bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+ and CD8+ T Cell Priming for Contact Hypersensitivity Occurs Independently of CD40-CD154 Interactions
Authors: Gorbachev Anton V. , Heeger Peter S. , Fairchild Robert L. 
Published: April 2014

AbstractThe primary effector cells of contact hypersensitivity (CHS) responses to dintrofluorobenzene (DNFB) are IFN-γ-producing CD8+ T cells, whereas CD4+ T cells regulate the magnitude and duration of the response. The requirement for CD40-CD154 engagement during CD8+ and CD4+ T cell priming by hapten-presenting Langerhans cells (hpLC) is undefined and was tested in the current study. Similar CHS responses to DNFB were elicited in wild-type and CD154−/− animals. DNFB sensitization of CD154−/− mice primed IFN-γ-producing CD8+ T cells and IL-4-producing CD4+ T cells. However, anti-CD154 mAb MR1 given during hapten sensitization inhibited hapten-specific CD8+, but not CD4+, T cell development and the CHS response to challenge. F(ab′)2 of MR1 failed to inhibit CD8+ T cell development and the CHS response suggesting that the mechanism of inhibition is distinct from that of CD40-CD154 blockade. Furthermore, anti-CD154 mAb did not inhibit CD8+ T cell development and CHS responses in mice depleted of CD4+ T cells or in CD4−/− mice. During in vitro proliferation assays, hpLC from mice treated with anti-CD154 mAb during DNFB sensitization were less stimulatory for hapten-primed T cells than hpLC from either control mice or mice depleted of CD4+ T cells before anti-CD154 mAb administration. These results demonstrate that development of IFN-γ-producing CD8+ T cells and the CHS response are not dependent on CD40-CD154 interactions. This study proposes a novel mechanism of anti-CD154 mAb-mediated inhibition of CD8+ T cell development where anti-CD154 mAb acts indirectly through CD4+ T cells to impair the ability of hpLC to prime CD8+ T cells.
Bacterial Lipopolysaccharide Activates HIV Long Terminal Repeat Through Toll-Like Receptor 4
Authors: Equils Ozlem , Faure Emmanuelle , Thomas Lisa , Bulut Yonca , Trushin Sergey , Arditi Moshe 
Published: April 2014

Abstract
In HIV-infected patients, concurrent infections with bacteria and viruses are known to induce HIV replication as assessed by increases in plasma HIV RNA levels. In the present study, we determined the cell surface receptor and molecular mechanisms of enterobacterial LPS-induced HIV transcription. Human dermal microvessel endothelial cells (HMEC) were transfected with an HIV-long terminal repeat (LTR)-luciferase construct and subsequently stimulated with purified bacterial LPS. Our studies demonstrate that human Toll-like receptor 4 (TLR4) mediates LPS-induced NF-κB and HIV-LTR activation in HMEC through IL-1 signaling molecules, namely myeloid differentiation protein, IL-1R-associated kinase, TNFR-associated factor, and NF-κB-inducing kinase. Cotransfection of HMEC with HIV-LTR-luciferase and TLR4 cDNA from LPS-hyporesponsive C3H/HeJ mice abrogates LPS-induced HIV transcription as does the use of dominant-negative mutants of the IL-1 signaling molecules. Transfection of HMEC with an HIV-LTR-mutant that lacks the NF-κB binding site or pretreatment of cells with chemical inhibitors of the NF-κB pathway also blocked LPS-induced HIV-LTR transactivation. These data support the conclusion that TLR4 mediates enterobacterial LPS-induced HIV transcription via IL-1 signaling molecules and NF-κB activation plays an important role in HIV-LTR transactivation.
Human Peripheral Blood Cells Differentially Recognize and Respond to Two Distinct CpG Motifs
Authors: Verthelyi Daniela , Ishii Ken J. , Gursel Mayda , Takeshita Fumihiko , Klinman Dennis M. 
Published: April 2014

AbstractOligodeoxynucleotides (ODN) that contain unmethylated CpG dinucleotides trigger a strong innate immune response in vertebrates. CpG ODN show promise as vaccine adjuvants, anti-allergens, and immunoprotective agents in animal models. Their transition to clinical use requires the identification of motifs that are optimally stimulatory in humans. Analysis of hundreds of novel ODN resulted in the identification and characterization of two structurally distinct “clusters” of immunostimulatory CpG ODN. One cluster (“D”) preferentially stimulates IFN-γ production by NK cells, whereas the other (“K”) stimulates cell proliferation and the production of IL-6 and IgM by monocytes and B cells. The distinct immunostimulatory properties of K and D ODN can improve the design of CpG-based products to achieve specific therapeutic goals.
Viral IL-10-Induced Immunosuppression Requires Th2 Cytokines and Impairs APC Function Within the Allograft
Authors: Qin Lihui , Ding Yaozhong , Tahara Hideaki , Bromberg Jonathan S. 
Published: April 2014

AbstractPrevious reports demonstrated that retroviral mediated gene transfer of viral IL-10 (vIL-10) prolongs allograft survival by decreasing donor-specific cytotoxic T lymphocyte precursor (CTLp) and IL-2-secreting helper T lymphocyte precursor (HTLp) frequency within graft-infiltrating cells (GIC). This report now shows that vIL-10 efficacy is dependent on CD4+ T cells, suggesting that immunosuppression may involve a switch from a Th1 to a Th2 alloresponse. In support of this, anti-IL-4 or anti-murine IL-10 (anti-mIL-10) mAbs, but not anti-IFN-γ mAb, administered at the time of vIL-10 gene transfer prevents enhanced graft survival. Because Th switching involves APC function, GIC were examined for their ability to present alloantigen. GIC from vIL-10-treated grafts were shown to be mostly of recipient (CBA) origin, yet were unable to elicit alloproliferative responses from donor type (C57BL/6) or third party (BALB/c) responders. The inability of vIL-10-treated GIC to stimulate the MLR was not due to the generation of negative regulatory cells or the production of immunosuppressive cytokines such as IL-4, mIL-10, or TGFβ. Using fractionated GIC subpopulations, the number of recipient type cells in the allografts was modestly reduced by vIL-10 gene transfer, while maintaining both APC phenotype and alloantigen presenting function. Conversely, after vIL-10 gene transfer, donor type GIC were unable to participate in direct alloantigen presentation. Therefore, local immunosuppression induced by vIL-10 gene transfer is CD4 T cell and IL-4 and mIL-10 dependent, and impairs direct alloantigen presentation through an alteration of donor type APC function.
Autologous Regulation of Naive T Cell Homeostasis Within the T Cell Compartment
Authors: Dummer Wolfgang , Ernst Bettina , LeRoy Eric , Lee Dong-Sup , Surh Charles D. 
Published: April 2014

AbstractNaive T cells undergo spontaneous slow proliferation on adoptive transfer into syngeneic T cell (T)-deficient hosts. Recent work has shown that such “homeostatic” T cell proliferation is driven by MHC molecules loaded with self-peptides rather than foreign peptides. Because naive T cells in normal T-sufficient hosts remain in interphase despite continuous contact with self-MHC/peptide ligands, T cells apparently inhibit homeostatic proliferation of neighboring T cells. To address this, we have investigated the requirements necessary for “bystander” T cells to inhibit homeostatic proliferation of other T cells. Three key findings are reported. First, homeostatic proliferation of T cells only occurs in specific microenvironments, namely the T cell compartment of the secondary lymphoid tissues. Second, direct entry into T cell compartments is also required for bystander inhibition of homeostatic proliferation. Third, bystander inhibition is mediated largely by naive rather than activated/memory T cells and does not require proliferation or TCR ligation. These findings suggest that homeostasis of naive T cells is unlikely to be regulated through competition for systemic soluble factors or for specific stimulatory self-MHC/peptide ligands. Rather, the data favor mechanisms that involve competition for local non-MHC stimulatory factors or direct cell-to-cell interactions between the T cells themselves within the T cell compartment.
Acquisition of CD80 (B7-1) by T Cells
Authors: Sabzevari Helen , Kantor Judy , Jaigirdar Adnan , Tagaya Yutaka , Naramura Mayumi , Hodge James W. , Bernon John , Schlom Jeffrey 
Published: April 2014

Abstract
Activation of T cells usually requires two signals. Signal 1 is mediated via a peptide-MHC on the APC; signal 2 is mediated via a costimulatory molecule on the APC surface. We demonstrate here that naive CD4+ T cells actually acquire the costimulatory molecule CD80 (B7-1) from syngeneic APCs after activation. This phenomenon was demonstrated showing acquisition of CD80 by T cells from CD80/CD86 (B7-2) knockout mice, and by treating T cells with cyclohexamide to further rule out endogenous expression of CD80 by T cells. Moreover, no CD80 mRNA could be detected in T cells that had acquired CD80. The amount of acquisition of CD80 by T cells was shown to be directly related to both the strength of signal 1 and the amount of CD80 on the APC. Specificity of this acquisition was also shown by the lack of acquisition by T cells from CD28 knockout mice (implicating CD28 in this process), the lack of acquisition of CD40 (another molecule on the APC surface) by T cells, and confocal microscopy studies. We demonstrate for the first time that 1) naive T cells, following acquisition of CD80 from APCs, were themselves shown to be capable of acting as APCs; and 2) memory T cells that have acquired CD80 from APCs undergo apoptosis in the presence of increased levels of signal 1. Thus we demonstrate both immunostimulatory and immunoregulatory functions as a result of CD80 acquisition by different T cell populations.
Ordered and Coordinated Rearrangement of the TCR α Locus: Role of Secondary Rearrangement in Thymic Selection
Authors: Huang Ching-Yu , Kanagawa Osami 
Published: April 2014

Abstract
The Ag receptor of the T lymphocyte is composed of an αβ heterodimer. Both α- and β-chains are products of the somatic rearrangement of V(D)J segments encoded on the respective loci. During T cell development, β-chain rearrangement precedes α-chain rearrangement. The mechanism of allelic exclusion ensures the expression of a single β-chain in each T cell, whereas a large number of T cells express two functional α-chains. Here we demonstrate evidence that TCR α rearrangement is initiated by rearranging a 3′ Vα segment and a 5′ Jα segment on both chromosomes. Rearrangement then proceeds by using upstream Vα and downstream Jα segments until it is terminated by successful positive selection. This ordered and coordinated rearrangement allows a single thymocyte to sequentially express multiple TCRs with different specificities to optimize the efficiency of positive selection. Thus, the lack of allelic exclusion and TCR α secondary rearrangement play a key role in the formation of a functional T cell repertoire.
Reduction in DNA Binding Activity of the Transcription Factor Pax-5a in B Lymphocytes of Aged Mice
Authors: Anspach Jillian , Poulsen Gail , Kaattari Ilsa , Pollock Roberta , Zwollo Patty 
Published: April 2014

Abstract
Aging has been associated with intrinsic changes of the humoral immune response, which may lead to an increased occurrence of autoimmune disorders and pathogenic susceptibility. The transcription factor Pax-5 is a key regulator of B cell development. Pax-5a/B cell-specific activator protein and an alternatively spliced isoform, Pax-5d, may have opposing functions in transcriptional regulation due to the lack of a transactivation domain in Pax-5d. To study B cell-specific changes that occur during the aging process, we investigated expression patterns of Pax-5a and 5d in mature B cells of young and aged mice. RNase protection assays showed a similar transcriptional pattern for both age groups that indicates that aging has no affect on transcription initiation or alternative splicing for either isoform. In contrast, a significant reduction in the DNA binding activity of Pax-5a but not Pax-5d protein was observed in aged B cells in vitro, while Western blot analyses showed that similar levels of Pax-5a and 5d proteins were present in both age groups. The observed decrease in Pax-5a binding activity correlated with changes in expression of two Pax-5 target genes in aged B cells. Expression of the Ig J chain and the secreted form of Ig μ, which are both known to be suppressed by Pax-5a in mature B cells, were increased in B cells of aged mice. Together, our studies suggest that changes associated with the aging phenotype cause posttranslational modification(s) of Pax-5a but not Pax-5d, which may lead to an abnormal B cell phenotype in aged mice, associated with elevated levels of J chain, and secretion of IgM.
IL-10 Is a Central Regulator of Cyclooxygenase-2 Expression and Prostaglandin Production
Authors: Berg Daniel J. , Zhang Juan , Lauricella Dina M. , Moore Steven A. 
Published: April 2014

AbstractIL-10 is a potent anti-inflammatory and immune regulatory cytokine. IL-10−/− mice produce exaggerated amounts of inflammatory cytokines when stimulated with LPS, indicating that endogenous IL-10 is a central regulator of inflammatory cytokine production in vivo. PGs are lipid mediators that are also produced in large amounts during the inflammatory response. To study the role of IL-10 in the regulation of PG production during the acute inflammatory response, we evaluated LPS-induced cyclooxygenase (COX) expression and PG production in wild-type (wt) and IL-10−/− mice. LPS-induced PGE2 production from IL-10−/− spleen cells was 5.6-fold greater than that from wt spleen cells. LPS stimulation resulted in the induction of COX-2 mRNA and protein in both wt and IL-10−/− spleen cells; however, the magnitude of increase in COX-2 mRNA was 5.5-fold greater in IL-10−/− mice as compared with wt mice. COX-1 protein levels were not affected by LPS stimulation in either wt or IL-10−/− mice. Neutralization of IFN-γ, TNF-α, or IL-12 markedly decreased the induction of COX-2 in IL-10−/− spleen cells, suggesting that increased inflammatory cytokine production mediates much of the COX-2 induction in IL-10−/− mice. Treatment of IL-10−/− mice with low doses of LPS resulted in a marked induction of COX-2 mRNA in the spleen, whereas wt mice had minimal expression of COX-2 mRNA. These findings indicate that, in addition to IL-10’s central role in the regulation of inflammatory cytokines, endogenous IL-10 is an important regulator of PG production in the response to LPS.
NF-κB Regulation by IκB Kinase-2 in Rheumatoid Arthritis Synoviocytes
Authors: Aupperle Karlfried R. , Bennett Brydon L. , Han Zuoning , Boyle David L. , Manning Anthony M. , Firestein Gary S. 
Published: April 2014

Abstract
IκB kinase-1 and IκB kinase-2 (IKK1 and IKK2; also called IKKα and IKKβ, respectively) are part of the signal complex that regulates NF-κB activity in many cell types, including fibroblast-like synoviocytes (FLS). We determined which of these two kinases is responsible for cytokine-induced NF-κB activation in synoviocytes and assessed the functional consequences of IKK1 or IKK2 overexpression and inhibition. FLS were infected with adenovirus constructs encoding either wild-type (wt) IKK1 or IKK2, the dominant negative (dn) mutant of both kinases, or a control construct encoding green fluorescence protein. Analysis of the NF-κB pathway revealed that cytokine-induced IKK activation, IκB degradation, and NF-κB activation was prevented in cells expressing the IKK2 dn mutant, whereas baseline NF-κB activity was increased by IKK2 wt. In addition, synthesis of IL-6 and IL-8, as well as expression of ICAM-1 and collagenase, was only increased by IKK2 wt, and their cytokine-induced production was abrogated by IKK2 dn mutant. However, the IKK1 dn mutant did not inhibit cytokine-mediated activation of NF-κB or any of the functional assays. These data indicate that IKK2 is the key convergence pathway for cytokine-induced NF-κB activation. Furthermore, IKK2 regulates adhesion molecule, matrix metalloproteinase, and cytokine production in FLS.
Serum Amyloid A (apoSAA) Expression Is Up-Regulated in Rheumatoid Arthritis and Induces Transcription of Matrix Metalloproteinases
Authors: Vallon Rüdiger , Freuler Felix , Desta-Tsedu Netsanet , Robeva Anna , Dawson Janet , Wenner Peter , Engelhardt Petra , Boes Ludwig , Schnyder Jörg , Tschopp Claude , Urfer Roman , Baumann Götz 
Published: April 2014

Abstract
The acute-phase reactant rabbit serum amyloid A 3 (SAA3) was identified as the major difference product in Ag-induced arthritis in the rabbit, a model resembling in many aspects the clinical characteristics of rheumatoid arthritis (RA) in humans. In Ag-induced arthritis, up-regulated SAA3 transcription in vivo was detected in cells infiltrating into the inflamed joint, in the area where pannus formation starts and, most notably, also in chondrocytes. The proinflammatory cytokine IL-1β induced SAA3 transcription in primary rabbit chondrocytes in vitro. Furthermore, rSAA3 protein induced transcription of matrix metalloproteinases in rabbit chondrocytes in vitro. In the human experimental system, IL-1β induced transcription of acute-phase SAA (A-SSA; encoded by SAA1/SAA2) in primary chondrocytes. Similar to the rabbit system, recombinant human A-SAA protein was able to induce matrix metalloproteinases’ transcription in chondrocytes. Further, immunohistochemistry demonstrated that A-SAA was highly expressed in human RA synovium. A new finding of our study is that A-SSA expression was also detected in cartilage in osteoarthritis. Our data, together with previous findings of SAA expression in RA synovium, suggest that A-SAA may play a role in cartilage destruction in arthritis.
Cutting Edge: The Class II Transactivator Prevents Activation-Induced Cell Death by Inhibiting Fas Ligand Gene Expression
Authors: Gourley Tania S. , Chang Cheong-Hee 
Published: April 2014

Abstract
The Fas:Fas ligand pathway is critical in regulating immune homeostasis by eliminating activated T cells that proliferated in response to an infection. Here, we show that the MHC class II transactivator (CIITA) can suppress this pathway by inhibiting transcription of the Fas ligand gene. CIITA can effectively repress transcription from the Fas ligand promoter in both T cell lines as well as primary cells. The repression appears to be at least partly due to interference of NFAT-mediated induction of Fas ligand gene transcription. T cells that express CIITA constitutively do not up-regulate Fas ligand on the cell surface after activation via the TCR. Consequently, these cells lack the ability to undergo activation-induced cell death, and to kill Fas-bearing target cells.
Fas-Mediated Apoptosis Causes Elimination of Virus-Specific Cytotoxic T Cells in the Virus-Infected Liver
Authors: Liu Zhang-Xu , Govindarajan Sugantha , Okamoto Shigefumi , Dennert Gunther 
Published: April 2014

AbstractImmunity to allogeneic MHC Ags is weak in rodent livers, raising questions as to the mechanisms that might control responses in this organ. Infection with an adenovirus vector reveals that T cell-mediated immunity to nonself-Ags in the liver is self-limiting. Virus-induced liver injury decreases and coincides with disappearance of virus-specific CTL, concomitant to an increase of apoptotic T cells early after infection. But whereas death in CD4 cells is independent of Fas, perforin, and TNF-α, that of CD8 cells requires Fas and not perforin or TNF-α pathways. Fas ligand is expressed on liver-infiltrating cells, pointing to death by fratricide that causes almost complete disappearance of virus-specific CTL 4 wk after infection. CTL elimination is virus dose dependent, and high doses induced high alanine aminotransferase values, elevated expression of Fas ligand on CD8 cells, and increased CD8 cell migration into the infected liver.
Phenotypic Distinction and Functional Characterization of Pro-B Cells in Adult Mouse Bone Marrow
Authors: Mojica Mariluz P. , Perry S. Scott , Searles A. Elena , Elenitoba-Johnson Kojo S. J. , Pierce L. Jeanne , Wiesmann Anne , Slayton William B. , Spangrude Gerald J. 
Published: April 2014

AbstractA lymphoid-committed progenitor population was isolated from mouse bone marrow based on the cell surface phenotype Thy-1.1negSca-1posc-KitlowLinneg. These cells were CD43posCD24pos on isolation and proliferated in response to the cytokine combination of steel factor, IL-7, and Flt3 ligand. Lymphoid-committed progenitors could be segregated into more primitive and more differentiated subsets based on expression of AA4.1. The more differentiated subset generated only B lymphoid cells in 92% of total colonies assayed, lacked T lineage potential, and expressed Pax5. These studies have therefore defined and isolated a B lymphoid-committed progenitor population at a developmental stage corresponding to the initial expression of CD45R.
The Roles of MHC Class II, CD40, and B7 Costimulation in CTL Induction by Plasmid DNA
Authors: Chan Kee , Lee Delphine J. , Schubert Amy , Tang Chih Min , Crain Brian , Schoenberger Stephen P. , Corr Maripat 
Published: April 2014

AbstractDNA-based vaccines generate potent CTL responses. The mechanism of T cell stimulation has been attributed to plasmid-transfected dendritic cells. These cells have also been shown to express plasmid-encoded proteins and to become activated by surface marker up-regulation. However, the increased surface expression of CD40 and B7 on these dendritic cells is insufficient to overcome the need for MHC class II-restricted CD4+ T cell help in the priming of a CTL response. In this study, MHC class II−/− mice were unable to generate a CTL response following DNA immunization. This deficit in CTL stimulation by MHC class II-deficient mice was only modestly restored with CD40-activating Ab, suggesting that there were other elements provided by MHC class II-restricted T cell help for CTL induction. CTL activity was also augmented by coinjection with a vector encoding the costimulatory ligand B7.1, but not B7.2. These data indicate that dendritic cells in plasmid DNA-injected mice require conditioning signals from MHC class II-restricted T cells that are both CD40 dependent and independent and that there are different roles for costimulatory molecules that may be involved in inducing optimal CTL activity.
The Production of IFN-γ by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-4
Authors: Schindler Heike , Lutz Manfred B. , Röllinghoff Martin , Bogdan Christian 
Published: April 2014

AbstractMacrophages release IFN-γ on combined stimulation with IL-12 and IL-18, but the signaling requirements of this process and its regulation by other cytokines are unknown. Here, we demonstrate that STAT4 is indispensable for IL-12/IL-18-induced production of IFN-γ by mouse peritoneal macrophages. Type 2 NO synthase (NOS2), which we previously found to be a prerequisite for IL-12-induced IFN-γ production in NK cells, was not required for IFN-γ production by these macrophages. IL-12 alone already induced the expression of IFN-γ mRNA, but nuclear translocation of STAT4, the release of IFN-γ protein, and the subsequent production of NO was strictly dependent on the simultaneous presence of IL-18. NF-κB, which mediates IL-18 effects in T cells, was only weakly activated by IL-12 and/or IL-18 in macrophages. Known inhibitors of macrophage functions (e.g., IL-4 and TGF-β) also suppressed macrophage IFN-γ production and the subsequent production of NOS2-derived NO. The inhibitory effect of IL-4 was paralleled by nuclear translocation of STAT6, which in EMSAs was able to bind to the same DNA oligonucleotide as STAT4. These results further define the production of IFN-γ by macrophages and point to a diversity in the signals required for IFN-γ production by various cell types.