bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Double-Negative T Cells in Systemic Lupus Erythematosus Provide Help for IgG and Are Restricted by CD1c
Authors: Sieling Peter A. , Porcelli Steven A. , Duong Baochau T. , Spada Franca , Bloom Barry R. , Diamond Betty , Hahn Bevra H. 
Published: April 2014

AbstractTo understand the mechanism of T cell help for IgG production in systemic lupus erythematosus (SLE) we investigated the response of CD4- and CD8-negative (double-negative (DN)) T cells because 1) DN T cells are present at unusually high frequency in patients with SLE and can induce pathogenic autoantibodies; 2) the DN T cell repertoire includes cells restricted by CD1 Ag-presenting molecules; and 3) CD1c is expressed on a population of circulating B cells. We derived DN T cell lines from SLE patients and healthy individuals. In the presence of CD1+ APCs, DN T cell lines from SLE patients produced both IL-4 and IFN-γ, whereas DN T cells from healthy donors produced IFN-γ, but no IL-4. In general, cells from patients with highly active disease produced high levels of IFN-γ; cells from those with little activity produced high IL-4. Coculture of CD1c-directly reactive T cells from healthy donors with CD1c+ B cells elicited IgM Abs, but little or no IgG. In contrast, CD1c-directly reactive T cells from SLE patients induced isotype switching, with a striking increase in IgG production. Neutralizing Abs to CD1c inhibited the ability of DN T cells to induce IgG production from CD1c+ B cells, further indicating that CD1c mediated the T and B cell interaction. IgG production was also inhibited by neutralizing Abs to IL-4, correlating with the cytokine pattern of DN T cells derived from these patients. The data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c+ B cells for IgG production and could therefore promote pathogenic autoantibody responses in SLE.
Evidence For Early Aging in the Mucosal Immune System
Authors: Koga Toshiya , McGhee Jerry R. , Kato Hirotomo , Kato Rie , Kiyono Hiroshi , Fujihashi Kohtaro 
Published: April 2014

AbstractDespite recent advances in the cellular and molecular analysis of induction and regulation of mucosal immune responses, little is yet known about differences which occur in aging. To address this important issue, we have compared the mucosal and systemic immune responses of aged (12- to 14-mo- or 2-year-old) and young adult (6- to 8-wk-old) C57BL/6 mice. Both aged and young mice were immunized weekly with three oral doses of 1 mg of OVA and 10 μg of cholera toxin (CT) as mucosal adjuvant. Both groups of mice over 1 or 2 years of age showed reduced levels of Ag-specific mucosal or systemic immune responses at day 21. An Ag-specific B cell enzyme-linked immunospot assay confirmed these results at the cellular level. When the Ag-induced cytokine responses were examined at both protein and mRNA levels, CD4+ T cells from spleen and Peyer’s patches of young adult mice revealed elevated levels of IL-4 production; however, these cytokine responses were significantly diminished in aged mice. In contrast to mucosal immunization, mice s.c. immunized with OVA plus CT resulted in impaired OVA-specific but intact CT B subunit-specific immune responses in 12- to 14-mo-old mice although the responses to both Ags were depressed in 2-year-old mice. These results provide the first evidence that the development of age-associated alterations possibly occurs earlier in the mucosal immune system than in the systemic immune compartment.
Cutting Edge: Gln22 of Mouse MD-2 Is Essential for Species-Specific Lipopolysaccharide Mimetic Action of Taxol
Authors: Kawasaki Kiyoshi , Gomi Kazunori , Nishijima Masahiro 
Published: April 2014

AbstractMD-2 associates with the extracellular domain of Toll-like receptor 4 (TLR4) and greatly enhances LPS signaling via TLR4. Taxol, which mimics the action of LPS on murine macrophages, induces signals via mouse TLR4-MD-2, but not via human TLR4-MD-2. Here we investigated the molecular basis for this species-specific action of Taxol. Expression of mouse MD-2 conferred both LPS and Taxol responsiveness on human embryonic kidney 293 cells expressing mouse TLR4, whereas expression of human MD-2 conferred LPS responsiveness alone, suggesting that MD-2 is responsible for the species-specificity as to Taxol responsiveness. Furthermore, mouse MD-2 mutants, in which Gln22 was changed to other amino acids, showed dramatically reduced ability to confer Taxol responsiveness, although their ability to confer LPS responsiveness was not affected. These results indicated that Gln22 of mouse MD-2 is essential for Taxol signaling but not for LPS signaling.
Outside-to-Inside Signal Through the Membrane TNF-α Induces E-Selectin (CD62E) Expression on Activated Human CD4+ T Cells
Authors: Harashima Shin-ichi , Horiuchi Takahiko , Hatta Nobuaki , Morita Chika , Higuchi Masanori , Sawabe Takuya , Tsukamoto Hiroshi , Tahira Tomoko , Hayashi Kenshi , Fujita Shigeru , Niho Yoshiyuki 
Published: April 2014

AbstractThe membrane TNF-α is known to serve as a precursor of the soluble form of TNF-α. Although it has been reported the biological functions of the membrane TNF-α as a ligand, the outside-to-inside (reverse) signal transmitted through membrane TNF-α is poorly understood. Here we report a novel function mediated by outside-to-inside signal via membrane TNF-α into the cells expressing membrane TNF-α. Activation by anti-TNF-α Ab against membrane TNF-α on human T cell leukemia virus (HTLV) I-infected T cell line, MT-2, or PHA-activated normal human CD4+ T cells resulted in the induction of an adhesion molecule, E-selectin (CD62E), on the cells with the peak of 12–24 h, which completely disappeared by 48 h. When wild-type or mutant membrane TNF-α (R78T/S79T) resistant to proteolytic cleavage was introduced into Jurkat or HeLa cells, E-selectin was induced by the treatment with anti-TNF-α Ab with the similar kinetics. Membrane TNF-α-expressing Jurkat cells also up-regulated E-selectin when brought into cell-to-cell contact with TNF receptor-expressing HeLa cells. Northern blot analysis and RT-PCR analysis showed that the membrane TNF-α-mediated E-selectin expression was up-regulated at the level of transcription. These results not only confirmed our previous findings of reverse signaling through membrane TNF-α, but also presented evidence that E-selectin was inducible in cell types different from endothelial cells. It is strongly suggested that membrane TNF-α is a novel proinflammatory cell surface molecule that transmits bipolar signals in local inflammation.
IgA Immunodeficiency Leads to Inadequate Th Cell Priming and Increased Susceptibility to Influenza Virus Infection
Authors: Arulanandam Bernard P. , Raeder Roberta H. , Nedrud John G. , Bucher Doris J. , Le Jianhua , Metzger Dennis W. 
Published: April 2014

AbstractIgA is considered to be the principal Ab involved in defense against pathogens in the mucosal compartment. Using mice with a targeted disruption in IgA gene expression (IgA−/− mice), we have examined the precise role of IgA in protective anti-influenza responses after intranasal vaccination. IgA−/− mice immunized intranasally with soluble hemagglutinin (hemagglutinin subtype 1) and neuraminidase (neuraminidase subtype 1) vaccine in the absence of adjuvant were found to be more susceptible to influenza virus infection than IgA+/+ mice (13 vs 75% survival after virus challenge). Inclusion of IL-12 during immunization restored the protective efficacy of the vaccine to that seen in IgA+/+ animals. IgA−/− mice had no detectable IgA expression, but displayed enhanced serum and pulmonary IgM and IgG Ab levels after IL-12 treatment. Assessment of T cell function revealed markedly depressed splenic lymphoproliferative responses to PHA in IgA−/− animals compared with IgA+/+ mice. Furthermore, IgA−/− animals displayed impaired T cell priming to the H1N1 subunit vaccine, with concomitant reduction in recall memory responses due to a defect in APC function. Collectively, these results provide evidence that a major role of IgA is to facilitate presentation of Ag to mucosal T cells. IL-12 treatment can overcome IgA deficiency by providing adequate T cell priming during vaccination.
IFN-γ Production by Th1 Cells Generated from Naive CD4+ T Cells Exposed to Norepinephrine
Authors: Swanson Michelle A. , Lee William T. , Sanders Virginia M. 
Published: April 2014

AbstractDuring activation in vivo, naive CD4+ T cells are exposed to various endogenous ligands, such as cytokines and the neurotransmitter norepinephrine (NE). To determine whether NE affects naive T cell differentiation, we used naive CD4+ T cells sort-purified from either BALB/c or DO11.10 TCR-transgenic mouse spleens and activated these cells with either anti-CD3/anti-CD28 mAbs or APC and OVA323–329 peptide, respectively, under Th1-promoting conditions. RT-PCR and functional assays using selective adrenergic receptor (AR) subtype antagonists showed that naive CD4+ T cells expressed only the β2AR subtype to bind NE and that stimulation of this receptor generated Th1 cells that produced 2- to 4-fold more IFN-γ. This increase was due to more IFN-γ produced per cell upon restimulation instead of more IFN-γ-secreting cells, as determined by IFN-γ-specific immunofluorescence and enzyme-linked immunospot. In contrast, Th1 cell differentiation was unaffected when naive T cells were exposed to NE and activated either in the presence of a neutralizing anti-IL-12 mAb or by APC from IL-12-deficient mice. Moreover, the addition of IL-12 to the IL-12-deficient APC cultures restored the ability of NE to increase Th1 differentiation. Taken together, these results indicate that a possible link may exist between the signaling pathways used by NE and IL-12 to increase naive CD4+ T cell differentiation to a Th1 cell.
The Identification of a Novel T Cell Activation State Controlled by a Diabetogenic Gene
Authors: Moore Jodene K. , Scheinman Robert I. , Bellgrau Donald 
Published: April 2014

AbstractThe cyclin-dependent kinase inhibitor p27kip regulates the cell cycle at the G1-S phase restriction point. S phase entry and cell cycle commitment in peripheral T cells requires p27kip degradation, normally initiated by the receipt of costimulatory signals such as those provided by B7.1 or IL-2. We have previously reported that T cells from BioBreeding (BB)-diabetes-prone (DP) rats exhibit decreased costimulatory requirements for activation and cell cycle entry. In the present study, we find that peripheral T cell subsets from BB-DP rats demonstrate activation-like characteristics, including significantly reduced levels of p27kip as well as increased levels of proliferating cell nuclear Ag (PCNA). Since our previous studies have established that expression of extracellular activation markers are relatively low in unmanipulated peripheral BB-DP T cells; this p27low PCNAhigh phenotype represents a novel activation state. Analyses of T cell subsets from congenic rats demonstrate that this phenotype segregates with the lyp diabetogenic locus and that the p27low PCNAhigh phenotype is T cell specific. This p27low PCNAhigh phenotype is not seen in medullary thymocytes, but appears abruptly in the recent thymic emigrant population, suggesting that the lyp locus does not act directly on cell cycle regulators but rather alters the interaction between T cells and the peripheral environment. These results provide a biochemical basis for costimulation-independent activation and suggest a mechanism whereby a diabetes susceptibility gene contributes to disease development.
Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells
Authors: Visintin Alberto , Mazzoni Alessandra , Spitzer Jessica H. , Wyllie David H. , Dower Steven K. , Segal David M. 
Published: April 2014

AbstractA number of pathogens induce immature dendritic cells (iDC) to migrate to lymphoid organs where, as mature DC (mDC), they serve as efficient APC. We hypothesized that pathogen recognition by iDC is mediated by Toll-like receptors (TLRs), and asked which TLRs are expressed during the progression of monocytes to mDC. We first measured mRNA levels for TLRs 1–5 and MD2 (a protein required for TLR4 function) by Northern analysis. For most TLRs, message expression decreased severalfold as monocytes differentiated into iDC, but opposing this trend, TLR3 and MD2 showed marked increases during iDC formation. When iDC were induced to mature with LPS or TNF-α, expression of most TLRs transiently increased and then nearly disappeared. Stimulation of iDC, but not mDC, with LPS resulted in the activation of IL-1 receptor-associated kinase, an early component in the TLR signaling pathway, strongly suggesting that LPS signals through a TLR. Surface expression of TLRs 1 and 4, as measured by mAb binding, was very low, corresponding to a few thousand molecules per cell in monocytes, and a few hundred or less in iDC. We conclude that TLRs are expressed in iDC and are involved in responses to at least one pathogen-derived substance, LPS. If TLR4 is solely responsible for LPS signaling in humans, as it is in mice, then its extremely low surface expression implies that it is a very efficient signal transducer in iDC.
Absence of CD43 Fails to Alter T Cell Development and Responsiveness
Authors: Carlow Douglas A. , Corbel Stéphane Y. , Ziltener Hermann J. 
Published: April 2014

AbstractGenetic elimination of CD43 has been associated with increased T cell adhesiveness and T cell hyperresponsiveness to mitogens and alloantigens. Therefore, we investigated whether T cell development was perturbed in CD43-deficient mice by breeding CD43null mice with male Ag (Hy)-specific TCR-transgenic mice. Neither positive nor negative thymic selection of male Ag-specific T cells were affected by CD43 status. Furthermore, we did not observe a substantial or consistent hyperresponsive pattern in HY-CD43null lymph node cells compared with littermate HY-CD43+/− lymph node cells upon analysis of in vitro T cell stimulation with male Ag or mitogen. These observations challenged original conclusions associating absence of CD43 with T cell hyperresponsiveness and led us to re-examine this association. Reported phenotypes of CD43null mice have been based on mice with a mixed 129×C57BL/6 genetic background. To exclude a possible influence of genetic background differences among individual mice we analyzed CD43null littermates that had been back-bred onto the C57BL/6 background for seven to eight generations. We found that CD43+ and CD43null littermates with the C57BL/6 background exhibited no differences in response to mitogen or alloantigen, thereby establishing that T cell hyperresponsiveness is not a general correlate of CD43 absence.
CD40 Ligation Ablates the Tolerogenic Potential of Lymphoid Dendritic Cells
Authors: Grohmann Ursula , Fallarino Francesca , Silla Silvia , Bianchi Roberta , Belladonna Maria L. , Vacca Carmine , Micheletti Alessandra , Fioretti Maria C. , Puccetti Paolo 
Published: April 2014

AbstractThe outcome of dendritic cell (DC) presentation of P815AB, a tolerogenic tumor/self peptide, depends on a balance between the respective immunogenic and tolerogenic properties of myeloid (CD8α−) and lymphoid (CD8α+) DC. We have previously shown that CD8− DC can be primed by IL-12 to overcome inhibition by the CD8+ subset and initiate immunogenic presentation in vivo when the two types of peptide-pulsed DC are cotransferred into recipient hosts. IFN-γ enhances the inhibitory activity of CD8+ DC on Ag presentation by the other subset, blocking the ability of IL-12-treated CD8− DC to overcome suppression. We report here that CD40 ligation on lymphoid DC ablated their inhibitory function on Ag presentation as well as IFN-γ potentiation of the effect. CD40 modulation of IFN-γ action on lymphoid DC involved a reduction in IFN-γR expression and tryptophan-degrading ability. This effect was accompanied in vitro by an impaired capacity of the CD40-modulated and IFN-γ-treated DC to initiate T cell apoptosis. In vivo, not only did CD40 triggering on lymphoid DC abrogate their tolerogenic activity, but it also induced the potential for immunogenic presentation of P815AB. Importantly, a pattern similar to P815AB as well as CD40 modulation of lymphoid DC function were observed on testing reactivity to NRP, a synthetic peptide mimotope recognized by diabetogenic CD8+ T cells in nonobese diabetic mice.
Complementary Effects of TNF and Lymphotoxin on the Formation of Germinal Center and Follicular Dendritic Cells
Authors: Wang Yang , Wang Jing , Sun Yonglian , Wu Qiang , Fu Yang-Xin 
Published: April 2014

AbstractThe formation of germinal centers (GC) around follicular dendritic cells (FDC) is a critical step in the humoral immune responses that depends on the cooperative effects of B cells and T cells. Mice deficient in either TNF or lymphotoxin (LT) fail to form both GC and FDC network in B cell follicles. To test a potential complementary effect of TNF and LT, a mixture of bone marrow cells from TNF−/− mice and LTα−/− mice was transferred into irradiated LTα−/− mice or TNF−/− mice. Interestingly, the formation of both GC and FDC clusters in B cell follicles was restored in such chimeric mice, suggesting that TNF and LT from different cells could complement one another. To identify the exact contributions of each subset to the complementary effect of TNF and LT, different sources of T and B cells from LTα−/− mice or TNF−/− mice were used for reconstitution. Our study demonstrates that either T or B cell-derived TNF is sufficient to restore FDC/GC in the presence of LT-expressing B cells. However, TNF itself is not required for GC reactions if the FDC network is already intact. Thus, the development and maintenance of these lymphoid structures depend on a delicate interaction between TNF and LT from different subsets of lymphocytes.
A Subset of Human Dendritic Cells Expresses IgA Fc Receptor (CD89), Which Mediates Internalization and Activation Upon Cross-Linking by IgA Complexes
Authors: Geissmann Frédéric , Launay Pierre , Pasquier Benoit , Lepelletier Yves , Leborgne Michelle , Lehuen Agnès , Brousse Nicole , Monteiro Renato C. 
Published: April 2014

AbstractImmature dendritic cells (DC) sample Ags within nonlymphoid tissues and acquire exogenous proteins/pathogens via scavenger receptors or Ig FcR such as FcγR and FcεR. IgA is present in a significant proportion among serum Ig and is the main isotype in mucosae, where DC are numerous. We found that a functional FcαR (CD89) was expressed in situ and in vitro on interstitial-type DC but not on Langerhans cell-type DC. Interstitial-type DC expressed CD89 as a 50- to 75-kDa glycoprotein with a 32-kDa protein core, which was down-regulated upon addition of TGF-β1. DC, FcαR specifically, bound IgA1 and IgA2. Cross-linking of CD89 on DC triggered endocytosis in time-dependent manner. In addition, internalization of polymeric IgA complexes induced the production of IL-10 and DC activation, as reflected by up-regulation of CD86 costimulatory molecules, class II MHC expression, and increased allostimulatory activity. Therefore, interstitial-type DC may use FcαR-mediated Ag sampling in the subepithelium to check tissue integrity while Langerhans cells inside epithelial layers may neglect IgA immune complexes.
Group 1 CD1 Genes in Rabbit
Authors: Hayes Sandra M. , Knight Katherine L. 
Published: April 2014

AbstractCD1 is an Ag-presenting molecule that can present lipids and glycolipids to T cells. The CD1 genes were first identified in the human, and since then, homologs have been identified in every mammalian species examined to date. Over a decade ago, CD1B and CD1D homologs were identified in the rabbit. We have extended this earlier study by identifying additional CD1 genes with the goal of developing the rabbit as an animal model to study the function of CD1 proteins. We constructed a thymocyte cDNA library and screened the library with CD1-specific probes. Based on nucleotide sequence analyses of the CD1+ cDNA clones obtained from the library, we have identified two CD1A genes and one CD1E gene as well as determined the complete sequence of the previously identified CD1B gene. The CD1E+ cDNA clones lacked the transmembrane and cytoplasmic domains and, if translated, would encode for a soluble or secreted CD1E protein. In addition, expression studies demonstrated that the CD1 genes were expressed in peripheral lymphoid tissues as well as in skin, gut, and lung. Of interest is the finding that CD1A2, CD1B, and CD1E genes were found to be expressed by rabbit B cell populations. The rabbit, with a complex CD1 locus composed of at least two CD1A genes, one CD1B gene, one CD1D gene, and one CD1E gene, is an excellent candidate as an animal model to study CD1 proteins.
The Effects of Granulocyte Colony-Stimulating Factor and Neutrophil Recruitment on the Pulmonary Chemokine Response to Intratracheal Endotoxin
Authors: Zhang Ping , Bagby Gregory J. , Kolls Jay K. , Welsh David A. , Summer Warren R. , Andresen Jeff , Nelson Steve 
Published: April 2014

Abstract
Although G-CSF has been shown to increase neutrophil (polymorphonuclear leukocyte, PMN) recruitment into the lung during pulmonary infection, relatively little is known about the local chemokine profiles associated with this enhanced PMN delivery. We investigated the effects of G-CSF and PMN recruitment on the pulmonary chemokine response to intratracheal LPS. Rats pretreated twice daily for 2 days with an s.c. injection of G-CSF (50 μg/kg) were sacrificed at either 90 min or 4 h after intratracheal LPS (100 μg) challenge. Pulmonary recruitment of PMNs was not observed at 90 min post LPS challenge. Macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) concentrations in bronchoalveolar lavage (BAL) fluid were similar in animals pretreated with or without G-CSF at this time. G-CSF pretreatment enhanced pulmonary recruitment of PMNs (5-fold) and greatly reduced MIP-2 and CINC levels in BAL fluid at 4 h after LPS challenge. In vitro, the presence of MIP-2 and CINC after LPS stimulation of alveolar macrophages was decreased by coculturing with circulating PMNs but not G-CSF. G-CSF had no direct effect on LPS-induced MIP-2 and CINC mRNA expression by alveolar macrophages. Pulmonary recruited PMNs showed a significant increase in cell-associated MIP-2 and CINC. Cell-associated MIP-2 and CINC of circulating PMNs were markedly increased after exposure of these cells to the BAL fluid of LPS-challenged lungs. These data suggest that recruited PMNs are important cells in modulating the local chemokine response. G-CSF augments PMN recruitment and, thereby, lowers local chemokine levels, which may be one mechanism resulting in the subsidence of the host proinflammatory response.