bluuebunny/crossref_metadata_2025_split huggingface dataset:
HVEM-LIGHT interactions promote generation of memory Th2 cells that mediate lung inflammation (91.8)
Authors: Soroosh Pejman , Doherty Taylor , So Takanori , Fukuyama Satoshi , Ware Carl , Croft Michael 
Published: January 2023

Abstract
Memory Th2 cells are important in the pathogenesis of allergic responses including asthma, orchestrating recruitment of eosinophils and other inflammatory cells. Members of the tumor necrosis factor (TNF) receptor superfamily have emerged as key contributors to T cell activity, and therefore we investigated whether the engagement of the herpesvirus entry mediator (HVEM) on T cells by the TNF family molecule LIGHT controls Th2 mediated lung inflammation. Using systems where either HVEM or LIGHT are only defective on responding antigen-specific T cells, we demonstrated that the presence of HVEM on T cells is indispensible for the generation and persistence of Th2 memory cells and for allergen-induced Th2 lung inflammation, despite having a limited effect on early Th2 effector responses. Using adoptive co-transfer experiments we demonstrate that HVEM-LIGHT interaction on CD4 T cells can support longevity of T cells and promote memory generation. We also observed reduced activity of protein kinase B (PKB/Akt) and NF-κB in HVEM-deficient effector CD4 T cells, correlating with their poor survival. Furthermore, expression of an active form of PKB in HVEM-deficient T cells rescued Th2 cell survival in vivo, and restored lung inflammation in recall responses. Collectively, our results demonstrate a critical role of HVEM signals in the pathogenesis of Th2 derived lung inflammation and suggest that blocking of HVEM-LIGHT interactions could be a novel therapeutic target for asthma
Temporal and spatial distribution of antigen following influenza virus infection (92.16)
Authors: Turner Damian , Lefrancois Leo 
Published: January 2023

Abstract
Memory CD8 T cells generated by vaccines are important for prevention of certain viral infections. However, our understanding of the factors that contribute to the development of memory CD8 T cell remains unclear. We hypothesized that, in response to a localized influenza virus (IAV) infection, CD8 T cells are recruited to the local draining lymph node (dLN) at different times and thus acquire different fates. We therefore studied the kinetics of recruitment and activation of naïve IAV-specific CD8 T cells in the dLN of the respiratory tract following IAV infection. We observed early antigen presentation in the dLN; however, we also observed evidence of antigen encounter in the spleen. To determine the differentiation outcome of CD8 T cells primed in disparate sites following a localized infection we adoptively transferred spleen-primed or dLN-primed cells into naïve mice and determined their survival and ability to respond upon recall. Surprisingly we found that CD8 T cells primed in the spleen differentiate into memory cells of equal longevity and with similar capacity to respond to recall as CD8 T cells that are primed in the dLN. Thus, in a model of respiratory IAV infection, virus-specific memory CD8 T cells are generated in the spleen in addition to the dLN. Antigen presentation in the spleen may therefore serve to ensure the involvement of a greater fraction of the virus-specific CD8 T cell repertoire after a local infection.
Characterization of a second C-type lectin-like gene in rat cytomegalovirus (92.8)
Authors: Voigt Sebastian , Friedrich Robert , Kutschenko Lara 
Published: January 2023

Abstract
Gene capture has been a prominent feature in herpesvirus evolution, and many of these hijacked genes serve immunomodulatory purposes. Recently, we characterised a lectin-like gene (RCTL) in the English isolate of rat cytomegalovirus (RCMV) that interacts with an inhibitory receptor on Natural Killer (NK) cells. Here, we show that RCMV encodes an additional, spliced lectin-like gene (RCTL2) that, compared to RCTL, is located at the opposite end of the viral genome. RCTL2 consists of four exons and is expressed in the early phase of viral replication. To analyse if RCTL2 can be expressed as a protein, we tagged the ORF with the FLAG sequence. After transfection of 293 cells, RCTL2 was detected by fluorescent microscopy and Western blot analysis. Treatment with tunicamycin reduced the protein size, thereby confirming predicted N-linked glycosylation sites. The sequence similarity of RCTL2 with RCTL and the reported interaction with NK cells of the latter suggest that RCTL2 is similarly involved in the modulation of the innate immune response and that the capture of lectin-like genes is beneficial for viral replication. This notion is supported by the existence of lectin-like genes in poxviruses.
CIKS/Act1 is required for collagen-induced arthritis (93.3)
Authors: Pisitkun Prapaporn , Claudio Estefania , Ren Nina , Wang Hongshan , Bolland Silvia , Siebenlist Ulrich 
Published: January 2023

Abstract
Collagen-induced arthritis (CIA) is a widely used animal model for human rheumatoid arthritis (RA). Th17 cells are thought to be critical for development of RA and CIA, mediated in part via production of IL-17. CIKS/Act1 is an important adaptor molecule for signaling by IL-17 and related cytokines. Although evidence suggests a role for IL-17 in RA, the physiologic relevance of CIKS/Act1 in RA and the CIA model has not been evaluated. We have applied the CIA model to CIKS deficient and wild-type (WT) B6 mice. Based on clinical scores and histochemical analyses, arthritis could be induced in WT, but not CIKS deficient mice. The production of collagen type 2-specific antibodies (CII-Abs) and neutrophil recruitment to the joint were also blocked in CIKS deficient mice. We also performed CIA model studies in mice with compound deficiency in CIKS and FcgammaRIIb (B6). Although the loss of FcgammaRIIb greatly exacerbated arthritis in the CIA model in CIKS-sufficient mice, arthritis and production of CII-Abs were still blocked in the absence of CIKS. In addition we determined that CIKS is not required in the collagen antibody-induced arthritis (CAIA) model, in contrast to this adaptor’s role in CIA. These data suggest a crucial role of CIKS during the generation of CII-Abs and clearly implicate the CIKS adaptor as essential for development of CIA and thus a potential therapeutic target in RA.
Activation of the nitric oxide-mitochondrial hyperpolarization-mTOR-Rab4 signaling pathway precedes disease development in lupus T cells (93.36)
Authors: Perl Andras , Telarico Tiffany , Singh Ram , Fernandez David 
Published: January 2023

Abstract
Nitric oxide (NO) dependent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation in Systemic Lupus Erythematosus. Activity of mTOR, which senses the mitochondrial membrane potential, is increased in lupus T cells, which promotes HRES-1/Rab4 expression. Rab4 overexpression enhances recycling and lysosomal degradation of immune synapse components, including CD4 and TCRζ. We investigated activity of the NO-MHP-mTOR-Rab4 signaling pathway in lupus-prone mice. Overexpression of Rab4 and loss of TCRζ were detected prior to disease onset of NZB/NZW (F1) mice at 5 months. Increased NO production, mitochondrial transmembrane potential, and mitochondrial mass were present after disease onset at 11 months. MRL/lpr mice exhibited increased expression of the mitochondrial voltage-dependent anion channel 1(VDAC1) protein, transaldolase (TAL), Rab4, mTOR activation, and enhanced CD3 and CD4 recycling at 2-3 months, prior to disease development. In conclusion, lupus-prone mice exhibit mitochondrial dysfunction, with increased NO production, MHP, elevated expression of VDAC1 and TAL, and mTOR activation. Increased Rab4 expression was associated with enhanced endocytic recycling of CD4 and CD3. The results suggest that activation of the NO-MHP-mTOR-Rab4 signaling pathway is detectable and precedes disease onset in lupus-prone mice.
Generation of a proinflammatory response by macrophage following infection with an O3:K6 serotype of Vibrio parahaemolyticus. (94.3)
Authors: Parent Michelle , Waters Stephanie , Blumerman Seth , Whitaker Brian , Joerger Torsten , Boyd E. 
Published: January 2023

Abstract
Vibrio parahaemolyticus, a Gram-negative bacterium, is the leading cause of seafood-related bacterial gastroenteritis in the United States. This emerging pathogen can causes self-limiting gastrointestinal infection, wound infection, and, in the immunocompromised host, significant systemic disease, leading to death. The CDC has recently reported a 47% increase in the number of culture confirmed V. parahaemolyticus infections since 1996-1998. There is a dearth of literature regarding the host response to, and subsequent elimination of, infection with this pathogen. In order to elucidate the immune response to infection, we have developed an in vitro model using the virulent clinical isolate V. parahaemolyticus RIMD2210633, an O3:K6 serotype. First, we determined that this isolate could infect RAW264.7 cells, a murine macrophage cell line. Additionally, infection resulted in the simultaneous detection of 7-amino-actinomycin D (7-AAD) and annexin-V positive cells, suggesting cell death with a loss of membrane integrity. Lastly, infection resulted in the production of the early proinflammatory cytokines interleukin-1 alpha (IL-1α) and interleukin 6 (IL-6). We a currently investigating the cellular pathways involved in this proinflammatory response and macrophage cell death. Here, we have begun to investigate those aspects of the immune response required to eliminate this gastrointestinal pathogen from infected host tissues.
Adoptive transfer of Tc17 CD8 T cells leads to tumor inhibition and anti-tumor response (95.15)
Authors: Yen Hung-Rong , Harris Timothy , Radojcic Vedran , Huang Dih-Dih , Grosso Joseph , Getnet Derese , Wada Satoshi , Goldberg Monica , Bruno Tullia , Durham Nicholas , Khazaie Khashayarsha , Luznik Leo , Lin Tzou-Yien , Pardoll Drew , Huang Ching-Tai , Drake Charles 
Published: January 2023

Abstract
Although CD4+ T cells that secrete IL-17 (TH17) have been fairly well-studied, we and others have shown that CD8 T cells can be cultured under similar skewing conditions, resulting in CD8 cells with a robust ability to secrete IL-17. The physiological role such CD8 T cells (Tc17) is not well understood. In our previous data, we showed that Tc17 can functionally convert to IFN-g producing cells, expand, and mediate autoimmunity in a self-antigen murine model. Because autoimmunity and antitumor immunity both involve the breaking of peripheral T cell tolerance, we performed experiments to test whether Tc17 could mediate anti-tumor immunity in implanted tumor models. In a preventive model, small numbers (0.1M) of sorted IFN-g-producing Tc1, IL-17-producing or IFN-g-producing Tc17 TCR-transgenic HA-recognizing CD8 T cells were adoptively transferred to immunocompetent recipient (Balb/C) mice on day -1, and 0.5M CT-26 tumor cells expressing HA as antigen were implanted into the footpad on day 0. Adoptive transfer of Tc17 was significantly superior to Tc1 in mediating an antitumor response and a better survival rate. Additional mechanisms are being explored.
Identification and characterization of putative proline directed serine/threonine kinase(s) directed against a functional PSP motif in STAT5 (95.6)
Authors: Mitra Abhisek 
Published: January 2023

Abstract
Hematological malignancies, such as leukemia and lymphoma, can develop from aberrant changes in cell signaling molecules that drive uncontrolled cell proliferation. Although there are numerous effector molecules that promote activation and expansion of T cells, one key pathway is the JAK (Janus Kinase)-STAT (Signal transducer and activator of transcription) cascade. These signaling proteins are activated in response to an array of cytokines, however constitutively activated JAKs and STATs have been described in several T cell malignancies. Indeed, a growing body of evidence suggests that dysregulated STAT5 may be a major contributor to certain types of T cell cancers. In addition to tyrosine phosphorylation of STAT5, serine phosphorylation within a Proline-Serine-Proline (PSP) or PXSP motif, located in the transactivation domain may also be equally important to its activation status, however the STAT5 serine-threonine kinase is not immediately known. Therefore, using a siRNA directed “loss of function” approach, proline directed serine/threonine kinases were screened for their ability to phosphorylate STAT5 in an IL-2 dependent manner. The results from this assay provide interesting insight into this family of kinases and their role in STAT5 regulation. Additionally, the data offers new information into the functional role of STAT5 serine phosphorylation and provides possible new therapeutic strategies for controlling diseases dependent upon this key signaling pathway.
A leukemic plasmacytoid dendritic cell line (PMDC05) as potent antigen presenting cells for anti-tumor cellular immunothrerapy (95.8)
Authors: Yamahira Akie , Narita Miwako , Nakamura Takeshi , Watanabe Norihiro , Kaji Masami , Taniguchi Tomoyo , Hashimoto Shigeo , Takahashi Masuhiro 
Published: January 2023

Abstract
We established a leukemic plasmacytoid dendritic cell (pDC) line (PMDC05) with potent antigen presenting capacity from leukemia cells of a patient with pDC acute leukemia. PMDC05 was positive for CD4, CD56, CD33, HLA-DR, CD123 (IL-3Rα) and CD86 in the absence of lineage markers. mRNA of TLR1, TLR2, TLR4, TLR7 and TLR9 were clearly expressed and among these TLRs, TLR7 was prominent. By culturing PMDC05 with IL-3, CpG-B or LPS, the expression of CD1a, CD80, CD83, CD86 or HLA-DR was remarkably enhanced. Production of IFN-α and IL-12p70 was enhanced by the stimulation with CpG-A and LPS, respectively. PMDC05, which was stimulated with 0.1 μg/mL LPS and loaded with 10 μg/mL WT1 peptides (HLA-A*2402-restricted, modified-type 9-mer peptide; CYTWNQMNL) for 24 hours, was irradiated (60 Gy) and co-cultured with allogeneic CD8+ T cells purified from PB-MNCs of HLA-A*2402+ healthy donor (PMDC05:CD8+ Tcells = 1:10). Induction of WT1-specific CTLs was evaluated by flow cytometry analysis using HLA-A*2402 WT1 tetramer every week. Although Daudi pulsed with WT1 peptides could not induce WT1 tetramer+CD8+ T cells during the co-culture up to 7 weeks, PMDC05 began to induce WT1 tetramer+CD8+ T cells at week 4 and the percentage of WT1 tetramer+ T cells in CD8+ T cells rose to more than 75% at week 7. These data suggested that PMDC05 could be efficiently used for generating CTLs specific for antigens of tumors and could be applicable for cellular immunotherapy for tumors.
Single Dose Nasal Immunotherapy Rapidly Recruits NK Cell-Dependent Regulatory T (Treg) Cells into Central Nervous System (CNS) to Ameliorate Experimental Autoimmune Encephalomyelitis (EAE) (96.12)
Authors: Huarte Eduardo , Rynda* Agnieszka , Maddaloni Massimo , Riccardi Carol , Pascual David 
Published: January 2023

Abstract
Reovirus protein sigma 1 (pσ1), engineered to deliver OVA mucosally, induced tolerance in mice even with a single, low dose. To test the efficacy of pσ1-based therapy, the extracellular domain of myelin oligodendrocyte glycoprotein (MOG29-146) was genetically fused to pσ1 (MOG-pσ1). Susceptible C57BL/6 mice were nasally dosed with PBS, MOG-pσ1, or recombinant (r)MOG and 3 wks later were challenged with MOG35-55-induced EAE. MOG-pσ1, not rMOG or PBS, abrogated EAE incidence evidenced by &gt;8-fold reductions in IFN-γ, IL-17, and IL-21, but greatly elevated IL-4 and IL-10. To test its therapeutic potential at the peak of MOG35-55-induced EAE (around day 15), mice were nasally treated with 50 μg of MOG-pσ1 or PBS. Strikingly, within 24 hrs of treatment with MOG-pσ1, &gt;2-fold reduction in clinical symptoms were obtained. This improved clinical response was accompanied by a significant increase of at least 4-fold in FoxP3+ Treg cells in the spinal cords of treated mice; however, such increases were not evident in head and neck lymph nodes or the spleen. This increase in Treg cell infiltration into the CNS appears to be NK cell-dependent since this infiltration was abated in NK cell-depleted mice. Finally, enhanced apoptosis (30%) of infiltrating CD11c+ CD11b+ DCs was observed, underscoring the complexity of this system. * Authors contributed equally to the work; supported by NIH AI-78938.
Beta-Endorphin Neuron Transplant in the Hypothalamus Reduces Pro-inflammatory Cytokines and Inflammation in the Ankle’s Joint and Ameliorates the Course of Adjuvant-Induced Arthritis (96.15)
Authors: Govorko Dmitry , Boyadjieva Nadka , Ortiguela Maria , Sarkar Dipak 
Published: January 2023

Abstract
In our recent study, we demonstrated that implantation of stem cell-derived beta-endorphin producing (BEP) neurons into the rat hypothalamus is capable of suppressing the level of inflammatory cytokines in a cancer model. In this study, we are reporting the effect of the BEP cells transplantation into the hypothalamus on the systemic inflammation exemplified by adjuvant-induced arthritis (AIA). Female Lewis rats were transplanted with BEP cells or the neuronal cortical cells into the paraventricular nuclei. AIA was induced by intradermal injection of the oil suspension of Mycobacterium butyricum at the base of the tail. The severity of the AIA was assessed by evaluating clinical parameters such as ankle circumference, paw thickness, and the articular index. BEP neuron transplanted rats exhibited a statistically significant reduction in the articular index (P &lt;0.05 at day 12), posterior paw thickness (P &lt; 0.05 at day 16) and ankle circumferences (P &lt; 0.01 at day 21) in comparison to cortical neuron transplanted rats. Concomitantly with the clinical parameters, the mRNA expression levels of pro-inflammatory cytokines such as TNF-alpha, Il-2, Il-6 and Il-17 significantly decreased in the ankle joints of BEP-treated rats in comparison to control. This study demonstrates for the first time that the central effect of BEP cell implantation into the rat hypothalamus reduces the inflammatory process development in the ankle joint and may ameliorate course of rheumatoid arthritis.
atRA restores the stability and functionality of nTregs in the inflammatory milieu (96.17)
Authors: Zheng Song Guo , Kong Ling , Zhou Xiaohui , Wang Julie , Shi Wei , Brand David , Fan Huimin , Liu Zhongmin , Zou Hejian 
Published: January 2023

Abstract
Natural Tregs play an important role in the maintenance of immune tolerance. Recent studies revealed that nTregs are plastic and unstable when stimulated with IL-6. They can be converted into either Th1, or Th17 or Th2 cells and lose phenotypic and functional characteristics in inflammatory milieu. all-trans Retinoic Acid (atRA) not only promotes Foxp3+ cell development, but restrains Th17 cell differentiation induced by IL-6+TGF-β. We here report that addition of atRA blocked Th17 conversion from nTregs. atRA-nTregs expressed lower levels of CD126 (IL-6Rα chain) and phosphorylated STAT3 compared to DMSO-nTregs when stimulated with IL-6. atRA- but not DMSO-nTregs maintained the suppressive activity in the presence of IL-6. Adoptive transfer of atRA- but not DMSO-pretreated nTregs to DBA/1 mice at day 28 after immunization with CII/CFA significantly reduced the severity of CIA. Using CFSE-labeled donor cells, we were able to observe that majority of nTreg cells lost Foxp3 expression, converted to IL-17-prodcuing cells, and &gt;20% converted into Th2 cells in draining lymph nodes at one week after adoptive transfer to the established CIA. Conversely, atRA-nTregs maintained Foxp3 expression and did not convert to Th1, Th2 and Th17 cells in CIA. atRA alters Treg plasticity and restores the functionality of nTregs in the inflammatory milieu. This study may provide a novel therapeutic approach of nTregs for the treatment of Rheumatoid Arthritis and other autoimmune diseases.
CXCR7 antagonism prevents leukocyte trafficking into the central nervous system and treats ongoing disease during experimental autoimmune encephalomyelitis. (96.5)
Authors: Cruz-Orengo Lillian , Holman David , Wright Melissa , Dorsey Denise , Klein Robyn 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is a neurological disorder characterized by the pathological trafficking of autoreactive leukocytes into the central nervous system (CNS). We previously showed that removal of CXCL12 from abluminal surfaces of the CNS microvasculature facilitates the entry of CXCR4-expressing leukocytes within MS tissues and in mice with experimental autoimmune encephalomyelitis (EAE), a model for MS. Recently, the orphan receptor CXCR7 was determined to bind CXCL12/11. Evidence suggests that CXCR7 mainly regulates CXCR4 signaling by sequestering CXCL12 from extracellular milieu. Using MS and EAE specimens, we tested the hypothesis that inhibition of CXCR7 would prevent leukocyte migration into the CNS and induction of autoimmunity. CXCR7 is expressed by both human and murine CNS endothelium and CXCR7 antagonism completely blocks CXCL12 internalization in brain microvascular cells in vitro. In vivo antagonism of CXCR7 led to dose-dependent inhibition of EAE and ameliorated clinical symptoms in mice with ongoing disease. Immunohistochemical analysis revealed increased leukocytes within meningeal vessels, decreased perivascular infiltrates and parenchymal entry of leukocytes compared with controls. Abluminal CXCL12 expression persisted only in mice treated with high doses of CXCR7 antagonist. The benefits of persistent abluminal CXCL12 location during EAE suggest that pharmacologic targeting of CXCR7 may have therapeutic utility for the treatment of MS.
Helminths abrogate antigen-specific gut inflammation in a novel murine model of non-IgE mediated food hypersensitivity (97.13)
Authors: Leung John , Hang Long , Blum Arthur , Setiawan Tommy , Stoyanoff Karynn , Weinstock Joel 
Published: January 2023

Abstract
Non-IgE mediated (NIE) food hypersensitivities (FH) affect 2 million Americans. Helminths protect from IgE-mediated FH. Their effect on NIEFH has not been studied. We developed a murine model of NIEFH featuring severe antigen-specific enterocolitis with Th1/Th17 polarization. We used this unique model to test if helminths protect against NIEFH. METHODS: Rag1-/- mice, IL10-/- T cells and ovalbumin (OVA)-specific, TCR transgenic OT2 T cells were used to develop the NIEFH model. 6-wk-old Rag mice were reconstituted with IL10-/- and OT2 T cells. To determine if helminths protect, mice were infected with H. polygyrus before feeding low dose NSAID for 2 wks followed by OVA for 1 wk. RESULTS: On a 4-pt scale, histology score of duodenum, ileum and colon were 0.15±0.3, 0.85±0.8 & 1.9±1.1 in helminth-infected mice (n=23) versus 3.8±0.5, 2.9±1.2 & 3.0±0.8 in non-infected group (n=10) [p&lt;0.02]. Laminar propria mononuclear cells (LPMC) from helminth-infected mice produced more IL10 in vitro than those from non-infected mice (1.4 vs 0.7 ng/ml, p&lt;0.01). IL10 production was enhanced by OVA stimulation, but not by anti-CD3/28. LPMC from infected mice displayed less IL17 and IFNg when stimulated by anti-CD3/28 in vitro (p&lt;0.01). CONCLUSION: Our study provides proof of concept that helminths protect against antigen-specific NIEFH. Abrogation of gut inflammation associates with suppressed IL17 & IFNg, and elevated IL10 production probably from non-T cell source. NIH, Broad Foundation