bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cleavage of the Glycosylphosphatidylinositol Anchor Affects the Reactivity of Thy-1 with Antibodies
Authors: Kukulansky Tova , Abramovitch Shirley , Hollander Nurit 
Published: January 2023

Abstract
Thy-1 protein, a member of the Ig superfamily, is bound to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. We demonstrate that following anchor cleavage by phospholipase C, the reactivity of the solubilized Thy-1 with several mAbs is lost, and its reactivity with polyclonal anti-Thy-1 Abs is markedly decreased. Hence, solubilized Thy-1 cannot be detected by a range of mAbs. In contrast, enzymatic cleavage of biotinylated Thy-1 yields an intact solubilized protein that can be detected by streptavidin. These results exclude a possible proteolytic degradation of solubilized Thy-1 and suggest that the marked decrease in Thy-1 immunoreactivity following delipidation is due to conformational changes in the Thy-1 protein. We further demonstrate that addition of phospholipase C to preformed Ab-Ag complexes causes dissociation and removal of Thy-1 from the complex, indicating that delipidation of Thy-1 induces a conformational change in Thy-1 that is sufficient to dissociate bound Ab. The possibility should therefore be considered that the GPI anchor affects the conformation of a protein to which it is linked.
Two Stages of Increased IgA Transfer During Lactation in the Marsupial,Trichosurus vulpecula(Brushtail Possum)
Authors: Adamski Frances M. , Demmer Jerome 
Published: January 2023

AbstractThe polymeric Ig receptor (pIgR) and J chain molecules are involved in the transfer of IgA across the mammary gland epithelia into milk. The J chain binds two IgA molecules to form dimeric IgA, and the pIgR transports this complex through epithelial cells. We report here the cloning of the first marsupial homologues for the pIgR and J chain from the brushtail possum. Marsupial young are born after a short gestation and are less developed than eutherian newborn. The pouch young is completely dependent on milk as its sole source of nutrition during early lactation and this phase can be considered to be equivalent to an external gestation. Two periods of increased expression of pIgR, J chain, and IgA heavy chain mRNAs were observed in the mammary gland during lactation. The first occurs for a brief period after birth of the pouch young and is likely to reflect IgA transfer via the colostrum. The second period of increased expression, which is unique to marsupials, occurs after the early lactation period and just before young exit the pouch. We propose that this represents a second colostral-like phase at the end of the external gestation.
Immunomodulatory Role of C10 Chemokine in a Murine Model of Allergic Bronchopulmonary Aspergillosis
Authors: Hogaboam Cory M. , Gallinat Chad S. , Taub Dennis D. , Strieter Robert M. , Kunkel Steven L. , Lukacs Nicholas W. 
Published: January 2023

AbstractThe immunomodulatory role of the chemokine C10 was explored in allergic airway responses during experimental allergic bronchopulmonary aspergillosis (ABPA). The intratracheal delivery of Asperigillus fumigatus Ag into A. fumigatus-sensitized mice resulted in significantly increased levels of C10 within the bronchoalveolar lavage, and these levels peaked at 48 h after A. fumigatus challenge. In addition, C10 levels in BAL samples were greater than 5-fold higher than levels of other chemokines such as monocyte-chemoattractant protein-1, eotaxin, and macrophage-inflammatory protein-1α. From in vitro studies, it was evident that major pulmonary sources of C10 may have included alveolar macrophages, lung fibroblasts, and vascular smooth muscle cells. Experimental ABPA was associated with severe peribronchial eosinophilia, bronchial hyperresponsiveness, and augmented IL-13 and IgE levels. The immunoneutralization of C10 with polyclonal anti-C10 antiserum 2 h before the intratracheal A. fumigatus challenge significantly reduced the airway inflammation and hyperresponsiveness in this model of ABPA, but had no effect on IL-10 nor IgE levels. Taken together, these data suggest that C10 has a unique role in the progression of experimental ABPA.
Human Cytomegalovirus Inhibits IFN-α-Stimulated Antiviral and Immunoregulatory Responses by Blocking Multiple Levels of IFN-α Signal Transduction
Authors: Miller Daniel M. , Zhang Yingxue , Rahill Brian M. , Waldman W. James , Sedmak Daniel D. 
Published: January 2023

AbstractThe type I IFNs represent a primordial, tightly regulated defense system against acute viral infection. IFN-α confers resistance to viral infection by activating a conserved signal transduction pathway that up-regulates direct antiviral effectors and induces immunomodulatory activities. Given the critical role of IFN-α in anti-human cytomegalovirus (HCMV) immunity and the profound ability of HCMV to escape the host immune response, we hypothesized that HCMV blocks IFN-α-stimulated responses by disrupting multiple levels of the IFN-α signal transduction pathway. We demonstrate that HCMV inhibits IFN-α-stimulated MHC class I, IFN regulatory factor-1, MxA and 2′,5-oligoadenylate synthetase gene expression, transcription factor activation, and signaling in infected fibroblasts and endothelial cells by decreasing the expression of Janus kinase 1 and p48, two essential components of the IFN-α signal transduction pathway. This investigation is the first to report inhibition of type I IFN signaling by a herpesvirus. We propose that this novel immune escape mechanism is a major means by which HCMV is capable of escaping host immunity and establishing persistence.
IL-1 Is an Effective Adjuvant for Mucosal and Systemic Immune Responses When Coadministered with Protein Immunogens
Authors: Staats Herman F. , Ennis Francis A. 
Published: January 2023

Abstract
Mucosal immunization with soluble protein Ag alone may induce Ag-specific tolerance, whereas mucosal immunization with Ag in the presence of a mucosal adjuvant may induce Ag-specific systemic and mucosal humoral and cell-mediated immune responses. The most widely used and studied mucosal adjuvant is cholera toxin (CT). Although the mechanism of adjuvanticity of CT is not completely understood, it is known that CT induces mucosal epithelial cells to produce the proinflammatory cytokines IL-1, IL-6, and IL-8 and up-regulates macrophage production of IL-1 and the costimulatory molecule B7.2. Because IL-1 may duplicate many of the activities of CT, we evaluated IL-1α and IL-1β for their ability to serve as mucosal adjuvants when intranasally administered with soluble protein Ags. IL-1α and IL-1β were as effective as CT for the induction of Ag-specific serum IgG, vaginal IgG and IgA, systemic delayed-type hypersensitivity, and lymphocyte proliferative responses when intranasally administered with soluble protein Ag. Our results indicate that IL-1α and IL-1β may be useful as mucosal vaccine adjuvants. Such an adjuvant may be useful, and possibly required, for vaccine-mediated protection against pathogens that infect via the mucosal surfaces of the host such as HIV.
Selection of HIV-Specific Immunogenic Epitopes by Screening Random Peptide Libraries with HIV-1-Positive Sera
Authors: Scala Giuseppe , Chen Xueni , Liu Weimin , Telles Jean Noel , Cohen Oren J. , Vaccarezza Mauro , Igarashi Tatsu , Fauci Anthony S. 
Published: January 2023

AbstractEfforts to develop a protective HIV-1 vaccine have been hindered by difficulties in identifying epitopes capable of inducing broad neutralizing Ab responses. In fact, the high mutation rate occurring in HIV-1 envelope proteins and the complex structure of gp120 as an oligomer associated with gp41 result in a high degree of antigenic polymorphism. To overcome these obstacles, we screened random peptide libraries using sera from HIV-infected subjects to identify antigenic and immunogenic mimics of HIV-1 epitopes. After extensive counterscreening with HIV-negative sera, we isolated peptides specifically recognized by Abs from HIV-1-infected individuals. These peptides behaved as antigenic mimics of linear or conformational HIV-1 epitopes generated in vivo in infected subjects. Consistent with these findings, sera of simian HIV-infected monkeys also recognized the HIV-specific epitopes. The selected peptides were immunogenic in mice, where they elicited HIV-specific Abs that effectively neutralized HIV-1 isolates. These results demonstrate that pools of HIV-1 mimotopes can be selected from combinatorial peptide libraries by taking advantage of the HIV-specific Ab repertoire induced by the natural infection.
Th2-Induced Airway Mucus Production Is Dependent on IL-4Rα, But Not on Eosinophils
Authors: Cohn Lauren , Homer Robert J. , MacLeod Heather , Mohrs Markus , Brombacher Frank , Bottomly Kim 
Published: January 2023

Abstract
Mucus hyperproduction in asthma results from airway inflammation and contributes to clinical symptoms, airway obstruction, and mortality. In human asthmatics and in animal models, excess mucus production correlates with airway eosinophilia. We previously described a system in which TCR transgenic CD4 Th2 cells generated in vitro were transferred into recipient mice and activated in the respiratory tract with inhaled Ag. Th2 cells stimulated airway eosinophilia and a marked increase in mucus production, while mice that received Th1 cells exhibited airway inflammation without eosinophilia or mucus. Mucus could be induced by IL-4−/− Th2 cells at comparable levels to mucus induced by IL-4+/+ Th2 cells. In the current studies we dissect further the mechanisms of Th2-induced mucus production. When IL-4−/− Th2 cells are transferred into IL-4Rα−/− mice, mucus is not induced, and BAL eosinophilia is absent. These data suggest that in the absence of IL-4, IL-13 may be critical for Th2-induced mucus production and eosinophilia. To determine whether eosinophils are important in mucus production, IL-5−/− Th2 cells were transferred into IL-5−/− recipients. Eosinophilia was abolished, yet mucus staining in the epithelium persisted. These studies show definitively that IL-5, eosinophils, or mast cells are not essential, but signaling through IL-4Rα is critically important in Th2 cell stimulation of mucus production.
T Cell-Tropic HIV gp120 Mediates CD4 and CD8 Cell Chemotaxis through CXCR4 Independent of CD4: Implications for HIV Pathogenesis
Authors: Iyengar Sujatha , Schwartz David H. , Hildreth James E. K. 
Published: January 2023

Abstract
HIV entry is determined by one or more chemokine receptors. T cell-tropic viruses bind CXCR4, whereas macrophage-tropic viruses use CCR5 and other CCRs. Infection with CXCR4 and CCR5-tropic HIV requires initial binding to CD4, and chemotaxis induced by the CCR5-tropic envelope has been reported to be strictly dependent on CD4 binding. We demonstrate that, in contrast to CD4-dependent gp120 signaling via CCR5, envelope signaling through CXCR4 is CD4 independent, inducing chemotaxis of both CD4 and CD8 T cells. Signaling by virus or soluble envelope through CXCR4 may affect pathogenesis by attracting and activating target and effector cells.
Long Term Prevention of Allergic Lung Inflammation in a Mouse Model of Asthma by CpG Oligodeoxynucleotides
Authors: Sur Sanjiv , Wild James S. , Choudhury Barun K. , Sur Nilanjana , Alam Rafeul , Klinman Dennis M. 
Published: January 2023

AbstractAsthma is an inflammatory disease of the airways that is induced by Th2 cytokines and inhibited by Th1 cytokines. Despite a steady increase in the incidence, morbidity, and mortality from asthma, no current treatment can reduce or prevent asthma for a prolonged period. We examined the ability of unmethylated CpG oligodeoxynucleotides (ODN), which are potent inducers of Th1 cytokines, to prevent the inflammatory and physiological manifestations of asthma in mice sensitized to ragweed allergen. Administration of CpG ODN 48 h before allergen challenge increased the ratio of IFN-γ to IL-4 secreting cells, diminished allergen-induced eosinophil recruitment, and decreased the number of ragweed allergen-specific IgE-producing cells. These effects of CpG ODN were sustained for at least 6 wk after its administration. Furthermore, there was a vigorous Th1 memory response to the recall Ag, inhibition of peribronchial and perivascular lung inflammation, and inhibition of bronchial hyperresponsiveness 6 wk after administration of CpG ODN. Administration of CpG ODN in IFN-γ −/− mice failed to inhibit eosinophil recruitment, indicating a critical role of IFN-γ in mediating these effects. This is the first report of a treatment that inhibits allergic lung inflammation in presensitized animals for a prolonged period and thus has relevance to the development of an effective long term treatment for asthma.
Phosphatidylinositol 3-Kinase-Dependent and -Independent Cytolytic Effector Functions
Authors: Fuller Claudette L. , Ravichandran Kodimangalam S. , Braciale Vivian L. 
Published: January 2023

Abstract
Two distinct forms of short-term cytolysis have been described for CD8+ CTLs, the perforin/granzyme- and Fas ligand/Fas (CD95 ligand (CD95L)/CD95)-mediated pathways. However, the difference in signal transduction events leading to these cytolytic mechanisms remains unclear. We used wortmannin, an irreversible antagonist of phosphatidylinositol 3-kinase (PI3-K) activity, to investigate the role of PI3-K in influenza-specific CD8+ CTL cytolytic effector function. We found that the addition of wortmannin at concentrations as low as 1 nM significantly inhibited both the Ag/MHC-induced cytolysis of CD95− target cells and serine esterase release. In strong contrast, W did not inhibit the Ag/MHC-induced CD95L expression or the CD95L/CD95-mediated cytolysis of CD95+ targets. A combination of wortmannin and blocking mAb against CD95L inhibited the cytolysis of CD95+ targets, indicating that the wortmannin-independent cytolysis was due to CD95L/CD95 mediated cytolysis. These findings suggest a differential role for PI3-K in mediating cytolysis and, thus far, the earliest difference between perforin/granzyme- and CD95L/CD95-dependent cytolysis. Our data reinforce the idea of a TCR with modular signal transduction pathways that can be triggered or inhibited selectively, resulting in differential effector function.
Effective Stimulation for IL-12 p35 mRNA Accumulation and Bioactive IL-12 Production of Antigen-Presenting Cells Interacted with Th Cells
Authors: Yamane Hidehiro , Kato Takuma , Nariuchi Hideo 
Published: January 2023

Abstract
Bioactive IL-12 is composed of two subunits, p35 and p40. In the APC-Th cell interaction, p40 mRNA accumulation in APC was shown to be up-regulated by stimulation with CD40 ligand (CD40L) on Th cells. However, the CD40-CD40L interaction scarcely induced p35 mRNA accumulation in APC. In the present experiments, p35 mRNA accumulation was induced in splenic macrophages/dendritic cells by the interaction with paraformaldehyde-fixed Th1 cells in the presence of Ag, and the p35 mRNA accumulation was abrogated by the inclusion of anti-I-A in cultures to block TCR/MHC class II interaction. The accumulation was also induced by the stimulation with agonistic anti-I-A. These results indicate that the interaction of the MHC class II molecule with TCR evokes an activation signal for p35 mRNA accumulation in APC. Furthermore, the production of bioactive IL-12 in macrophages/dendritic cells stimulated with CD40L was enhanced by the inclusion of agonistic anti-I-A. The p35 mRNA accumulation and IL-12 production of macrophages/dendritic cells induced by stimulation with OVA-specific fixed Th1 clone expressing CD40L were also enhanced by adding OVA in cultures. These results indicate that the p35 mRNA accumulation induced by MHC class II stimulation plays a role in bioactive IL-12 production.
In Vivo Inhibition of NF-κB in T-Lineage Cells Leads to a Dramatic Decrease in Cell Proliferation and Cytokine Production and to Increased Cell Apoptosis in Response to Mitogenic Stimuli, But Not to Abnormal Thymopoiesis
Authors: Ferreira Valérie , Sidénius Nicolai , Tarantino Nadine , Hubert Pascale , Chatenoud Lucienne , Blasi Francesco , Körner Marie 
Published: January 2023

Abstract
To understand the role of NF-κB complexes in T cell development and activation, we have generated transgenic mice in which RelA and c-Rel complexes were selectively inhibited in the T-lineage cells by specific expression of a trans-dominant form of IκBα. Transgene expression did not affect the thymic development, but led to lowered numbers of splenic T cells and to a dramatic decrease in the ex vivo proliferative response of splenic T lymphocytes. Analysis of IL-2 and IL-2Rα expression demonstrated that the perturbation of the proliferation response was not attributable to an abnormal expression of these genes. In contrast, expression of IL-4, IL-10, and IFN-γ was strongly inhibited in the transgenic T cells. The proliferative deficiency of the transgenic T cells was associated with an increased apoptosis. These results point out the involvement of NF-κB/Rel family proteins in growth signaling pathways by either regulating proteins involved in the IL-2 signaling or by functionally interfering with the cell cycle progression.
Igα and Igβ Are Required for Efficient Trafficking to Late Endosomes and to Enhance Antigen Presentation
Authors: Siemasko Karyn , Eisfelder Bartholomew J. , Stebbins Christopher , Kabak Shara , Sant Andrea J. , Song Wenxia , Clark Marcus R. 
Published: January 2023

Abstract
The B cell Ag receptor (BCR) is a multimeric complex, containing Igα and Igβ, capable of internalizing and delivering specific Ags to specialized late endosomes, where they are processed into peptides for loading onto MHC class II molecules. By this mechanism, the presentation of receptor-selected epitopes to T cells is enhanced by several orders of magnitude. Previously, it has been reported that, under some circumstances, either Igα or Igβ can facilitate the presentation of Ags. However, we now demonstrate that if these Ags are at low concentrations and temporally restricted, both Igα and Igβ are required. When compared with the BCR, chimeric complexes containing either chain alone were internalized but failed to access the MHC class II-enriched compartment (MIIC) or induce the aggregation and fusion of its constituent vesicles. Furthermore, Igα/Igβ complexes in which the immunoreceptor tyrosine-based activation motif tyrosines of Igα were mutated were also incapable of accessing the MIIC or of facilitating the presentation of Ag. These data indicate that both Igα and Igβ contribute signaling, and possibly other functions, to the BCR that are necessary and sufficient to reconstitute the trafficking and Ag-processing enhancing capacities of the intact receptor complex.
Modulation of CD28 Expression: Distinct Regulatory Pathways During Activation and Replicative Senescence
Authors: Vallejo Abbe N. , Brandes Johann C. , Weyand Cornelia M. , Goronzy Jörg J. 
Published: January 2023

Abstract
The costimulatory molecule CD28 has a restricted tissue distribution and is expressed on T cells and some plasmacytoma cells. Although CD28 is constitutively expressed, its expression is transiently down-regulated following T cell activation and declines progressively with in vitro senescence. In vivo, CD8+ T cells and, less frequently, CD4+ T cells may completely lose CD28 surface expression during chronic infections and with aging. This correlates with changes of nuclear protein-binding activities to two motifs, site α and β, within the CD28 minimal promoter. Both α- and β-bound complexes are found only in lymphoid tissues, in CD28+ T cells, and in some transformed B cells. These complexes are coordinately expressed except during replicative senescence, which is characterized by the down-modulation of site β- but not site α-binding activities. In contrast, T cell activation induces a parallel decline in both site α- and β-binding activities. CD4+ and CD8+ T cells differ in their β-binding profiles, which may explain the more pronounced down-regulation of CD28 in senescent CD8+ T cells. In vivo expanded CD4+CD28null and CD8+CD28null T cells uniformly lack α- and β-bound complexes, resembling the pattern seen in chronically activated cells and not of senescent cells.
Combination Gene Therapy with CD86 and the MHC Class II Transactivator in the Control of Lung Tumor Growth
Authors: Martin Brian K. , Frelinger John G. , Ting Jenny P.-Y. 
Published: January 2023

Abstract
Early reports suggest that the costimulatory molecule CD86 (B7-2) has sporadic efficacy in tumor immunity, whereas changes in cancer immunity mediated by the MHC class II transactivator (CIITA) have not been extensively investigated. CIITA activates MHC class II expression in most cells; however, in the Line 1 lung carcinoma model system, CIITA activates MHC class I and well as class II. Here we show that CD86 is very effective in inducing a primary immune response against Line 1. Tumor cells expressing CD86 grew in only 50% of the mice injected with live cells, and those mice that developed tumors did so with significantly delayed kinetics. Furthermore, irradiated CD86-expressing Line 1 cells served as an effective tumor vaccine, demonstrating that CD86 is effective in inducing tumor immunity in the Line 1 system. These data suggest that if CIITA and CD86 cooperate, enhanced tumor immunity could be achieved. CIITA alone was mildly beneficial in slowing primary tumor growth but only when expressed at low levels. Clones expressing high levels of class II MHC grew as fast as or faster than parental tumor, and CIITA expression in a tumor vaccine assay lacked efficacy. When CIITA and CD86 were coexpressed, there was no cooperative immune protection from tumor growth. Cells that coexpress both genes also failed as a cancer vaccine, suggesting a negative role for CIITA in this lung carcinoma. These data suggest that human cancer vaccine trials utilizing CIITA gene therapy alone or in combination with CD86 should be approached with caution.
Mycobacterium tuberculosis CDC1551 Induces a More Vigorous Host Response In Vivo and In Vitro, But Is Not More Virulent Than Other Clinical Isolates
Authors: Manca Claudia , Tsenova Liana , Barry Clifton E. , Bergtold Amy , Freeman Sherry , Haslett Patrick A. J. , Musser James M. , Freedman Victoria H. , Kaplan Gilla 
Published: January 2023

Abstract
Mycobacterium tuberculosis CDC1551, a clinical isolate reported to be hypervirulent and to grow faster than other isolates, was compared with two other clinical isolates (HN60 and HN878) and two laboratory strains (H37Rv and Erdman). The initial (1–14 days) growth of CDC1551, HN60, HN878, and H37Rv was similar in the lungs of aerosol-infected mice, but growth of Erdman was slower. Thereafter, the growth rate of CDC1551 decreased relative to the other strains which continued to grow at comparable rates up to day 21. In the lungs of CDC1551-infected mice, small well-organized granulomas with high levels of TNF-α, IL-6, IL-10, IL-12, and IFN-γ mRNA were apparent sooner than in lungs of mice infected with the other strains. CDC1551-infected mice survived significantly longer. These findings were confirmed in vitro. The growth rates of H37Rv and CDC1551 in human monocytes were the same, but higher levels of TNF-α, IL-10, IL-6, and IL-12 were induced in monocytes after infection with CDC1551 or by exposure of monocytes to lipid fractions from CDC1551. CD14 expression on the surface of the monocytes was up-regulated to a greater extent by exposure to the lipids of CDC1551. Thus, CDC1551 is not more virulent than other M. tuberculosis isolates in terms of growth in vivo and in vitro, but it induces a more rapid and robust host response.