bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective Immunity from Naive CD8+ T Cells Activated In Vitro with MHC Class I Binding Immunogenic Peptides and IL-2 in the Absence of Specialized APCs
Authors: Hauser Conrad , Zipprich Frank , Leblond Isabelle , Wirth Susanne , Hügin Ambros W. 
Published: January 2023

Abstract
Ag-specific CTL can protect against tumors and some viral infections and may be useful for adoptive immunotherapy. Here, we show that purified CD8+ T cells from naive C57BL/6 mice can be primed in vitro with different immunogenic peptides, which bind to MHC class I gene products, and IL-2 to exhibit specific and MHC-restricted effector function in vitro and in vivo protection against lymphocytic choriomeningitis virus infection and B16.F10 melanoma lung metastases. Limiting dilution assays in the absence of feeder cells with highly purified CD8+ T cells from two transgenic mice strains, each expressing a different MHC class I-restricted TCR, indicated that only peptide and IL-2, but not TCR− cells, were required for the growth of naive CD8+ T cells. These alternative minimal requirements for the activation and expansion of specific CD8+ T lymphocytes, without the need for professional APC, may be exploited for adoptive immunotherapy.
Involvement of Thioredoxin in Rheumatoid Arthritis: Its Costimulatory Roles in the TNF-α-Induced Production of IL-6 and IL-8 from Cultured Synovial Fibroblasts
Authors: Yoshida Shinichi , Katoh Tetsuji , Tetsuka Toshifumi , Uno Kazuko , Matsui Nobuo , Okamoto Takashi 
Published: January 2023

AbstractThioredoxin (TRX) is a cellular reducing catalyst induced by oxidative stress and is involved in the redox regulation of transcription factors such as NF-κB. We found that the serum TRX concentration was elevated in patients with rheumatoid arthritis (RA) as compared with values from healthy individuals and patients with osteoarthritis (33.6 ± 35.1 vs 11.8 ± 6.6 ng/ml, p &lt; 0.01). Moreover, the TRX concentration in the synovial fluid (SF) was much more elevated in RA patients than in osteoarthritis patients (103.4 ± 53.3 vs 24.6 ± 17.4 ng/ml, p &lt; 0.001). Multiple regression analysis revealed that the serum C-reactive protein value was better correlated with the linear combination of SF TNF-α and SF TRX values than with SF TNF-α alone, suggesting that TRX might play a subsidiary role in the rheumatoid inflammation. We thus examined the effect of TRX on the TNF-α-induced IL-6 and IL-8 production using rheumatoid synovial fibroblast cultures. The extents of IL-6 and IL-8 production in response to TNF-α were greatly augmented by TRX as compared with TNF-α alone. TRX alone did not have such effects. We also found that TRX appeared to accelerate the nuclear translocation of NF-κB, a major transcriptional regulator for production of IL-6 and IL-8 on stimulation with TNF-α. Consistent with these findings, the IκBα phosphorylation at Ser32 and its subsequent degradation in response to TNF-α was facilitated by TRX. These findings indicate that the elevated TRX concentration in SF of RA patients might be involved in the aggravation of rheumatoid inflammation by augmenting the NF-κB activation pathway.
Osteoclast Differentiation Factor Acts as a Multifunctional Regulator in Murine Osteoclast Differentiation and Function
Authors: Jimi Eijiro , Akiyama Shuichi , Tsurukai Taro , Okahashi Nobuo , Kobayashi Kanichiro , Udagawa Nobuyuki , Nishihara Tatsuji , Takahashi Naoyuki , Suda Tatsuo 
Published: January 2023

Abstract
Osteoclast differentiation factor (ODF), a novel member of the TNF ligand family, is expressed as a membrane-associated protein by osteoblasts/stromal cells. The soluble form of ODF (sODF) induces the differentiation of osteoclast precursors into osteoclasts in the presence of M-CSF. Here, the effects of sODF on the survival, multinucleation, and pit-forming activity of murine osteoclasts were examined in comparison with those of M-CSF and IL-1. Osteoclast-like cells (OCLs) formed in cocultures of murine osteoblasts and bone marrow cells expressed mRNA of RANK (receptor activator of NF-κB), a receptor of ODF. The survival of OCLs was enhanced by the addition of each of sODF, M-CSF, and IL-1. sODF, as well as IL-1, activated NF-κB and c-Jun N-terminal protein kinase (JNK) in OCLs. Like M-CSF and IL-1, sODF stimulated the survival and multinucleation of prefusion osteoclasts (pOCs) isolated from the coculture. When pOCs were cultured on dentine slices, resorption pits were formed on the slices in the presence of either sODF or IL-1 but not in that of M-CSF. A soluble form of RANK as well as osteoprotegerin/osteoclastogenesis inhibitory factor, a decoy receptor of ODF, blocked OCL formation and prevented the survival, multinucleation, and pit-forming activity of pOCs induced by sODF. These results suggest that ODF regulates not only osteoclast differentiation but also osteoclast function in mice through the receptor RANK.
In Situ T Cell Responses Against Melanoma Comprise High Numbers of Locally Expanded T Cell Clonotypes
Authors: thor Straten Per , Guldberg Per , Grønbæk Kirsten , Hansen Mia Riise , Kirkin Alexei F. , Seremet Tina , Zeuthen Jesper , Becker Jürgen C. 
Published: January 2023

Abstract
It is well established that melanoma cells express Ags that are recognized by autologous T cells in vitro. Tumor-infiltrating lymphocytes in situ comprise clonotypic T cells, suggesting that their expansion is driven by Ag stimulation. Still, little is known about the detailed characteristics of the in situ T cell response. In the present study, we scrutinized this response by analyzing multiple metastatic lesions for the presence of clonotypic T cells. This approach was chosen to distinguish whether the clonal T cell expansion occurs as a systemic or localized phenomenon. TCR clonotype mapping of six s.c. metastases from two patients revealed the presence of multiple (from 40 to &gt;60) clonotypic T cells in all lesions. Clonotypic T cells were present in TCR β-variable regions expressed both at high and low levels. Comparison of the T cell clonotypes present in different lesions from individual patients demonstrated that, in general, clonotypes were exclusively detected in a single lesion. Hence, anti-melanoma T cell responses are much more heterogeneous than previously anticipated and accommodate a predominance of strictly localized T cell clonotypes.
Increased Apoptosis in Patients with Major Depression: A Preliminary Study
Authors: Eilat Eran , Mendlovic Shlomo , Doron Adiel , Zakuth Vera , Spirer Zvi 
Published: January 2023

Abstract
Apoptosis is a programmed cell death that can be observed in normal cells. Major depression poses a combination of a depressed and destructive autoimmune reaction. We measured apoptosis in the PBLs of seven patients with major depression and in age- and sex-matched controls. We observed significantly increased apoptosis in the PBLs of depressive patients (p &lt; 0.05). These preliminary results could contribute to an understanding of the interactions of the CNS with the immune system, which could lead to the increased vulnerability of the CNS in depressive disorders. Further studies are needed to establish these results.
Polyriboinosinic Polyribocytidylic Acid (Poly(I:C)) Induces Stable Maturation of Functionally Active Human Dendritic Cells
Authors: Verdijk Rob M. , Mutis Tuna , Esendam Ben , Kamp Janine , Melief Cees J. M. , Brand Anneke , Goulmy Els 
Published: January 2023

Abstract
For vaccination strategies and adoptive immunotherapy purposes, immature dendritic cells (DC) can be generated from adherent monocytes using GM-CSF and IL-4. Presently, the only clinically applicable method to induce stable maturation of DC is the use of supernatants of activated monocytes (monocyte-conditioned medium (MCM)). MCM contains an undefined mixture of cytokines and is difficult to standardize. Here we report that stable maturation of DC can be simply induced by the addition of polyriboinosinic polyribocytidylic acid (poly(I:C)), a synthetic dsRNA clinically applied as an immunomodulator. Poly(I:C)-treated DC show a mature phenotype with high expression levels of HLA-DR, CD86, and the DC maturation marker CD83. This mature phenotype is retained for 48 h after cytokine withdrawal. In contrast to untreated DC, poly(I:C)-treated DC down-regulate pinocytosis, produce high levels of IL-12 and low levels of IL-10, induce strong T cell proliferation in a primary allo MLR, and effectively present peptide Ags to HLA class I-restricted CTL. In conclusion, we present a simple methodology for the preparation of clinically applicable mature DC.
Specialized Ability of Thymic Epithelial Cells to Mediate Positive Selection Does Not Require Expression of the Steroidogenic Enzyme P450scc
Authors: Jenkinson Eric J. , Parnell Sonia , Shuttleworth John , Owen John J. T. , Anderson Graham 
Published: January 2023

AbstractThymic epithelial cells are uniquely efficient in mediating positive selection, suggesting that in addition to providing peptide/MHC complexes for TCR ligation, they may also provide additional support for this process. Recent studies have shown that although engagement of either the TCR or glucocorticoid (GC) receptors can individually induce apoptosis in thymocytes, together these signals are mutually antagonistic. This had led to the suggestion that local GC production by thymic epithelial cells, by opposing TCR signaling for apoptosis, provides the basis of the ability of these cells to mediate thymocyte positive selection. In this paper we have examined this possibility directly and shown that highly purified cortical epithelial cells, which have the functional ability to mediate positive selection in reaggregate cultures, do not express mRNA for the key steroidogenic enzyme P405scc. Thus we conclude that the ability of thymic epithelial cells to support positive selection does not rely on their ability to produce GC. However, we find that P450scc mRNA is up-regulated in thymocytes on the initiation of positive selection, raising the possibility that any local protective effect of steroid production is mediated at the level of thymocytes themselves.
Generation of an Immunodominant CTL Epitope Is Affected by Proteasome Subunit Composition and Stability of the Antigenic Protein
Authors: Gileadi Uzi , Moins-Teisserenc Hélène T. , Correa Isabel , Booth Bruce L. , Dunbar P. Rod , Sewell Andrew K. , Trowsdale John , Phillips Rodney E. , Cerundolo Vincenzo 
Published: January 2023

AbstractGeneration of the HLA-A0201 (A2) influenza Matrix 58–66 epitope contained within the full-length Matrix protein is impaired in cells lacking the proteasome subunits low molecular protein 2 (LMP2) and LMP7. This Ag presentation block can be relieved by transfecting the wild-type LMP7 cDNA into LMP7-deficient cells. A mutated form of LMP7, lacking the two threonines at the catalytic active site, was equally capable of relieving the block in presentation of the influenza Matrix A2 epitope. These observations were extended by analyzing whether modification of the influenza Matrix protein could overcome the block in presentation of the A2 Matrix epitope. Expression of either a rapidly degraded form of the full-length Matrix protein or shorter Matrix fragments led to an efficient presentation of the A2 influenza Matrix epitope by LMP7-negative cells. These findings demonstrate two main points: 1) LMP7 incorporation into the proteasome is of greater importance for the generation of the influenza A2 Matrix epitope than the presence of the LMP7’s catalytic site; and 2) the interplay between cytosolic proteases and stability of target proteins is of importance in optimization of Ag presentation. These observations may have relevance to the immunodominance of tumor and viral epitopes and raise the possibility that generation of shorter protein fragments could be a mechanism to ensure optimal Ag presentation by cells expressing low levels of LMP7.
Peptide Presentation to an Alloreactive CTL Clone Is Modulated Through Multiple Mechanisms Involving Polymorphic and Conserved Residues in HLA-B27
Authors: García-Peydró Marina , Paradela Alberto , Lamas José R. , López de Castro José A. 
Published: January 2023

AbstractThis study addressed the mechanisms by which HLA class I polymorphism modulates allorecognition. CTL 27S69 is an alloreactive clone raised against HLA-B*2705, with a known peptide epitope. This CTL cross-reacts with B*2702, which differs from B*2705 in the D77N, T80I, and L81A changes, but not with B*2701, which has D74Y, D77N, and L81A changes. To explain this differential recognition, B*2705 mutants mimicking subtype changes were used. The A81 mutant was not recognized, despite binding the natural epitope in vivo, suggesting that, when bound to this mutant, this peptide adopts an inappropriate conformation. The N77 and I80 mutations restored recognition in the N77A81 or I80A81 mutants. These compensatory effects explain the cross-reaction with B*2702. The Y74 and the Y74N77 mutants were weakly recognized or not recognized by CTL 27S69. This correlated with the absence or marginal presence of the peptide epitope in the Y74N77-bound pool. As with B*2701, exogenous addition of the peptide epitope sensitized Y74 and Y74N77 targets for lysis, indicating that failure to cross-react with B*2701 or these mutants was due to poor binding of the peptide in vivo and not to inappropriate presentation. The abrogating effect of Y74 was critically dependent upon the K70 residue, conserved among subtypes, as demonstrated with mutants at this position. Thus, HLA polymorphism affects allorecognition by modulating peptide binding or the conformation of bound peptides. Compensatory mutations and indirect effects of a polymorphic residue on residues conserved play a critical role.
CXC Chemokine Receptor-2 Ligands Are Necessary Components of Neutrophil-Mediated Host Defense in Invasive Pulmonary Aspergillosis
Authors: Mehrad Borna , Strieter Robert M. , Moore Thomas A. , Tsai Wan C. , Lira Sergio A. , Standiford Theodore J. 
Published: January 2023

AbstractInvasive pulmonary aspergillosis is a devastating complication of immunosuppression, which occurs in association with neutrophil dysfunction or deficiency. ELR+ CXC chemokines are a subfamily of chemokines that play a critical role in neutrophil chemotaxis and activation both in vitro and in vivo. We hypothesized that interaction of these ligands with CXC chemokine receptor-2 (CXCR2), their sole murine receptor, is a major component of neutrophil-dependent pulmonary host defense against Aspergillus fumigatus. In immunocompetent animals, neutrophils were recruited to the lung in response to intratracheally administered A. fumigatus conidia. In a model of transient in vivo depletion of neutrophils, animals developed invasive pulmonary aspergillosis, associated with delayed influx of neutrophils into the lung. In both normal and neutrophil-depleted animals, the ELR+ CXC chemokines MIP-2 and KC were induced in response to intratracheal administration of conidia. Ab-mediated neutralization of the common ELR+ CXC chemokine receptor, CXCR2, resulted in development of invasive disease indistinguishable from the disease in neutrophil-depleted animals, while control animals were highly resistant to the development of infection. CXCR2 neutralization was associated with reduced lung neutrophil influx and resulted in a marked increase in mortality compared with controls. In contrast, animals with constitutive lung-specific transgenic expression of KC were resistant to the organism, with reduced mortality and lower lung burden of fungus. We conclude that CXCR2 ligands are essential mediators of host defense against A. fumigatus, and may be important targets in devising future therapeutic strategies in this disease.
Prostaglandin E2 Selectively Inhibits Human CD4+ T Cells Secreting Low Amounts of Both IL-2 and IL-4
Authors: He Xiaowen , Stuart John M. 
Published: January 2023

AbstractPGE2 is a potent inflammatory mediator with profound immune regulatory actions. The present study examined the effects of PGE2 on the activation/proliferation of CD4+ T cells using 37 cloned CD4+ T cell lines. Ten T cell clones sensitive to PGE2 and 10 T cell clones resistant to PGE2, as measured by proliferation in response to anti-CD3 Ab, were selected for comparison. It was found that the PGE2-sensitive T cells were characterized by low production (&lt;200 pg/ml) of both IL-2 and IL-4, while PGE2-resistant T cells secreted high levels (&gt;1000 pg/ml) of IL-2, IL-4, or both. The roles of IL-2 and IL-4 were confirmed by the finding that addition of exogenous lymphokines could restore PGE2-inhibited proliferation, and PGE2-resistant Th1-, Th2-, and Th0-like clones became PGE2 sensitive when IL-2, IL-4, or both were removed using Abs specific for the respective lymphokines. In addition, we showed that the CD45RA expression in PGE2-sensitive T cells was significantly lower than that in PGE2-resistant cells (mean intensity, 1.2 ± 0.6 vs 7.8 ± 5.7; p = 0.001). In contrast, CD45RO expression in PGE2-sensitive T cells was significantly higher that that in PGE2-resistant cells (mean intensity, 55.7 ± 15.1 vs 33.4 ± 12.9; p = 0.02). In summary, PGE2 predominantly suppressed CD45RA−RO+ CD4+ T cells with low secretion of both IL-2 and IL-4.
Inactivation of NF-κB by EBV BZLF-1-Encoded ZEBRA Protein in Human T Cells
Authors: Dreyfus David H. , Nagasawa Masayuki , Pratt Joanne C. , Kelleher Colm A. , Gelfand Erwin W. 
Published: January 2023

Abstract
We have previously shown that the EBV ZEBRA protein (also denoted EB1, Z, or Zta) encoded by the BZLF open reading frame is expressed in primary human thymocytes and in human T lymphoblastoid cell lines infected by EBV. Expression of EBV-encoded gene products in T lymphocytes could contribute to viral pathogenesis during acute EBV infection as well as in individuals coinfected with EBV and HIV. HPB-ALL and Jurkat T lymphoblastoid cell lines transiently and stably expressing ZEBRA were characterized in this work. Expression of ZEBRA protein in human T lymphoblastoid cells was associated with decreased expression of an NF-κB reporter gene, altered expression of the NF-κB p50 protein subunit, and decreased DNA binding by components of NF-κB. These observations suggest that inactivation of NF-κB transcription by ZEBRA in EBV-infected T cells may be a novel mechanism of viral pathogenesis analogous in part to over-expression of the endogenous cytoplasmic inhibitor of NF-κB, IκBα.
VSVΔG MARV GP and VSVΔG ZEBOV GP induce strong and rapid anti-viral state in mouse peritoneal macrophages through type I interferon stimulation (128.11)
Authors: Silaghi Alex , Fernando Lisa , Alimonti Judie , Stroeher Ute , Feldmann Heinz , Jones Steven M 
Published: January 2023

Abstract
Replacement of Vesicular Stomatitis Virus (VSV) G protein with the Marburg (MARV) and Ebola (ZEBOV) viruses' glycoproteins (GP) led to the most effective experimental post-exposure therapeutics available against filoviruses.
We hypothesize that the therapeutic effect is partly dependent on activation of innate immune mechanisms, as animals die before the adaptive immune response is activated. Macrophages are primary target cells of MARV, ZEBOV and the recombinant VSVs. Thus, we investigated the innate anti-viral mechanisms that are activated in J774A.1 murine macrophages by VSVΔG MARV GP and VSVΔG ZEBOV GP.
The infections result in rapid induction of anti-viral state, as measured by resistance to challenge with a high MOI of a VSV expressing GFP. There is a significant induction of anti-viral state by 6 hours post-infection and by 24 hours post-infection the cells are almost completely resistant to subsequent infections, which correlates with phosphorylation of IRF-3 and IFN-α and IFN-β production. Blockage of the IFN-α/β Receptor, neutralizes 70%-90% of the anti-viral effects suggesting that the anti-viral state induced after VSVΔG MARV GP or VSVΔG ZEBOV GP infections are type I interferon-dependent. In conclusion, the post-exposure protection may be dependent on type I interferon induction and subsequent activation of anti-viral pathways, which may inhibit filovirus replication in target cells.
A novel mechanism for Galectin-1 inhibition of endothelial cell fusion in Nipah virus infection; a critical component of vascular mediated innate immunity and host defense (128.3)
Authors: Garner Omai B , Aguilar Hector , Fulcher Jennifer , Levroney Ernest , Lee Benhur , Baum Linda 
Published: January 2023

Abstract
The vascular endothelium plays a critical role in the pathogenesis of many viral infections, either via direct infection of endothelial cells, or via damage to endothelia by the immune system. Nipah virus (NiV) is an emerging viral pathogen, of the genus Paramyxoviridae, but little is known about NiV biology or the immune response to NiV. The virus targets endothelial cells, with endothelial syncytia formation being the pathogenic hallmark of infection. Endothelial cell fusion requires expression of NiV-F and NiV-G envelope glycoproteins, and specific N-glycans on NiV-F regulate the extent of endothelial cell fusion.
We have found that galectin-1, an endogenous lectin expressed by activated endothelia, inhibits NiV mediated endothelial cell fusion and syncytia formation by a direct effect on NiV-F. Specifically, galectin-1 regulates endothelial cell fusion triggered by NiV-F by binding glycans on NiV-F and thus retaining immature NiV-F on the cell surface, restricting endocytosis necessary for NiV-F maturation, and inhibiting the mature NiV-F protein from fusing endothelial cell membranes. This suggests that endogenous galectin-1 may regulate the extent of endothelial cell damage in Nipah virus infection. These findings may be broadly applicable to other vascular diseases in which endothelial damage and syncytia formation occur.
Reduced antigen-specific CD8+ T cell responses as a result of increased bacterial translocation in chronic ethanol consuming mice (129.17)
Authors: Gurung Prajwal , Young Betty M , Turner Lucas E , Coleman Ruth A , Wiechert Susan , Waldschmidt Thomas J , Legge Kevin L , Cook Robert T 
Published: January 2023

Abstract
Chronic ethanol consumption leads to increased translocation of bacterial products such as LPS and PGN. Previously, we have shown that chronic ethanol consumption results in reduced antigen-specific CD8+ T cell responses following attenuated Listeria monocytogenes (actA-LM) inoculation. We hypothesized that reduced antigen-specific CD8+ T cell response in chronic ethanol mice can be modeled by treatment with bacterial products. Control water mice were pretreated with either LPS or TLR-2 agonist to mimic systemic bacterial product translocation and their response to actA-LM inoculation was evaluated. Antigen-specific CD8+ T cell responses to actA- LM were reduced in Pam3CSK4 or LPS treated mice, similar to ethanol mice. Further analyses showed that the reduction of antigen-specific CD8+ T cells in TLR agonist treated mice was due to an indirect effect on antigen presenting cells, as well as a direct effect on CD8+ T cells. None of the TLR agonist effects on CD8+ T cells was reversed by prior depletion of natural Treg cells, or by the depletion of all CD4+ T cells, nor was the reduction of IL2Rb reversed by several days in culture. Reduction of antigen-specific CD8+ T cells was also independent of IL-10. The data as a whole clearly indicate that TLR agonists resulting from bacterial translocation represent one potent mechanism for alteration of antigen-specific CD8+ T cell responses.