bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Severity of Experimental Allergic Encephalomyelitis in lyn−/− Mice in the Absence of Elevated Proinflammatory Cytokine Response in the Central Nervous System
Authors: Du Caigan , Sriram Subramaniam 
Published: April 2014

Abstract
lyn, a member of the src kinase family, is an important signaling molecule in B cells. lyn−/− mice display hyperactive B-1 cells and IgM hyperglobulinemia. The role of lyn on T cell function and development of Th1-mediated inflammatory disease is not known. Therefore, we examined the effect of disruption of the lyn gene on the development of experimental allergic encephalomyelitis (EAE), a well-established Th1-mediated autoimmune disease. Following immunization with myelin oligodendrocyte protein (MOG) p35-55, lyn−/− mice had higher clinical and pathological severity scores of EAE when compared with wild type (WT). The increase in the severity of EAE in lyn−/− mice was not associated with a commensurate increase in the production of proinflammatory cytokines in the CNS. lyn−/− mice with EAE showed elevation in serum anti-IgM MOG Ab levels over that seen in WT mice, along with a modest increase in the mRNA levels of complement C5 and its receptor, C5aR, in the spinal cord. Transfer of serum from MOG-immunized lyn−/− mice worsened EAE in WT mice, suggesting a pathogenic role for anti-MOG IgM Abs in EAE. These observations underscore the potential role of lyn in regulation of Th1-mediated disease and the role of autoantibodies and complement in the development of EAE.
Cutting Edge: Polarized Th Cell Response Induction by Transferred Antigen-Pulsed Dendritic Cells Is Dependent on IL-4 or IL-12 Production by Recipient Cells
Authors: MacDonald Andrew S. , Pearce Edward J. 
Published: April 2014

AbstractTo assess the influence of dendritic cell (DC) production of polarizing cytokines on Th2 and Th1 development we transferred Ag-pulsed DC generated from wild-type, IL-4−/−, or IL-12−/− mice into wild-type, IL-4−/−, or IL-12−/− recipients. We found that DC IL-4 was not necessary for Th2 induction and that, surprisingly, DC IL-12 was not an absolute requirement for Th1 development. However, DC IL-12 production facilitated optimal Th1 response development. Critically, recipient ability to produce IL-4 or IL-12 was essential for either Th2 or Th1 development. These data help delineate the source and importance of IL-4 and IL-12 in the process of induction of polarized T cell responses by DC.
Cutting Edge: Analysis of Human Vα24+CD8+ NK T Cells Activated by α-Galactosylceramide-Pulsed Monocyte-Derived Dendritic Cells
Authors: Takahashi Tsuyoshi , Chiba Shigeru , Nieda Mie , Azuma Takeshi , Ishihara Soichiro , Shibata Yoichi , Juji Takeo , Hirai Hisamaru 
Published: April 2014

AbstractHuman Vα24+ NKT cells constitute a counterpart of mouse Vα14+ NKT cells, both of which use an invariant TCR-α chain. The human Vα24+ NKT cells as well as mouse Vα14+ NKT cells are activated by glycolipids in a CD1d-restricted manner and produce many immunomodulatory cytokines, possibly affecting the immune balance. In mice, it has been considered from extensive investigations that Vα14+CD8+ NKT cells that express invariant TCR do not exist. Here we introduce human Vα24+CD8+ NKT cells. These cells share important features of Vα24+ NKT cells in common, but in contrast to CD4−CD8− (double-negative) or CD4+ Vα24+ NKT cells, they do not produce IL-4. Our discovery may extend and deepen the research field of Vα24+ NKT cells as well as help to understand the mechanism of the immune balance-related diseases.
Cutting Edge: Single-Chain Trimers of MHC Class I Molecules Form Stable Structures That Potently Stimulate Antigen-Specific T Cells and B Cells
Authors: Yu Yik Y. L. , Netuschil Nikolai , Lybarger Lonnie , Connolly Janet M. , Hansen Ted H. 
Published: April 2014

AbstractWe report in this work the expression and characterization of class I molecules expressed as single-chain trimers consisting of an antigenic peptide-spacer-β2-microglobulin-spacer H chain. Our results indicate that these single-chain constructs assemble efficiently, maintain their covalent structure, and are unusually stable at the cell surface. Consequently, these constructs are at least 1000-fold less accessible to exogenous peptide than class I molecules loaded with endogenous peptides, and they are potent simulators of peptide-specific CTL and Abs. Our combined findings suggest that single-chain trimers may have applications as DNA vaccines against virus infection or tumors.
Germinal Center B Cells Constitute a Predominant Physiological Source of IL-4: Implication for Th2 Development In Vivo
Authors: Johansson-Lindbom Bengt , Borrebaeck Carl A. K. 
Published: April 2014

Abstract
Protective immunity depends upon the capability of the immune system to properly adapt the response to the nature of an infectious agent. CD4+ Th cells are implicated in this orchestration by secreting a polarized pattern of cytokines. Although Th2 development in animal models and in human cells in vitro to a large extent depends on IL-4, the nature of the cells that provide the initial IL-4 in vivo is still elusive. In this report, we describe the anatomical localization as well as the identity of IL-4-producing cells in human tonsil, a representative secondary lymphoid organ. We demonstrate that IL-4 production is a normal and intrinsic feature of germinal center (GC) B cells. We also show that expression of IL-4 is highly confined to the GCs, in which the B cells constitute the prevalent cellular source. Furthermore, immunofluorescence analysis of colon mucosa reveals a strikingly similar pattern of IL-4-expressing cells compared with tonsils, demonstrating that IL-4 production from GC B cells is not a unique feature of the upper respiratory tract. Our results show that GCs provide the most appropriate microenvironment for IL-4-dependent Th2 polarization in vivo and imply a critical role for GC B cells in this differentiation process.
Transgenic Expression of Numb Inhibits Notch Signaling in Immature Thymocytes But Does Not Alter T Cell Fate Specification
Authors: French Michelle B. , Koch Ute , Shaye Rachel E. , McGill Melanie A. , Dho Sascha E. , Guidos Cynthia J. , McGlade C. Jane 
Published: April 2014

Abstract
The conserved adaptor protein Numb is an intrinsic cell fate determinant that functions by antagonizing Notch-mediated signal transduction. The Notch family of membrane receptors controls cell survival and cell fate determination in a variety of organ systems and species. Recent studies have identified a role for mammalian Notch-1 signals at multiple stages of T lymphocyte development. We have examined the role of mammalian Numb (mNumb) as a Notch regulator and cell fate determinant during T cell development. Transgenic overexpression of mNumb under the control of the Lck proximal promoter reduced expression of several Notch-1 target genes, indicating that mNumb antagonizes Notch-1 signaling in vivo. However, thymocyte development, cell cycle, and survival were unperturbed by mNumb overexpression, even though transgenic Numb was expressed at an early stage in thymocyte development (CD4−CD8−CD3− cells that were CD44+CD25+ or CD44−CD25+; double-negative 2/3). Moreover, bone marrow from mNumb transgenic mice showed no defects in thymopoiesis in competitive repopulation experiments. Our results suggest that mNumb functions as a Notch-1 antagonist in immature thymocytes, but that suppression of Notch-1 signaling at this stage does not alter γδ/αβ or CD4/CD8 T cell fate specification.
Donor T Cell Activation Initiates Small Bowel Allograft Rejection Through an IFN-γ-Inducible Protein-10-Dependent Mechanism
Authors: Zhang Zheng , Kaptanoglu Levent , Haddad Wael , Ivancic David , Alnadjim Ziad , Hurst Stephen , Tishler Darren , Luster Andrew D. , Barrett Terrence A. , Fryer Jonathan 
Published: April 2014

AbstractThe poor success in controlling small bowel (SB) allograft rejection is partially attributed to the unique immune environment in the donor intestine. We hypothesized that Ag-induced activation of donor-derived T cells contributes to the initiation of SB allograft rejection. To address the role of donor T cell activation in SB transplantation, SB grafts from DO11.10 TCR transgenic mice (BALB/c, H-2Ld+) were transplanted into BALB/c (isografts), or single class I MHC-mismatched (Ld-deficient) BALB/c H-2dm2 (dm2, H-2Ld−) mutant mice (allografts). Graft survival was followed after injection of control or antigenic OVA323–339 peptide. Eighty percent of SB allografts developed severe rejection in mice treated with antigenic peptide, whereas &lt;20% of allografts were rejected in mice treated with control peptide (p &lt; 0.05). Isografts survived &gt;30 days regardless of OVA323–339 administration. Activation of donor T cells increased intragraft expression of proinflammatory cytokine (IFN-γ) and CXC chemokine IFN-γ-inducible protein-10 mRNA and enhanced activation and accumulation of host NK and T cells in SB allografts. Treatment of mice with neutralizing anti-IFN-γ-inducible protein-10 mAb increased SB allograft survival in Ag-treated mice (67%; p &lt; 0.05) and reduced accumulation of host T cells and NK cells in the lamina propria but not mesenteric lymph nodes. These results suggest that activation of donor T cells after SB allotransplantation induces production of a Th1-like profile of cytokines and CXC chemokines that enhance infiltration of host T cells and NK cells in SB allografts. Blocking this pathway may be of therapeutic value in controlling SB allograft rejection.
Naive CD4+ T Cells Exhibit Distinct Expression Patterns of Cytokines and Cell Surface Molecules on Their Primary Responses to Varying Doses of Antigen
Authors: Ise Wataru , Totsuka Mamoru , Sogawa Yoshitaka , Ametani Akio , Hachimura Satoshi , Sato Takehito , Kumagai Yoshihiro , Habu Sonoko , Kaminogawa Shuichi 
Published: April 2014

AbstractThe amount of an Ag used for stimulation affects the type and magnitude of T cell responses. In this study we have investigated the primary response of naive CD4+ T cells derived from OVA-specific TCR-transgenic mice (OVA23-3) upon stimulation with varying doses of the antigenic peptide, OVA323–339. IL-4 expression was maximal with 50 nM Ag and decreased significantly with increasing doses. In contrast, IFN-γ expression, which was also detected at 50 nM Ag, increased with increasing doses. The expression patterns of mRNA for the Th2-specific transcription factors GATA-3 and c-Maf were parallel to that of IL-4. These expression profiles were not altered by the addition of anti-IL-4 plus anti-IL-12 mAbs, suggesting that cytokine receptor signaling is not essential. Naive CD4+ T cells stimulated with 5 nM Ag elicited IgM secretion from cocultured B cells, whereas those stimulated with 50 nM Ag or more elicited apoptosis of B cells. This may be because at lower doses of Ag (5 nM), naive CD4+ T cells express CD40 ligand and OX40, whereas at higher doses (50 nM), they express Fas ligand. Clearly, the expression of each type of molecule depends on the Ag dose, and different molecules had different expression patterns. Thus, in the primary response, naive CD4+ T cells can exhibit different functions depending on the dose of Ag.
Superantigen-Induced TCR α Locus Secondary Rearrangement: Role in Tolerance Induction
Authors: Huang Ching-Yu , Golub Rachel , Wu Gillian E. , Kanagawa Osami 
Published: April 2014

Abstract
Immunization with superantigen in vivo induces transient activation of superantigen-specific T cells, followed by a superantigen-nonresponsive state. In this study, using a TCR α knock-in mouse in which the knock-in α-chain can be replaced with endogenous α-chain through secondary rearrangement, we show that immunization of superantigen changes the TCR α-chain expression on peripheral superantigen-specific T cells, induces expression of recombination-activating genes, and generates DNA double-strand breaks at the TCR α-chain locus. These results suggest that viral superantigens are capable of inducing peripheral TCR revision. Our findings thus provide a new perspective on pathogen-immune system interaction.
Genetically Modified HLA Class I Molecules Able to Inhibit Human NK Cells Without Provoking Alloreactive CD8+ CTLs
Authors: Sharland Alexandra , Patel Amy , Lee Josie Han , Cestra Aimee E. , Saidman Susan , Waneck Gerald L. 
Published: April 2014

AbstractHuman NK cells are likely to be important effectors of xenograft rejection. Expression of HLA class I molecules by transfected porcine cells can protect them from human NK cell-mediated lysis; however, this strategy has the potential to augment the anti-graft response by recipient CD8+ T cells recognizing foreign pig peptides presented by HLA. In this study we show that the introduction of a mutation (D227K) in the α3 domain of HLA-Cw3 abrogates its recognition by CD8-dependent T cells but leaves intact its ability to function as an inhibitory ligand for NK cells. Such genetically modified molecules may have potential therapeutic applications in the prevention of delayed xenograft rejection and in the facilitation of allogeneic and xenogeneic bone marrow engraftment.
Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity
Authors: Wang Binghe , Feliciani Claudio , Howell Brandon G. , Freed Irwin , Cai Qinchao , Watanabe Hideaki , Sauder Daniel N. 
Published: April 2014

AbstractThe epidermal Langerhans cells (LC), a member of the dendritic cell family, and the LC-derived cytokine IL-12 play a pivotal role in the initiation of contact hypersensitivity (CHS), a Th1 immune response in the skin. Because IL-18, another LC-derived cytokine, shares functional and biological properties with IL-12, we examined a potential role for IL-18 in CHS initiation. Our studies demonstrated that during the induction phase of murine CHS, IL-18 mRNA was significantly up-regulated in the skin-draining lymph nodes (LN). Migratory hapten-modified LC in LN expressed high levels of IL-18 mRNA and secreted functional IL-18 protein. LN cells produced significant amounts of IFN-γ following in vitro IL-12 stimulation, which could be partially blocked by anti-IL-18 Ab, suggesting a synergistic role for endogenous IL-18 in IFN-γ production by LN cells. Because mature IL-18 requires cleavage of immature precursors by caspase-1, we further examined IL-12-induced IFN-γ production in caspase-1−/− LN cells. An impaired IFN-γ production was seen in caspase-1−/− LN cells, which could be restored by addition of exogenous IL-18, supporting a role for caspase-1-cleaved, mature IL-18 in IFN-γ production. Finally, in vivo studies showed that CHS responses were significantly inhibited in mice treated with neutralizing IL-18 Ab as well as in caspase-1−/− mice deficient in mature IL-18, indicating functional relevance for IL-18 in CHS. Taken together, our studies demonstrate that LC-derived IL-18 significantly contributes to CHS initiation.
DQ 65–79, a Peptide Derived from HLA Class II, Induces IκB Expression
Authors: Jiang Yun , Chen Daniel , Lyu Shu-Chen , Ling Xuefeng , Krensky Alan M. , Clayberger Carol 
Published: April 2014

AbstractA synthetic peptide corresponding to residues 65–79 of the α helix of the α-chain of the class II HLA molecule DQA03011 (DQ 65–79) inhibits the proliferation of human T lymphocytes in an allele nonrestricted manner. By using microarray technology, we found that expression of 29 genes was increased or decreased in a human CTL cell line after treatment with DQ 65–79. This study focuses on one of these genes, IκB-α, whose expression is increased by DQ 65–79. IκB proteins, including IκB-α and IκB-β, are increased in T cells treated with DQ 65–79. Nuclear translocation of the NF-κB subunits p65 and p50 is decreased in T cells after treatment with DQ 65–79, while elevated levels of p65 and p50 are present in cytosol. DQ 65–79 inhibits the degradation of IκB-α mRNA and inhibits the activity of IκB kinase. These findings indicate that the DQ 65–79 peptide increases the level of IκB proteins, thereby preventing nuclear translocation of the transcription factor, NF-κB, and inhibiting T cell proliferation.
Yin Yang 1, Oct1, and NFAT-4 Form Repeating, Cyclosporin-Sensitive Regulatory Modules Within the Murine CD21 Intronic Control Region
Authors: Zabel Mark D. , Wheeler Wells , Weis Janis J. , Weis John H. 
Published: April 2014

Abstract
The murine complement receptor type 2 gene (Cr2/CD21) is expressed by murine B and follicular dendritic cells, but not murine T cells. We have previously shown that appropriate transcriptional control of the CD21 gene requires the CD21 promoter as well as intronic sequences. We have also demonstrated that altering chromatin structure by inhibiting histone deacetylases induces CD21 expression in murine T cells by increasing the accessibility of promoter and intronic regulatory elements. In this report, we identify seven distinct regulatory areas within the first intron of the murine CD21 gene that are conserved between mouse and human CD21 intronic sequences. EMSA competition and supershift analyses reveal the formation of multiple DNA-protein complexes at these sites that include Yin Yang 1, Oct1, and NFAT-4. NFAT-containing complexes were altered in B cells treated with the NFAT inhibitor cyclosporin A and correlated with a repression of CD21 gene transcription implicating NFAT transcriptional control. Functional data revealed that no single region conferred cell-specific reporter gene expression, but rather the entire CD21 regulatory element was required to confer cell-specific gene expression. Taken together, these data demonstrate the formation of repeating, overlapping regulatory modules, all of which are required to coordinately control the cell-specific expression of the murine CD21 gene. We propose a model in which Yin Yang 1 and Oct1 may recruit histone deacetylase to multiple sites in the CD21 intronic regulatory element in nonexpressing cells and NFAT either displaces this histone deacetylase or recruits a histone acetylase to allow the formation of a functional transcriptional complex in expressing cells.
The Rac2 Guanosine Triphosphatase Regulates B Lymphocyte Antigen Receptor Responses and Chemotaxis and Is Required for Establishment of B-1a and Marginal Zone B Lymphocytes
Authors: Croker Ben A. , Tarlinton David M. , Cluse Leonie A. , Tuxen Alana J. , Light Amanda , Yang Feng-Chun , Williams David A. , Roberts Andrew W. 
Published: April 2014

AbstractWe have defined roles for the hemopoietic-specific Rho guanosine triphosphatase, Rac2, in B lymphocyte development and function through examination of rac2−/− mice. Rac2-deficient mice displayed peripheral blood B lymphocytosis and marked reductions in peritoneal cavity B-1a lymphocytes, marginal zone B lymphocytes, and IgM-secreting plasma cells as well as reduced concentrations of serum IgM and IgA. The rac2−/− B lymphocytes exhibited reduced calcium flux following coligation of B cell AgR and CD19 and reduced chemotaxis in chemokine gradients. T cell-independent responses to DNP-dextran were of reduced magnitude, but normal kinetics, in rac2−/− mice, while T-dependent responses to nitrophenyl-keyhole limpet hemocyanin were subtly abnormal. Rac2 is therefore an essential element in regulating B lymphocyte functions and maintaining B lymphocyte populations in vivo.
Transmembrane TNF Induces an Efficient Cell-Mediated Immunity and Resistance toMycobacterium bovisBacillus Calmette-Guérin Infection in the Absence of Secreted TNF and Lymphotoxin-α
Authors: Olleros Maria L. , Guler Reto , Corazza Nadia , Vesin Dominique , Eugster Hans-Pietro , Marchal Gilles , Chavarot Pierre , Mueller Christoph , Garcia Irene 
Published: April 2014

AbstractThe contribution of a transmembrane (Tm) form of TNF to protective immunity against Mycobacterium bovis bacillus Calmette-Guérin (BCG) was studied in transgenic (tg) mice expressing a noncleavable Tm TNF but lacking the TNF/lymphotoxin-α (LT-α) locus (Tm TNF tg mice). These mice were as resistant to BCG infection as wild-type mice, whereas TNF/LT-α−/−, TNF−/−, and LT-α−/− mice succumbed. Tm TNF tg mice developed granulomas of smaller size but at 2- to 4-fold increased frequencies compared with wild-type mice. Granulomas were mainly formed by monocytes and activated macrophages expressing Tm TNF mRNA and accumulating acid phosphatase. NO synthase 2 activation as a key macrophage bactericidal mechanism was low during the acute phase of infection in Tm TNF tg mice but was still sufficient to limit bacterial growth and increased in late infection. While infection with virulent Mycobacterium tuberculosis resulted in very rapid death of TNF/LT-α−/− mice, it also resulted in survival of Tm TNF tg mice which presented an increase in the number of CFU in spleen (5-fold) and lungs (10-fold) as compared with bacterial load of wild-type mice. In conclusion, the Tm form of TNF induces an efficient cell-mediated immunity and total resistance against BCG even in the absence of LT-α and secreted TNF. However, Tm TNF-mediated protection against virulent M. tuberculosis infection can also be efficient but not as strong as in BCG infection, in which cognate cellular interactions may play a more predominant role in providing long-term surveillance and containment of BCG-infected macrophages.
Preferential Infection of Immature Dendritic Cells and B Cells by Mouse Mammary Tumor Virus
Authors: Vacheron Sonia , Luther Sanjiv A. , Acha-Orbea Hans 
Published: April 2014

AbstractUntil now it was thought that the retrovirus mouse mammary tumor virus preferentially infects B cells, which thereafter proliferate and differentiate due to superantigen-mediated T cell help. We describe in this study that dendritic cells are infectable at levels comparable to B cells in the first days after virus injection. Moreover, IgM knockout mice have chronically deleted superantigen-reactive T cells after MMTV injection, indicating that superantigen presentation by dendritic cells is sufficient for T cell deletion. In both subsets initially only few cells were infected, but there was an exponential increase in numbers of infected B cells due to superantigen-mediated T cell help, explaining that at the peak of the response infection is almost exclusively found in B cells. The level of infection in vivo was below 1 in 1000 dendritic cells or B cells. Infection levels in freshly isolated dendritic cells from spleen, Langerhans cells from skin, or bone marrow-derived dendritic cells were compared in an in vitro infection assay. Immature dendritic cells such as Langerhans cells or bone marrow-derived dendritic cells were infected 10- to 30-fold more efficiently than mature splenic dendritic cells. Bone marrow-derived dendritic cells carrying an endogenous mouse mammary tumor virus superantigen were highly efficient at inducing a superantigen response in vivo. These results highlight the importance of professional APC and efficient T cell priming for the establishment of a persistent infection by mouse mammary tumor virus.