bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development
Authors: Vettermann Christian , Herrmann Kai , Albert Christine , Roth Edith , Bösl Michael R. , Jäck Hans-Martin 
Published: April 2014

Abstract
Precursor BCR (pre-BCR) signaling governs proliferation and differentiation of pre-B cells during B lymphocyte development. However, it is controversial as to which parts of the pre-BCR, which is composed of Igμ H chain, surrogate L chain (SLC), and Igα-Igβ, are important for signal initiation. Here, we show in transgenic mice that the N-terminal non-Ig-like (unique) tail of the surrogate L chain component λ5 is critical for enhancing pre-BCR-induced proliferation signals. Pre-BCRs with a mutated λ5 unique tail are still transported to the cell surface, but they deliver only basal signals that trigger survival and differentiation of pre-B cells. Further, we demonstrate that the positively charged residues of the λ5 unique tail, which are required for pre-BCR self-oligomerization, can also mediate binding to stroma cell-associated self-Ags, such as heparan sulfate. These findings establish the λ5 unique tail as a pre-BCR-specific autoreactive signaling motif that could increase the size of the primary Ab repertoire by selectively expanding pre-B cells with functional Igμ H chains.
Synoviocyte Innate Immune Responses: I. Differential Regulation of Interferon Responses and the JNK Pathway by MAPK Kinases
Authors: Yoshizawa Toshio , Hammaker Deepa , Sweeney Susan E. , Boyle David L. , Firestein Gary S. 
Published: April 2014

Abstract
JNK is a key regulator of matrix metalloproteinase production in rheumatoid arthritis. It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix metalloproteinase expression in cultured fibroblast-like synoviocytes (FLS). However, the functions of MKK4 and MKK7 in synoviocyte innate immune responses have not been determined. TNF, peptidoglycan (PGN), and LPS stimulation led to higher and more prolonged MKK7 phosphorylation compared with MKK4 in FLS. However, this pattern was reversed in poly(I-C) stimulated cells. siRNA knockdown studies showed that TNF, PGN, and LPS-induced JNK and c-Jun phosphorylation are MKK7 dependent, while poly(I-C) responses require both MKK4 and MKK7. Poly(I-C)-induced expression of IP-10, RANTES, and IFN-β mRNA was decreased in MKK4- or MKK7-deficient FLS. However, MKK4 and MKK7 deficiency did not affect phosphorylation of IκB kinase-related kinases in the TLR3 signaling pathway. MKK7, but not MKK4 deficiency, significantly decreased poly(I-C)-mediated IRF3 dimerization, DNA binding, and IFN-sensitive response element-mediated gene transcription. These results were mimicked by the JNK inhibitor SP600125, indicating that JNK can directly phosphorylate IRF3. In contrast, deficiency of either MKK4 or MKK7 decreased AP-1 transcriptional activity. Therefore, JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 requires both MKK4 and MKK7, with the former activating c-Jun and the latter activating both c-Jun and IRF3 through JNK-dependent mechanisms.
Human Invariant NKT Cells Display Alloreactivity Instructed by Invariant TCR-CD1d Interaction and Killer Ig Receptors
Authors: Patterson Scott , Chaidos Aristeidis , Neville David C. A. , Poggi Alessandro , Butters Terry D. , Roberts Irene A. G. , Karadimitris Anastasios 
Published: April 2014

Abstract
Invariant NKT (iNKT) cells are a subset of highly conserved immunoregulatory T cells that modify a variety of immune responses, including alloreactivity. Central to their function is the interaction of the invariant TCR with glycosphingolipid (GSL) ligands presented by the nonpolymorphic MHC class I molecule CD1d and their ability to secrete rapidly large amounts of immunomodulatory cytokines when activated. Whether iNKT cells, like NK and conventional T cells, can directly display alloreactivity is not known. We show in this study that human iNKT cells and APC can establish a direct cross-talk leading to preferential maturation of allogeneic APC and a considerably higher reactivity of iNKT cells cultured with allogeneic rather that autologous APC. Although the allogeneic activation of iNKT cells is invariant TCR-CD1d interaction-dependent, GSL profiling suggests it does not involve the recognition of disparate CD1d/GSL complexes. Instead, we show that contrary to previous reports, iNKT cells, like NK and T cells, express killer Ig receptors at a frequency similar to that of conventional T cells and that iNKT cell allogeneic activation requires up-regulation and function of activating killer Ig receptors. Thus, iNKT cells can display alloreactivity, for which they use mechanisms characteristic of both NK and conventional T cells.
IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development
Authors: Vang Kieng B. , Yang Jianying , Mahmud Shawn A. , Burchill Matthew A. , Vegoe Amanda L. , Farrar Michael A. 
Published: April 2014

Abstract
Common γ chain (γc)-receptor dependent cytokines are required for regulatory T cell (Treg) development as γc−/− mice lack Tregs. However, it is unclear which γc-dependent cytokines are involved in this process. Furthermore, thymic stromal lymphopoietin (TSLP) has also been suggested to play a role in Treg development. In this study, we demonstrate that developing CD4+Foxp3+ Tregs in the thymus express the IL-2Rβ, IL-4Rα, IL-7Rα, IL-15Rα, and IL-21Rα chains, but not the IL9Rα or TSLPRα chains. Moreover, only IL-2, and to a much lesser degree IL-7 and IL-15, were capable of transducing signals in CD4+Foxp3+ Tregs as determined by monitoring STAT5 phosphorylation. Likewise, IL-2, IL-7, and IL-15, but not TSLP, were capable of inducing the conversion of CD4+CD25+Foxp3− thymic Treg progenitors into CD4+Foxp3+ mature Tregs in vitro. To examine this issue in more detail, we generated IL-2Rβ−/− × IL-7Rα−/− and IL-2Rβ−/− × IL-4Rα−/− mice. We found that IL-2Rβ−/− × IL-7Rα−/− mice were devoid of Tregs thereby recapitulating the phenotype observed in γc−/− mice; in contrast, the phenotype observed in IL-2Rβ−/− × IL-4Rα−/− mice was comparable to that seen in IL-2Rβ−/− mice. Finally, we observed that Tregs from both IL-2−/− and IL-2Rβ−/− mice show elevated expression of IL-7Rα and IL-15Rα chains. Addition of IL-2 to Tregs from IL-2−/− mice led to rapid down-regulation of these receptors. Taken together, our results demonstrate that IL-2 plays the predominant role in Treg development, but that in its absence the IL-7Rα and IL-15Rα chains are up-regulated and allow for IL-7 and IL-15 to partially compensate for loss of IL-2.
Synthetic Peptide Dendrimers Block the Development and Expression of Experimental Allergic Encephalomyelitis
Authors: Wegmann Keith W. , Wagner Cynthia R. , Whitham Ruth H. , Hinrichs David J. 
Published: April 2014

Abstract
Multiple Ag peptides (MAPs) containing eight proteolipid protein (PLP)139–151 peptides arranged around a dendrimeric branched lysine core were used to influence the expression and development of relapsing experimental allergic encephalomyelitis (EAE) in SJL mice. The PLP139–151 MAPs were very efficient agents in preventing the development of clinical disease when administered after immunization with the PLP139–151 monomeric encephalitogenic peptide in CFA. The treatment effect with these MAPs was peptide specific; irrelevant multimeric peptides such as guinea pig myelin basic protein GPBP72–84 MAP (a dendrimeric octamer composed of the 72–84 peptide) and PLP178–191 MAP (a dendrimeric octamer composed of the PLP178–191 peptide) had no treatment effect on PLP139–151-induced EAE. PLP139–151 MAP treatment initiated after clinical signs of paralysis also altered the subsequent course of EAE; it limited developing signs of paralysis and effectively limited the severity and number of disease relapses in MAP-treated mice over a 60-day observation period. PLP139–151 MAP therapy initiated before disease onset acts to limit the numbers of Th17 and IFN-γ-producing cells that enter into the CNS. However, Foxp3+ cells entered the CNS in numbers equivalent for nontreated and PLP139–151 MAP-treated animals. The net effect of PLP139–151 MAP treatment dramatically increases the ratio of Foxp3+ cells to Th17 and IFN-γ-producing cells in the CNS of PLP139–151 MAP-treated animals.
Two Macrophage Colony-Stimulating Factor Genes Exist in Fish That Differ in Gene Organization and Are Differentially Expressed
Authors: Wang Tiehui , Hanington Patrick C. , Belosevic Miodrag , Secombes Christopher J. 
Published: April 2014

Abstract
Mammalian macrophage CSF (MCSF; CSF-1) is the primary regulator of the mononuclear phagocyte lineage. We, for the first time, report the complete sequencing of five MCSF cDNAs from three fish species, rainbow trout, zebrafish, and goldfish. Despite the difference in the lengths of the MCSF transcripts, all of the fish MCSF molecules encode a signal peptide, a CSF-1 domain, a transmembrane domain, and an intracellular region. Each fish MCSF gene has a unique exon/intron structure. The primordial MCSF gene may have had a nine exon/eight intron structure. In this model, insertion of an intron in exon 6 in primitive fish created the fish type I MCSF, while the loss of this exon or part of the original exon 6 created the fish type II MCSF. Investigation of alternative splicing variants in trout suggests that no mammalian equivalent splice variants exist. The two trout MCSF genes are differentially expressed in vivo and contributed differently to the high-level expression of MCSF in spleen and head kidney. In contrast to the up-regulation of MCSF by PMA in mammals, in trout MCSF1 expression is down-regulated by PMA treatment. As in mammals, recombinant trout MCSF1 can promote the growth of head kidney leukocytes, and it up-regulates the expression of CXCR3 in head kidney macrophages, with the latter suggesting a role of MCSF in the trafficking of macrophages to sites of inflammation or injury where the CXCR3 ligands are expressed. Thus MCSF has an important role in the immune system of fish as in mammals.
In Vivo Suppression of Naive CD4 T Cell Responses by IL-2- and Antigen-Stimulated T Lymphocytes in the Absence of APC Competition
Authors: Inaba Hiroto , Steeves Meredith , Nguyen Phuong , Geiger Terrence L. 
Published: April 2014

Abstract
After stimulation, T cells enter a transient refractory period, promoted by IL-2, during which they are resistant to re-stimulation. We previously demonstrated that these IL-2- and Ag-stimulated refractory T cells are able to suppress the Ag-induced proliferation of naive T cells in vitro. We show here that, after adoptive transfer, these T cells are also able to suppress naive T cell proliferation in vivo. More interestingly, potently suppressive T cells can be generated directly in vivo by stimulation with Ag and supplemental IL-2. The activity of the suppressive cells is dose dependent, and the suppressor and suppressed T cells need not be restricted to the same MHC or Ag. Similar to its role in promoting T cell-mediated suppression in vitro, IL-2 is critical for the induction of suppressive activity in activated T cells in vivo. Supplemental IL-2, however, cannot overcome the suppressive activity in target T cells, indicating that suppression is not mediated by competition for this cytokine. Although the activated T cells block naive T cell proliferation, the naive cells do engage Ag and up-regulate the CD25 and CD69 activation markers after stimulation. Therefore, activated T cells stimulated in the presence of IL-2 develop MHC- and Ag-unrestricted suppressive activity. These results provide a new mechanism for competition among CD4+ T lymphocytes, in which initial waves of responding T cells may inhibit subsequently recruited naive T cells. They further suggest a novel negative feedback loop limiting the expansion of T cell responses that may be present during vigorous immune responses or after IL-2 immunotherapy.
A Polypyrimidine Tract-Binding Protein-Dependent Pathway of mRNA Stability Initiates with CpG Activation of Primary B Cells
Authors: Porter Joseph F. , Vavassori Stefano , Covey Lori R. 
Published: April 2014

Abstract
The mRNA encoding CD154, a critical protein involved in both humoral and cell-mediated immune responses, is regulated at the posttranscriptional level by the binding of complex I, a polypyrimidine tract-binding (PTB) protein-containing complex, which acts to increase message stability at late times of activation. Our current work focuses on analyzing a similar complex in B cells, designated B-cpx I, which is increased in B cells activated by CpG engagement of the TLR9 receptor but not by activation through CD40. Expression profiling of transcripts from primary B cells identified 31 mRNA transcripts with elevated PTB binding upon activation. Two of these transcripts, Rab8A and cyclin D2, contained binding sites for B-cpx I in their 3′ untranslated regions (UTRs). Analysis of turnover of endogenous Rab8A transcript in B cells revealed that like CD154, the mRNA half-life increased following activation and insertion of the Rab8A B-cpx I binding site into a heterologous transcript led to a 3-fold increase in stability. Also, short hairpin RNA down-regulation of PTB resulted in a corresponding decrease in Rab8A mRNA half-life. Overall these data strongly support a novel pathway of mRNA turnover that is expressed both in T cells and B cells and depends on the formation of a PTB-containing stability complex in response to cellular activation.
Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1
Authors: McKimmie Clive S. , Fraser Alasdair R. , Hansell Chris , Gutiérrez Laura , Philipsen Sjaak , Connell Laura , Rot Antal , Kurowska-Stolarska Mariola , Carreno Paz , Pruenster Monika , Chu Chung-Ching , Lombardi Giovanna , Halsey Christina , McInnes Iain B. , Liew Foo Y. , Nibbs Robert J. , Graham Gerard J. 
Published: April 2014

Abstract
D6 scavenges inflammatory chemokines and is essential for the regulation of inflammatory and immune responses. Mechanisms explaining the cellular basis for D6 function have been based on D6 expression by lymphatic endothelial cells. In this study, we demonstrate that functional D6 is also expressed by murine and human hemopoietic cells and that this expression can be regulated by pro- and anti-inflammatory agents. D6 expression was highest in B cells and dendritic cells (DCs). In myeloid cells, LPS down-regulated expression, while TGF-β up-regulated expression. Activation of T cells with anti-CD3 and soluble CD28 up-regulated mRNA expression 20-fold, while maturation of human macrophage and megakaryocyte precursors also up-regulated D6 expression. Competition assays demonstrated that chemokine uptake was D6 dependent in human leukocytes, whereas mouse D6-null cells failed to uptake and clear inflammatory chemokines. Furthermore, we present evidence indicating that D6 expression is GATA1 dependent, thus explaining D6 expression in myeloid progenitor cells, mast cells, megakaryocytes, and DCs. We propose a model for D6 function in which leukocytes, within inflamed sites, activate D6 expression and thus trigger resolution of inflammatory responses. Our data on D6 expression by circulating DCs and B cells also suggest alternative roles for D6, perhaps in the coordination of innate and adaptive immune responses. These data therefore alter our models of in vivo D6 function and suggest possible discrete, and novel, roles for D6 on lymphatic endothelial cells and leukocytes.
EBF1 Is Essential for B-Lineage Priming and Establishment of a Transcription Factor Network in Common Lymphoid Progenitors
Authors: Zandi Sasan , Mansson Robert , Tsapogas Panagiotis , Zetterblad Jenny , Bryder David , Sigvardsson Mikael 
Published: April 2014

Abstract
Development of B-lymphoid cells in the bone marrow is a process under strict control of a hierarchy of transcription factors. To understand the development of a B-lymphoid-restricted functional network of transcription factors, we have investigated the cell autonomous role of the transcription factor EBF1 in early B cell development. This revealed that even though transplanted EBF1-deficient fetal liver cells were able to generate common lymphoid progenitors (CLPs) as well as B220+CD43+AA4.1+ candidate precursor B cells, none of these populations showed signs of B lineage priming. The isolated CLPs were able to generate T lymphocytes in vitro supporting the idea that the phenotype of EBF1-deficient mice is restricted to the development of the B lineage. Furthermore, EBF deficient CLPs displayed a reduction in Ig H chain recombination as compared with their wild-type counterpart and essentially lacked transcription of B-lineage-associated genes. Among the genes displaying reduced expression in the EBF1 deficient CLPs were the transcription factors Pax5, Pou2af1 (OcaB), and FoxO1 that all appear to be direct genetic targets for EBF1 because their promoters contained functional binding sites for this factor. This leads us to suggest that EBF1 regulates a transcription factor network crucial for B lineage commitment.
Contribution of Mutation, Recombination, and Gene Conversion to Chicken Mhc-B Haplotype Diversity
Authors: Hosomichi Kazuyoshi , Miller Marcia M. , Goto Ronald M. , Wang Yujun , Suzuki Shingo , Kulski Jerzy K. , Nishibori Masahide , Inoko Hidetoshi , Hanzawa Kei , Shiina Takashi 
Published: April 2014

Abstract
The Mhc is a highly conserved gene region especially interesting to geneticists because of the rapid evolution of gene families found within it. High levels of Mhc genetic diversity often exist within populations. The chicken Mhc is the focus of considerable interest because of the strong, reproducible infectious disease associations found with particular Mhc-B haplotypes. Sequence data for Mhc-B haplotypes have been lacking thereby hampering efforts to systematically resolve which genes within the Mhc-B region contribute to well-defined Mhc-B-associated disease responses. To better understand the genetic factors that generate and maintain genomic diversity in the Mhc-B region, we determined the complete genomic sequence for 14 Mhc-B haplotypes across a region of 59 kb that encompasses 14 gene loci ranging from BG1 to BF2. We compared the sequences using alignment, phylogenetic, and genome profiling methods. We identified gene structural changes, synonymous and non-synonymous polymorphisms, insertions and deletions, and allelic gene rearrangements or exchanges that contribute to haplotype diversity. Mhc-B haplotype diversity appears to be generated by a number of mutational events. We found evidence that some Mhc-B haplotypes are derived by whole- and partial-allelic gene conversion and homologous reciprocal recombination, in addition to nucleotide mutations. These data provide a framework for further analyses of disease associations found among these 14 haplotypes and additional haplotypes segregating and evolving in wild and domesticated populations of chickens.
The Major Bactericidal Activity of Human Seminal Plasma Is Zinc-Dependent and Derived from Fragmentation of the Semenogelins
Authors: Edström Anneli M. L. , Malm Johan , Frohm Birgitta , Martellini Julie A. , Giwercman Aleksander , Mörgelin Matthias , Cole Alexander M. , Sørensen Ole E. 
Published: April 2014

AbstractOne of the major roles of seminal plasma is to provide antimicrobial protection for the spermatozoa in the female reproductive tract. We found that the bactericidal activity of seminal plasma was highest after resolution of the seminal clot and that this antibacterial activity subsequently became greatly diminished. The antibacterial activity was derived from peptides generated by fragmentation of the semenogelins while the semenogelin holoproteins displayed no antibacterial activity. After ejaculation the semenogelin-derived peptides were fragmented to smaller and smaller fragments over time and thereby lost antibacterial activity. This paralleled the loss of antibacterial activity of whole seminal plasma both in vitro and after sexual intercourse. Moreover, the antibacterial activity of the semenogelin-derived peptides generated in seminal plasma was strictly zinc-dependent both at neutral and low pH. These data provide novel roles for the resolution of seminal clots and for the high zinc concentration in human seminal plasma.
Combined Triggering of Dendritic Cell Receptors Results in Synergistic Activation and Potent Cytotoxic Immunity
Authors: Wells James W. , Cowled Christopher J. , Farzaneh Farzin , Noble Alistair 
Published: April 2014

Abstract
Elimination of malignant cells and intracellular infections involves collaboration between CTLs and Th1 inflammation. Dendritic cells drive this response via costimulation and cytokines. We have defined key signals required for the exponential expansion of specific CD8+ T cells in vivo in mice. Immunization with two or more TLR agonists, anti-CD40, IFN-γ, and surfactant were sufficient to drive unprecedented levels of CD8 response to peptide or protein Ag and highly polarized Th1 CD4 responses. CD40 signaling was required for CD8 expansion but could be provided by a concomitant CD4 Th response in place of anti-CD40. Triggering of these pathways activated migration and activation of myeloid and plasmacytoid dendritic cells and secretion of IL-12. Cross-presentation can thus be exploited to induce potent cytotoxic responses and long-term memory to peptide/protein Ags. When combined with a tumor-associated peptide from tyrosinase-related protein 2, our combined adjuvant approach effectively halted tumor growth in an in vivo melanoma model and was more effective than anti-CD40 and a single TLR agonist. Antitumor immunity was associated with long-lived effector memory CD8 cells specific for the naturally processed and presented tumor Ag, and tumor protection was partially but not entirely dependent on CD8 T cells. This flexible strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development.
B Lymphocyte Activation by Coinfection Prevents Immune Control of Friend Virus Infection
Authors: Marques Rute , Antunes Inês , Eksmond Urszula , Stoye Jonathan , Hasenkrug Kim , Kassiotis George 
Published: April 2014

Abstract
Although the adaptive immune response almost invariably fails to completely eliminate retroviral infections, it can exert significant protection from disease and long-term control of viral replication. Friend virus (FV), a mouse retrovirus, causes persistent infection in all strains of mice and erythroleukaemia in susceptible strains, the course of which can be strongly influenced by both genetic and extrinsic factors. In this study we examine the impact of coinfection on the requirements for immune control of FV infection. We show that congenic C57BL/6 mice, in which the introduction of an allele of the Friend virus susceptibility 2 gene provides the potential for FV-induced leukemia development, effectively resist FV infection, and both T cell- and Ab-dependent mechanisms contribute to their resistance. However, we further demonstrate that coinfection with lactate dehydrogenase-elevating virus (LDV) renders these otherwise immunocompetent mice highly susceptible to FV infection and subsequent disease. The presence of LDV delays induction of FV-specific neutralizing Abs and counteracts the protective contribution of adaptive immunity. Importantly, the disease-enhancing effect of LDV coinfection requires the presence of a polyclonal B cell repertoire and is reproduced by direct polyclonal B cell activation. Thus, immune activation by coinfecting pathogens or their products can contribute to the pathogenicity of retroviral infection.