO-dependent suppression and driving CD40-mediated DC activation. When IDO was blocked, required CD40L signal could derive from pre-activated memory conventional CD4+ helper cells (if available), reprogrammed Tregs, or exogenous anti CD40 agonist antibody. Agonist antibody and the IDO inhibitor drug 1-methyl-tryptophan showed potent synergy. Chemotherapy allowed extensive reprogramming of Tregs in tumor draining lymph nodes in response to anti-tumor vaccine, but only if IDO was blocked with 1MT. The effects of pharmacologic IDO inhibitor on Treg reprogramming was fully recapitulated by blocking the CTLA4 pathway. Thus reprogrammed Tregs participate as previously unrecognized contributors early CD8+ T cell responses against tumors.
Infection with the helminthic parasite Heligmosomoides bakeri alters B cell function and impairs vaccine induced antibody responses (166.1)
Authors: Wroblewska Joanna , Iweala Onyinye , Kline Austin , Urban Joseph , Nagler Cathryn 
Published: January 2023

Abstract
Worldwide endemic infection with gastrointestinal helminths is a potential challenge to successful vaccination in underdeveloped regions. In the current study we demonstrate that infection with the natural murine pathogen H. bakeri significantly reduced serum antibody responses to both parenteral immunization with ovalbumin (OVA) adsorbed to alum and oral vaccination with an attenuated OVA-expressing Salmonella strain. The reduction in serum antibody responses correlates with a helminth-mediated increase in the proportions of IL-10 secreting CD4+FoxP3+Tregs and CD4+FoxP3-Tr1 cells. ImageStream analysis showed that the vaccine was predominantly detectable in macrophages and dendritic cells in the mesenteric lymph node (MLN) of uninfected mice. Salmonella vaccine-carrying CD19+ B cells were increased, and macrophages were reduced, in the MLN of H. bakeri infected mice. Helminth infection also altered the effector function of CD19+ B cells, which express high amounts of TGF-β after infection, and can act as antigen presenting cells to induce IL-10 secreting T cells in vitro. Taken together, these data suggest that helminth infection alters vaccine efficacy by multiple complementary mechanisms, including inducing an immunosuppressive T cell environment, altering antigen presentation, and modulating B effector function.
Ag-specific recall of cytokine producing CD4 and CD8 T cells in humans immunized with genetically attenuated Plasmodium falciparum sporozoite vaccine (166.12)
Authors: Zarling Stasya , Spring Michele , Ehrler Lindsey , Chalom Isaac , Funk Theresa , Cowman Alan , Ockenhouse Christian , Speake Cate , Heppner D. , Duffy Patrick , Kappe Stefan , Krzych Urszula 
Published: January 2023

Abstract
A Plasmodium falciparum (Pf) genetically attenuated parasite (Pf GAP) vaccine, engineered by deletion of 2 pre-erythrocytic genes, was administered to 6 subjects by bites from Anopheles mosquitoes. Previous studies of immune responses elicited by recombinant malaria vaccines show that protection is linked to Ag-specific T cells producing IFN-γ, TNF, and/or IL-2. In this study we asked if Pf GAP vaccine induced Ag-specific T cell responses characterized by inflammatory cytokines. We analyzed pre- and post vaccination PBMC for Ag-specific T cell responses to well characterized pre-erythrocytic and erythrocytic P. falciparum protein and peptide Ags. Additionally, we examined responses to several novel Pf liver-stage Ag (Pf LSA) because Pf LSA-dependent immunity might contribute to GAP-induced protection. IFN-γ and TNF responses to multiple antigens were significantly enhanced post vaccination; IFN-γ responses were primarily attributed to CD8+ T cells while TNF was secreted primarily by CD4+ T cells. Notably, a subject with a breakthrough peripheral parasitemia did show positive IFN-γ responses to erythrocytic-stage Ags, but no responses were recalled with the novel Pf LSA. In summary, two exposures to a Pf GAP vaccine induced persisting T cell responses specific for Pf LSA in humans. Future trials that assess the efficacy of Pf GAP vaccines should examine the role of LSA-specific responses in protection.
Identification of live attenuated vaccine candidates for tularemia prophylaxis (166.20)
Authors: Bakshi Chandra Shekhar , Mahawar Manish , Metzger Dennis , Malik Meenakshi 
Published: January 2023

Abstract
Francisella tularensis (Ft) is the causative agent of a fatal human disease, tularemia. Ft was used in bioweapon programs in the past and is now classified as a category A agent owing to its possible use as a bioterror agent. Despite over a century since its discovery, an effective vaccine is yet to be developed. A live attenuated vaccine strain (LVS) exists; however, an unknown cause of attenuation and adverse effects in immunized individuals eluded its licensing as a vaccine. This study identified potential vaccine candidates for prophylaxis of respiratory tularemia. Five mutants of Ft LVS [FTL_0057, FTL_0291, FTL_0304, FTL_0325 and superoxide dismutase B (SodB)] were tested for their protective efficacy against Ft SchuS4 challenge. BALB/c mice were immunized intranasally (i.n.) with these mutants. Doses as high as 5x10(3) CFU (for SodB) or 1x10(7) CFU (for other mutants) did not cause any adverse reaction in immunized mice. A kinetic experiment revealed that the immunized mice cleared the mutants by days 14-21 post-immunization (PI). I.n. challenge with 100 CFU of Ft SchuS4 30 days PI protected 100% of mice immunized with SodB, FTL_0057, FTL_0291 and FTL_0325 mutants, while all the mice immunized with FTL_0304 mutant succumbed to infection. Mice that survived the challenge cleared Ft SchuS4 by day 45 post-challenge. This study has identified superior, safer and genetically defined live attenuated vaccine candidates for prevention of respiratory tularemia.
Overcoming the immune inhibitory environment associated with Staphylococcus aureus biofilms by activated macrophage transfer (166.6)
Authors: Heim Cortney , Hanke Mark , Kielian Tammy 
Published: January 2023

Abstract
Staphylococcus aureus (S. aureus) can establish biofilm infections on natural and artificial surfaces, which are typically recalcitrant to antibiotic therapy. Our laboratory has shown that S. aureus biofilms evade macrophage (MΦ) anti-microbial activity, further complicating biofilm eradication. To overcome the local immune inhibitory environment created by S. aureus biofilms, we have examined whether local administration of IFN-γ and peptidoglycan activated MΦs facilitates biofilm clearance in vivo using two treatment paradigms. In a prophylactic approach, mice received activated MΦs at 12, 24, and 48 h post-infection, whereupon bacterial burdens on infected catheters and surrounding tissues were quantitated at days 3 or 14 post-infection to evaluate the longevity of MΦ-mediated biofilm clearance. For established biofilms, activated MΦs were introduced at days 7 and 9 post-infection. In both treatment paradigms, activated MΦs led to significant reductions in bacterial burdens on infected catheters and catheter-associated tissues compared to vehicle controls. In addition, many proinflammatory mediators were significantly elevated in MΦ-treated animals in both models, indicating that MΦ administration is capable of overcoming the local immune inhibitory environment created during S. aureus biofilm formation. Collectively, these findings demonstrate that the local administration of activated MΦs enhances the host immune response to facilitate S. aureus biofilm clearance.