bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracytoplasmic delivery of listeriolysin O by a vaccinal strain of Bacillus anthracis induces CD8-mediated protection against Listeria monocytogenes.
Authors: Sirard J C , Fayolle C , de Chastellier C , Mock M , Leclerc C , Berche P 
Published: January 2023

Abstract
The facultative intracellular pathogen Listeria monocytogenes secretes a 58-kDa hemolysin, listeriolysin O (LLO), that allows bacteria to access the cytoplasm and to multiply inside infected cells. LLO is also a protective Ag required for the development of specific immunity. We studied the capacity of a new bacterial vector, derived from an attenuated strain of Bacillus anthracis, to deliver in vivo LLO and to induce protection against L. monocytogenes infection. The hly gene encoding LLO was fused to a B. anthracis regulatory region induced in vivo and was integrated into a resident plasmid of this bacterium. This recombinant strain secreted a functional LLO in vitro and inside phagosomes of bone marrow macrophages. This LLO production enabled the conversion of the extracellular replicating B. anthracis into an intracytoplasmic bacterium. LLO+ B. anthracis thus mimicked the intracellular behavior of L. monocytogenes in macrophages. Specific protection of mice against lethal doses of L. monocytogenes was induced by immunization with LLO+ B. anthracis. The immunity was mediated by CD8+ T lymphocytes and was associated with the activation of LLO-specific MHC class I-restricted CD8+ CTL, able to recognize the immunodominant H-2d-restricted epitope 91-99 of LLO. This study, therefore, suggests that intracytoplasmic delivery of LLO by B. anthracis is sufficient to induce a MHC class I-restricted CD8-mediated protection against L. monocytogenes. The LLO+ B. anthracis recombinant strain represents a potential vector for delivering foreign Ags involved in CD8-mediated protective responses.
Comparison of tethering and rolling of eosinophils and neutrophils through selectins and P-selectin glycoprotein ligand-1.
Authors: Patel K D , McEver R P 
Published: January 2023

Abstract
We compared the abilities of selectins and the selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), to support tethering and rolling of eosinophils and neutrophils under physiologic flow conditions. Eosinophils and neutrophils accumulated on P-selectin at similar site densities and rolled at similar velocities, but fewer eosinophils than neutrophils accumulated at any P-selectin density. Compared with neutrophils, few eosinophils accumulated on E-selectin except at high densities, and those cells that did accumulate rolled faster than neutrophils. Examination of the mechanisms for accumulation revealed that eosinophils and neutrophils formed similar numbers of primary tethers to P-selectin, whereas eosinophils formed fewer primary tethers to E-selectin than did neutrophils. Compared with neutrophils, adherent eosinophils also supported fewer leukocyte-leukocyte interactions, resulting in diminished secondary tethers to either P- or E-selectin. Studies with mAbs to L-selectin and PSGL-1 demonstrated that neither cell type used L-selectin to form primary tethers to P- or E-selectin. Both eosinophils and neutrophils used the NH2 terminus of PSGL-1 to form primary tethers to P-selectin, but not to E-selectin. Both cell types used L-selectin and PSGL-1 to promote leukocyte-leukocyte interactions and secondary tethers to P- or E-selectin. However, eosinophils developed significantly fewer secondary interactions, probably because they express less L-selectin than do neutrophils.
Common and Distinct Signaling Pathways Mediate the Induction of TNF-α and IL-5 in IgE Plus Antigen-Stimulated Mast Cells
Authors: Csonga R. , Prieschl E. E. , Jaksche D. , Novotny V. , Baumruker T. 
Published: January 2023

AbstractA small number of signaling cascades represented by mitogen-activated protein kinases, phosphoinositol-3-kinase, protein kinase C, signal transducers and activators of transcription, Ca2+/calcineurin, and a few other molecules are linked to an incomparably large number of surface receptors. Parallel activation of several of these pathways and the existence of isozymes for a number of signal transmitting molecules generate the required complexity and specificity matching the receptor variety. Here we show that the proinflammatory mediator TNF-α and the growth factor IL-5 are activated along common and distinct signaling cascades in allergically stimulated murine mast cells. Both of them are dependent on Ca2+ influx, activation of calcineurin and nuclear factor of activated T cells as well as a member of the atypical PKC family, most likely PKCμ. Additionally, mitogen-activated protein kinases for TNF-α and members of the classical or nonclassical PKCs for IL-5, respectively, were identified as additional required pathways. Inhibition of the classical and nonclassical PKCs, however, does not abrogate IL-5 induction but instead leads to a switch to mitogen-activated protein kinases, which then become essential. The activated branches of this “salvage” signaling cascade are represented by extracellular signal-regulated kinase 1/2 and c-jun NH2 terminal kinase 1 in allergically stimulated mast cells.
Differences Between Responses of Naive and Activated T Cells to Anergy Induction
Authors: Hayashi Robert J. , Loh Dennis Y. , Kanagawa Osami , Wang Fanping 
Published: January 2023

Abstract
T cell unresponsiveness to Ag stimulation can be induced by several means. The precise mechanism by which this process occurs remains poorly understood. Preincubating T cells with either EDCI-fixed APC or ionomycin is a proven means of inducing T cell anergy with reduced IL-2 production in response to Ag stimulation. Using T cells from mice expressing the TCR transgene DO11.10, which is specific for a peptide (323–339) derived from hen egg OVA, we demonstrate that naive cells obtained directly from the host are resistant to the anergy induction by either fixed APC or ionomycin. TCR transgenic mice also deficient in the recombination-activating gene-2 (RAG-2−/−), preventing the formation of T cells with endogenous TCRs, were immunized with OVA, and in vivo activated T cells with low expression of CD62 were isolated. These primed cells possess the same sensitivity to ionomycin-induced anergy as in vitro activated cell lines. This unresponsive state most profoundly affects Ag-induced IL-2 production, with IFN-γ and IL-3 affected to a lesser degree and no effect observed on IL-4 production. Thus, T cells in vivo can be distinguished phenotypically by their susceptibility to anergic stimuli. Anergy so induced affects selected T cell functions.
Successful Adoptive Cellular Immunotherapy Is Dependent on Induction of a Host Immune Response Triggered by Cytokine (IFN-γ and Granulocyte/Macrophage Colony-Stimulating Factor) Producing Donor Tumor-Infiltrating Lymphocytes
Authors: Nagoshi Makoto , Goedegebuure Peter S. , Burger Ulrike L. , Sadanaga Noriaki , Chang Maximilian P. , Eberlein Timothy J. 
Published: January 2023

Abstract
Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and systemic low dose rIL-2 effectively eradicates pulmonary metastases of the murine MCA-105 sarcoma. We described earlier that host CD8+ T cells are critical for tumor eradication and that successful treatment is associated with production of high levels of IFN-γ and granulocyte/macrophage (GM)-CSF by donor TIL in vitro. Here, we propose the mechanism through which adoptively transferred Thy-1.1+ TIL induce a host antitumor response in congenic Thy-1.2+ tumor-bearing mice. Donor Thy-1.1+ TIL were detected at the tumor site 12 h after transfer. These Thy-1.1+ cells produced IFN-γ and GM-CSF in situ. The percentage of Thy-1.1+ TIL at the tumor site increased up to 16.4 ± 4.9% 24 h after transfer but decreased to undetectable levels thereafter. In contrast, the percentages of host cells producing IFN-γ and GM-CSF continued to increase at the tumor site. These increases were significantly higher in TIL + rIL-2-treated mice compared with untreated mice and rIL-2-treated mice 48 h after TIL transfer. The appearance of IFN-γ+ and GM-CSF+ cells was followed by a large influx of host CD4+, CD8+, and Thy-1.2+ TIL and eventually by tumor eradication. This response was tumor specific since TIL obtained from MCA-205 did not induce high levels of IFN-γ and GM-CSF and did not induce tumor eradication of MCA-105 tumor. Coinjection of Thy-1.1+ TIL and anti-IFN-γ or anti-GM-CSF mAb significantly inhibited antitumor efficacy of the TIL + rIL-2 treatment. We conclude that successful adoptive immunotherapy in this model is mediated through cytokine production by adoptively transferred TIL that induce a host T cell-dependent antitumor response.
Distinct Classes of Chaperoned IL-6 in Human Blood: Differential Immunological and Biological Availability
Authors: Ndubuisi MacKevin I. , Patel Kirit , Rayanade Ravi J. , Mittelman Abraham , May Lester T. , Sehgal Pravin B. 
Published: January 2023

AbstractTransport of IL-6 in blood is fundamental to the biology of this cytokine. In the present study, IL-6 transport, immunological reactivity, and biological availability were investigated in blood from melanoma patients subjected to different active specific immunization regimens (an anti-idiotypic mAb immunization protocol (mAb-keyhole limpet hemocyanin (KLH)-Calmette-Guérin bacillus (BCG), an autologous anti-cancer vaccine protocol (AAAP), or both). Sera were subjected to Sephadex G-200 gel filtration chromatography, and the structure and biological activity of IL-6 complexes in the eluate fractions were probed using five IL-6 ELISAs and two bioassays. Sera from patients administered mAb-KLH+BCG followed by AAAP contained three distinct classes of IL-6 eluting at 30, 200, and 450 kDa, each with its characteristic ELISA reactivity and bioactivity: the 30- and 450-kDa complexes were bioactive in the B9 and Hep3B assays, but the 200-kDa complex was not. The 30- and 450-kDa IL-6 complexes were preferentially reactive in the 7IL6/5IL6 ELISA, the 200-kDa IL-6 complexes were preferentially reactive in the 4IL6/5IL6 ELISA, while the three commercial ELISAs (R&D, Endogen, and Genzyme) detected essentially only the 30-kDa IL-6. In contrast, 1) sera from AAAP patients contained biologically active 30- and 450-kDa IL-6 complexes, while 2) sera from mAb-KLH+BCG patients contained 200-kDa IL-6 complexes inactive in ex vivo bioassays. Both the 450- and 200-kDa complexes included soluble IL-6R, with the 200-kDa complexes additionally containing ligand-occupied anti-IL-6 and anti-soluble IL-6R IgG. The data indicate the existence of specific mechanisms that regulate the transport and function of IL-6 in vivo.
Models for Antigen Receptor Gene Rearrangement. I. Biased Receptor Editing in B Cells: Implications for Allelic Exclusion
Authors: Mehr Ramit , Shannon Michele , Litwin Samuel 
Published: January 2023

Abstract
Recent evidence suggests that lymphocyte Ag receptor gene rearrangement does not always stop after the expression of the first productively rearranged receptor. Light chain gene rearrangement in B cells, and α-chain rearrangement in T cells can continue, which raises the question: how is allelic exclusion maintained, if at all, in the face of continued rearrangement? In this and the accompanying paper, we present comprehensive models of Ag receptor gene rearrangement and the interaction of this process with clonal selection. Our B cell model enables us to reconcile observations on the κ:λ ratio and on κ allele usage, showing that B cell receptor gene rearrangement must be a highly ordered, rather than a random, process. We show that order is exhibited on three levels: a preference for rearranging κ rather than λ light chain genes; a preference to make secondary rearrangements on the allele that has already been rearranged, rather than choosing the location of the next rearrangement at random; and a sequentiality of J segment choice within each κ allele. This order, combined with the stringency of negative selection, is shown to lead to effective allelic exclusion.
Expression and Function of TNF-Related Apoptosis-Inducing Ligand on Murine Activated NK Cells
Authors: Kayagaki Nobuhiko , Yamaguchi Noriko , Nakayama Masafumi , Takeda Kazuyoshi , Akiba Hisaya , Tsutsui Hiroko , Okamura Haruki , Nakanishi Kenji , Okumura Ko , Yagita Hideo 
Published: January 2023

Abstract
TNF-related apoptosis-inducing ligand (TRAIL), a new member of TNF family, induces apoptotic cell death of various tumor cells. We recently showed that TRAIL mediates perforin- and Fas ligand (FasL)-independent cytotoxic activity of human CD4+ T cell clones. In the present study, we investigated the expression and function of TRAIL on murine lymphocytes by using newly generated anti-murine TRAIL mAbs. Although freshly isolated T, B, or NK cells did not express a detectable level of TRAIL on their surface, a remarkable level of TRAIL expression was induced preferentially on CD3− NK1.1+ NK cells after stimulation with IL-2 or IL-15. In contrast, TRAIL expression was not induced by IL-18, whereas it efficiently potentiated lymphokine-activated killer activity of NK cells. In addition to perforin inactivation and neutralization of FasL by anti-FasL mAb, neutralization of TRAIL by anti-TRAIL mAb was needed for the complete inhibition of IL-2- or IL-15-activated NK cell cytotoxicity against mouse fibrosarcoma L929 target cells, which were susceptible to both FasL and TRAIL. These results indicated preferential expression of TRAIL on IL-2- or IL-15-activated NK cells and its potential involvement in lymphokine-activated killer activity.
α(1,3)-Fucosyltransferase VII and α(2,3)-Sialyltransferase IV Are Up-Regulated in Activated CD4 T Cells and Maintained After Their Differentiation into Th1 and Migration into Inflammatory Sites
Authors: Blander J. Magarian , Visintin Irene , Janeway Charles A. , Medzhitov Ruslan 
Published: January 2023

Abstract
Activated Th1 CD4 T cells bind to P-selectin and migrate into inflamed tissue, whereas Th2 cells do not. We show that α(1,3)-fucosyltransferase VII (FucT-VII) and α(2,3)-sialyltransferase IV (ST3GalIV), which are crucial for the biosynthesis of functional P-selectin ligands, are absent in naive CD4 T cells, but are rapidly up-regulated upon activation. Th1 or Th2 differentiation in the presence of polarizing cytokines leads to down-regulation of FucT-VII mRNA selectively in Th2 but not in Th1 cells. Influencing the differentiation by varying the priming dose of antigenic peptide results in similar FucT-VII down-regulation only in Ag-specific Th2 cells. ST3GalIV levels remain elevated. FucT-VII and ST3GalIV mRNAs are also up-regulated by Th1 cells primed in vivo and recruited into the lymph nodes draining delayed-type hypersensitivity sites. We identify FucT-VII gene expression as a principal difference between Th1 and Th2 cells, and underscore the importance of FucT-VII and ST3GalIV expression for the biosynthesis of functional selectin ligands.
Cross-Reactivity of Myelin Basic Protein-Specific T Cells with Multiple Microbial Peptides: Experimental Autoimmune Encephalomyelitis Induction in TCR Transgenic Mice
Authors: Grogan Jane L. , Kramer Achim , Nogai Axel , Dong Liying , Ohde Manuela , Schneider-Mergener Jens , Kamradt Thomas 
Published: January 2023

Abstract
Activation of autoreactive T cells is a crucial event in the pathogenesis of autoimmune diseases. Cross-reactivity between microbial and self Ags (molecular mimicry) is one hypothesis that could explain the activation of autoreactive T cells. We have systematically examined this hypothesis in experimental autoimmune encephalomyelitis using mice bearing exclusively myelin basic protein (MBP)-specific T cells (designated T+ α−). A peptide substitution analysis was performed in which each residue of the MBPAc1–11 peptide was exchanged by all 20 naturally occurring amino acids. This allowed the definition of the motif (supertope) that is recognized by the MBPAc1–11-specific T cells. The supertope was used to screen protein databases (SwissProt and TREMBL). By the search, 832 peptides of microbial origin were identified and synthesized. Of these, 61 peptides induced proliferation of the MBPAc1–11-specific transgenic T cells in vitro. Thus, the definition of a supertope by global amino acid substitution can identify multiple microbial mimic peptides that activate an encephalitogenic TCR. Peptides with only two native MBP-residues were sufficient to activate MBPAc1–11-specific T cells in vitro, and experimental autoimmune encephalomyelitis could be induced by immunizing mice with a mimic peptide with only four native MBP residues.
The Signal Transduction Pathway of CD23 (FcεRIIb) Targets IκB Kinase
Authors: Ten Rosa M. , McKinstry Melissa J. , Trushin Sergey A. , Asin Susana , Paya Carlos V. 
Published: January 2023

Abstract
Alveolar macrophages play a crucial role in initiating the inflammatory response in allergic asthma through the cross-linking of the low affinity IgE receptors (FcεRIIb or CD23) by IgE-allergen immunocomplexes. We have previously shown that CD23 cross-linking in monocytes and U937 cells targets IκBα, leading to the activation of the transcription factor NF-κB. We demonstrate in this paper that CD23-initiated signaling in U937 cells leads to hyperphosphorylation of IκBα at Ser32/Ser36 residues. Overexpression of a dominant-negative IκBα transgene containing mutations at Ser32/Ser36 completely inhibits degradation of IκBα, NF-κB activation, and gene transcription that follows CD23 cross-linking. Investigation of the second messengers mediating the CD23-dependent activation of NFκB demonstrates that IκB kinases (IKKs) but not p90rsk are selectively activated following CD23 cross-linking and mediates the phosphorylation of IκBα. Cotransfection experiments with an IKKβ negative dominant completely inhibit CD23 induced NFκB activation. Furthermore, the activation of tyrosine kinase(s) by CD23 is required for the induction of IKK activity, IκBα degradation, and NF-κB nuclear translocation. Taken together, our results show that CD23 cross-linking in the monocytic lineage induces tyrosine kinase activation followed by activation of IKK, which phosphorylates IκBα at the N-terminal domain (Ser32/Ser36), inducing its degradation, NF-κB activation and gene transcription.
β2-Microglobulin-Deficient Background Ameliorates Lethal Phenotype of the TGF-β1 Null Mouse
Authors: Kobayashi Shigetoshi , Yoshida Kunihiro , Ward Jerrold M. , Letterio John J. , Longenecker Glenn , Yaswen Linda , Mittleman Barbara , Mozes Edna , Roberts Anita B. , Karlsson Stefan , Kulkarni Ashok B. 
Published: January 2023

AbstractTGF-β1 null (TGF-β1−/−) mice die at 3–4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-β1−/− mice, we generated TGF-β1−/− mice in the genetic background of β2-microglobulin deficiency (β2M−/−). TGF-β1−/−;β2M−/− mice had improved survival compared with TGF-β1−/− mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-β1−/− mice. In vivo depletion of CD8+ T cells in TGF-β1−/− mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-β1−/−;β2M−/− mice was also lower than that in TGF-β1−/− mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-β1−/−;β2M−/− mice, when compared with that in TGF-β1−/− mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-β1−/− mice and CD8+ T cells may have a contribution to the inflammation in TGF-β1−/− mice.
An HLA-A2 Polyepitope Vaccine for Melanoma Immunotherapy
Authors: Mateo Luis , Gardner Joy , Chen Qiyuan , Schmidt Christopher , Down Michelle , Elliott Suzanne L. , Pye Stephanie J. , Firat Hüseyin , Lemonnier Francois A. , Cebon Jonathon , Suhrbier Andreas 
Published: January 2023

AbstractEpitope-based vaccination strategies designed to induce tumor-specific CD8 CTL are being widely considered for cancer immunotherapy. Here we describe a recombinant poxvirus vaccine that codes for ten HLA-A2-restricted epitopes derived from five melanoma Ags conjoined in an artificial polyepitope or polytope construct. Target cells infected with the melanoma polytope vaccinia were recognized by three different epitope-specific CTL lines derived from HLA-A2 melanoma patients, and CTL responses to seven of the epitopes were generated in at least one of six HLA-A2-transgenic mice immunized with the construct. CTL lines derived from vaccinated transgenic mice were also able to kill melanoma cells in vitro. Multiple epitopes within the polytope construct were therefore shown to be individually immunogenic, illustrating the feasibility of the polytope approach for melanoma immunotherapy. Tumor escape from CTL surveillance, through down regulation of individual tumor Ags and MHC alleles, might be overcome by polytope vaccines, which simultaneously target multiple cancer Ags.
MDP (Muramyl Dipeptide) Limits Anatomical Damage and Neurological Dysfunction in Rat with Contusive Spinal Cord Injury (SCI) (101.16)
Authors: Garg Maneesh S , Patel Monal , Puzis Raisa , Alexander Marcillo E , Pereira Francisco C , Bunge Mary B , Pearse Damien D 
Published: January 2023

Abstract
MDP is the minimum structural unit responsible for the immunoadjuvancy of bacterial cell wall peptidoglycans. Many properties of MDP manifest potential therapeutic efficacy for SCI. These include
stimulation of phagocytosis of immunocompetent cells, thereby facilitating myelin removal with minimal beneficial proinflammatory cytokine alterations,reduced glutamate release,increased intra- and extra-cellular Mg2+, thereby blocking NMDA receptors, andsuppressor cytokine expression, such as IL-10.
The current experiment delivered MDP by injection, 6 hours post T8 moderate contusive spinal cord injury in adult Fischer rats. At 2 wk after injury, histological examination revealed reductions in lesion volume associated with deposits of chondroitin sulfate proteoglycan and more myelinated axons. The activated (ED1+) macrophage/microglia count was higher in the more limited injury site of MDP animals. Concurrently, most were Mac1+, indicating active phagocytosis. Furthermore, MDP treated animals displayed fewer ED1+ cells rostral and caudal to the lesion compared with controls. Behaviorally, MDP animals displayed frequent co-ordination with weight-supported steps (BBB, 13.7 ± 1.6) compared with the occasional stepping in controls (BBB, 10 ± 0.6; n=6, p&lt;0.05). Thus, MDP appears to be a novel therapeutic agent to treat acute SCI.
Supported by CRF, Hollfelder Foundation, and Miami Project