bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inducible Costimulatory Molecule-B7-Related Protein 1 Interactions Are Important for the Clonal Expansion and B Cell Helper Functions of Naive, Th1, and Th2 T Cells
Authors: Smith Karen M. , Brewer James M. , Webb Phillip , Coyle Anthony J. , Gutierrez-Ramos Carlos , Garside Paul 
Published: April 2014

Abstract
Inducing T cell responses requires at least two distinct signals: 1) TCR engagement of MHC-peptide and 2) binding of CD28 to B7.1/2. However, the recent avalanche of newly described costimulatory molecules may represent additional signals which can modify events after the initial two-signal activation. Inducible costimulatory molecule (ICOS) is a CD28 family member expressed on T cells rapidly following activation that augments both Th1 and Th2 T cell responses and has been implicated in sustaining rather than initiating T cell responses. Although it is known that blockade of ICOS-B7-related protein 1 (B7RP-1) in vivo dramatically reduces germinal center formation and Ab production, the mechanism(s) remains unclear. An optimal T cell-dependent Ab response requires T and B cell activation, expansion, differentiation, survival, and migration, and the ICOS-B7RP-1 interaction could be involved in any or all of these processes. Understanding this will have important implications for targeting ICOS-B7RP-1 therapeutically. We have therefore used a double-adoptive transfer system, in which all of the above events can be analyzed, to assess the role of ICOS-B7RP-1 in T cell help for B cell responses. We have shown that ICOS signaling is involved in the initial clonal expansion of primary and primed Th1 and Th2 cells in response to immunization. Furthermore, while ICOS-B7RP-1 interactions have no effect on the migration of T cells into B cell follicles, it is essential for their ability to support B cell responses.
Human Heat Shock Protein 60 Induces Maturation of Dendritic Cells Versus a Th1-Promoting Phenotype
Authors: Flohé Stefanie B. , Brüggemann Jutta , Lendemans Sven , Nikulina Marina , Meierhoff Guido , Flohé Sascha , Kolb Hubert 
Published: April 2014

AbstractHeat shock protein (HSP) 60 nonspecifically activates cells of the innate immune system. In the present study, we characterized the effects of human HSP60 maturation, cytokine release, and T cell-activating capacity of bone marrow-derived dendritic cells (DC). Furthermore, we analyzed HSP60-induced signal transduction in DC. HSP60 strongly stimulated DC for maturation and release of TNF-α, IL-12, and IL-1β. However, HSP60 elicited only a weak IL-10 response in DC suggesting a Th1 bias. HSP60-treated DC induced proliferation of allogeneic T cells. Again, a Th1 bias was noted in that cocultures of allogeneic T cells and HSP60-treated DC released IFN-γ but only small amounts of IL-10 and no detectable IL-4. Signaling via Toll-like receptor 4 was involved in HSP60-induced cytokine release and maturation because DC of C3H/HeJ mice with a mutant Toll-like receptor 4 showed deficient response to HSP60. HSP60 was found to rapidly activate the mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase as well as IκB in DC. Phosphorylation of these signaling molecules was also mediated by LPS, but with much slower kinetics. Thus, HSP60 stimulates DC more rapidly than LPS and elicits a Th1-promoting phenotype. These results suggest that DC play a pivotal role in priming for destructive Th1-type responses at sites of local HSP60 release.
CD7 Is a Differentiation Marker That Identifies Multiple CD8 T Cell Effector Subsets
Authors: Aandahl Einar M. , Sandberg Johan K. , Beckerman Karen P. , Taskén Kjetil , Moretto Walter J. , Nixon Douglas F. 
Published: April 2014

AbstractThe adaptive immune response of human CD8 T cells to invading pathogens involves the differentiation of naive cells into memory and effector cells. However, the lineage relationship between memory and effector cells and the differentiation of CD8 T cells into distinct subsets of effector cell subpopulations are subjects of considerable debate. CD7 identifies three populations of CD8 T cells: CD7 high (CD7high), low (CD7low), and negative (CD7neg) that translate into subsets with distinct functional properties. The CD7high subset contains naive and memory cells and the CD7low and CD7neg subsets contain effector cells. The effector cells can functionally be divided into cytokine-secreting effector CD8 T cells and lytic effector CD8 T cells. These data provide a model of human CD8 T cell differentiation in which specialized distinct subpopulations can be identified by expression of CD7.
Human Invariant Vα24-JαQ TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1− T Cells in Transgenic Mice
Authors: Capone Myriam , Cantarella Daniela , Schümann Jens , Naidenko Olga V. , Garavaglia Claudio , Beermann Friederich , Kronenberg Mitchell , Dellabona Paolo , MacDonald H. Robson , Casorati Giulia 
Published: April 2014

Abstract
A sizable fraction of T cells expressing the NK cell marker NK1.1 (NKT cells) bear a very conserved TCR, characterized by homologous invariant (inv.) TCR Vα24-JαQ and Vα14-Jα18 rearrangements in humans and mice, respectively, and are thus defined as inv. NKT cells. Because human inv. NKT cells recognize mouse CD1d in vitro, we wondered whether a human inv. Vα24 TCR could be selected in vivo by mouse ligands presented by CD1d, thereby supporting the development of inv. NKT cells in mice. Therefore, we generated transgenic (Tg) mice expressing the human inv. Vα24-JαQ TCR chain in all T cells. The expression of the human inv. Vα24 TCR in TCR Cα−/− mice indeed rescues the development of inv. NKT cells, which home preferentially to the liver and respond to the CD1d-restricted ligand α-galactosylceramide (α-GalCer). However, unlike inv. NKT cells from non-Tg mice, the majority of NKT cells in Vα24 Tg mice display a double-negative phenotype, as well as a significant increase in TCR Vβ7 and a corresponding decrease in TCR Vβ8.2 use. Despite the forced expression of the human CD1d-restricted TCR in Cα−/− mice, staining with mCD1d-α-GalCer tetramers reveals that the absolute numbers of peripheral CD1d-dependent T lymphocytes increase at most by 2-fold. This increase is accounted for mainly by an increased fraction of NK1.1− T cells that bind CD1d-α-GalCer tetramers. These findings indicate that human inv. Vα24 TCR supports the development of CD1d-dependent lymphocytes in mice, and argue for a tight homeostatic control on the total number of inv. NKT cells. Thus, human inv. Vα24 TCR-expressing mice are a valuable model to study different aspects of the inv. NKT cell subset.
Distinct Thresholds for CD8 T Cell Activation Lead to Functional Heterogeneity: CD8 T Cell Priming Can Occur Independently of Cell Division
Authors: Auphan-Anezin Nathalie , Verdeil Grégory , Schmitt-Verhulst Anne-Marie 
Published: April 2014

Abstract
To examine the bases for CD8 T cell functional heterogeneity, we analyzed responses to partial vs full agonist Ag. An extended period of interaction with APCs was required to set the threshold required for cell division in response to partial as compared with full agonist Ag. Acquisition of cytolytic function was restricted to the divided T cell population. In contrast, the threshold for commitment to produce IFN-γ and express some activation markers appeared lower and independent of cell division. Indeed, we characterized a T cell population stimulated in response to the partial agonist that was committed to produce IFN-γ, but failed to divide or secrete IL-2. Importantly, this activated nondivided population behaved as “primed” rather than “anergized,” indicating 1) that priming of CD8 T cells may be induced by suboptimal stimulation independent of cell division and 2) that encounter with Ag does not always induce a complete differentiation program in naive CD8 T cells, as previously reported.
HIV Envelope Induces Virus Expression from Resting CD4+ T Cells Isolated from HIV-Infected Individuals in the Absence of Markers of Cellular Activation or Apoptosis
Authors: Kinter Audrey L. , Umscheid Craig A. , Arthos James , Cicala Claudia , Lin Yin , Jackson Robert , Donoghue Eileen , Ehler Linda , Adelsberger Joseph , Rabin Ronald L. , Fauci Anthony S. 
Published: April 2014

Abstract
Resting CD4+ T cells containing integrated HIV provirus constitute one of the long-lived cellular reservoirs of HIV in vivo. This cellular reservoir of HIV had been thought to be quiescent with regard to virus replication based on the premise that HIV production in T cells is inexorably linked to cellular activation as determined by classical activation markers. The transition of T cells within this HIV reservoir from a resting state to an activated HIV-producing state is believed to be associated with a shorten life span due to susceptibility to activation-associated apoptosis. Evidence is mounting, however, that HIV production may occur in T cells that have not undergone classic T cell activation. HIV encodes several proteins, including envelope and Nef, which trigger a variety of signaling pathways associated with cellular activation, thereby facilitating HIV replication in nondividing cells. The present study demonstrates that production of infectious virus from resting CD4+ T cells isolated from HIV-infected individuals can be induced following exposure of these cells to HIV-1 recombinant (oligomeric gp140) envelope protein. Envelope-mediated induction of HIV expression occurs in the presence of reverse transcriptase inhibitors and is not associated with markers of classic T cell activation, proliferation, or apoptosis. The ability of HIV envelope to induce virus replication in HIV-infected resting CD4+ T cells without triggering apoptosis provides a mechanism for the virus itself to directly participate in the maintenance of HIV production from this cellular reservoir.
Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques
Authors: De Boer Rob J. , Mohri Hiroshi , Ho David D. , Perelson Alan S. 
Published: April 2014

Abstract
We determined average cellular turnover rates by fitting mathematical models to 5-bromo-2′-deoxyuridine measurements in SIV-infected and uninfected rhesus macaques. The daily turnover rates of CD4+ T cells, CD4− T cells, CD20+ B cells, and CD16+ NK cells in normal uninfected rhesus macaques were 1, 1, 2, and 2%, respectively. Daily turnover rates of CD45RA− memory T cells were 1%, and those of CD45RA+ naive T cells were 0.5% for CD4+ T cells and ∼1% for CD4−CD45RA+ T cells. In SIV-infected monkeys with high viral loads, the turnover rates of T cells were increased ∼2-fold, and that of memory T cells ∼3-fold. The turnover of CD4+CD45RA+ naive T cells was increased 2-fold, whereas that of CD4−CD45RA+ naive T cells was marginally increased. B cells and NK cells also had increased turnover in SIV-infected macaques, averaging 3 and 2.5% per day, respectively. For all cell types studied here the daily turnover rate increased with the decrease of the CD4 count that accompanied SIV infection. As a consequence, the turnover rates of CD4+ T cells, CD4− T cells, B cells, and NK cells within each monkey are strongly correlated. This suggests that the cellular turnover of different lymphocyte populations is governed by a similar process which one could summarize as “generalized immune activation.” Because the viral load and the CD4 T cell count are negatively correlated we cannot determine which of the two plays the most important role in this generalized immune activation.
Long-Term Maintenance of gp120-Specific Immune Responses by Genetic Vaccination with the HIV-1 Envelope Genes Linked to the Gene Encoding Flt-3 Ligand
Authors: Sailaja Gangadhara , Husain Sajid , Nayak Bishnu P. , Jabbar Abdul M. 
Published: April 2014

Abstract
DNA vaccines target dendritic cells (DC) to induce Ag-specific immune responses in animals. Potent HIV-specific immunity could be achieved by efficient priming of the immune system by DNA vaccines. We investigated a novel DNA vaccine approach based on the role of growth factors in DC expansion and differentiation. To this end, we constructed chimeric genes encoding the HIV envelope glycoproteins physically linked to the extracellular domain of Fms-like tyrosine kinase receptor-3 ligand (FLex; a DC growth factor; both mouse (m)FLex and human (h)FLex). These chimeric gene constructs synthesized biologically active, oligomeric FLex:gp120 fusion proteins and induced DC expansion (CD11c+CD11b+) when injected i.v. into mice. This DC expansion is comparable to that achieved by FLex DNA encoding native FLex protein. When delivered intramuscularly as DNA vaccines, hFLex:gp120 induced high frequencies of gp120-specific CD8+ T cells in the presence or absence of FLex DNA-induced DC expansion, but gp120 and mFLex:gp120 elicited only low to moderate levels of Ag-specific CD8+ T cells. In contrast, mFLex:gp120 induced high levels of anti-gp120 Abs under identical conditions of DNA vaccination. However, the Ab levels in mice immunized with DNA vaccines encoding hFLex:gp120 and gp120 proteins were low without DC expansion, but reached high levels comparable to that elicited by mFLex:gp120 only after the second boost in the presence of DC expansion. Importantly, the gp120-specific CD8+ T cells persisted at high frequency for 114 days (16 wk) after a booster injection. These experiments provide insight into the importance of modulating DC function in vivo for effective genetic vaccination in animals.
Regulatory CD8+ T Cells Control Neonatal Tolerance to a Th2-Mediated Autoimmunity
Authors: Field Anne-Christine , Caccavelli Laure , Bloch Marie-Françoise , Bellon Blanche 
Published: April 2014

Abstract
Exposure of newborn animals to a foreign Ag may result in immunological tolerance to that specific Ag, a phenomenon called neonatal tolerance. We have previously reported that neonatal administration to Brown-Norway rats of mercury, a heavy metal toxicant, induces a dominant tolerance, specific for the chemical otherwise responsible for Th2 cell-mediated autoimmune responses in this susceptible strain of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or delete responses, and sustain regulatory functions effective against autoreactive T cells. Here, we address whether such a tolerant response is due to the generation of regulatory cells. The results suggest that the CD8+ T cell subset is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance following mercury recall in animals under a neonatal tolerance protocol. Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as well as transfer of CD8+ T cells from tolerant animals prevent naive syngeneic rats from developing pathologic Th2 immune responses. These observations indicate that CD8+ T cells are endowed with regulatory functions in neonatal tolerance and mediate active suppression. Moreover, neonatal tolerance induced the expansion of CD8+CD45RChigh T cells and the emergence of a high percentage of IFN-γ-synthesizing CD8+ T cells, which probably reflects the implication of regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses Th2 autoimmune responses via generation of a CD8+ cell-mediated regulatory response.
Selective Induction of High Avidity CTL by Altering the Balance of Signals from APC
Authors: Oh SangKon , Hodge James W. , Ahlers Jeffrey D. , Burke Donald S. , Schlom Jeffrey , Berzofsky Jay A. 
Published: April 2014

Abstract
High avidity CTL are most effective at clearing viruses and cancer cells. Therefore, understanding the mechanisms involved in induction of high avidity CTL is critical for effective vaccines. However, no vaccine approach to selectively induce high avidity CTL in vivo has been discovered. In a new approach, signals from MHC class I (signal 1) and costimulatory molecules (signal 2) were adjusted by varying Ag dose and by use of recombinant poxvirus expressing a triad of costimulatory molecules (B7-1, ICAM-1, and LFA-3), respectively. Independent of CTL avidity, a strong signal 1 resulted in an increased frequency of CD8+ CTL. However, a strong signal 2 was necessary for the induction of high avidity CD8+ CTL that killed target cells more efficiently, and signal 2 played a more crucial role in the absence of a strong signal 1. Only CTL induced with strong signal 2 killed tumor cells endogenously expressing low levels of Ag. Signal 2 contributed to the induction of high avidity CD8+ CTL in both primary and secondary responses. Thus, although signal 2 has been known to increase the quantity of CTL response, in this study we show that it also improves the quality of CTL response. Our data also suggested that dendritic cells play an important role in induction of high avidity CD8+ CTL in vivo. This strategy to selectively induce higher avidity CTL may lead to more effective vaccines for viruses and cancer.
NKT Cells Provide Help for Dendritic Cell-Dependent Priming of MHC Class I-Restricted CD8+ T Cells In Vivo
Authors: Stober Detlef , Jomantaitė Ieva , Schirmbeck Reinhold , Reimann Jörg 
Published: April 2014

AbstractDendritic cells (DC) are potent APCs for naive T cells in vivo. This is evident by inducing T cell responses through adoptive DC transfer. Priming specific CTL responses in vivo often requires “help”. We study alternative sources of help in DC-dependent priming of MHC class I-restricted CTL. Priming an anti-viral CTL response in naive B6 mice by adoptive transfer of antigenic peptide-pulsed DC required CD4+ T cell help. CTL priming was facilitated by providing MHC class II-dependent specific help. Furthermore, transfers of MHC class II-deficient pulsed DC into naive, normal hosts, or DC transfers into naive, CD4+ T cell-depleted hosts primed CTL inefficiently. Pretreatment of DC with immune-stimulating oligodeoxynucleotides rendered them more efficient for CD4+ T cell-independent priming of CTL. DC copresenting a Kb-binding antigenic peptide and the CD1d-binding glycolipid α-galactosyl-ceramide efficiently primed CTL in a class II-independent way. To obtain NKT cell-dependent help in CTL priming, the same DC had to present both the peptide and the glycolipid. CTL priming by adoptive DC transfer was largely NK cell-dependent. The requirement for NK cells was only partially overcome by recruiting NKT cell help into DC-dependent CTL priming. NKT cells thus are potent helper cells for DC-dependent CTL priming.
Prime Boost Vaccination Strategies: CD8 T Cell Numbers, Protection, and Th1 Bias
Authors: Woodberry Tonia , Gardner Joy , Elliott Suzanne L. , Leyrer Sonja , Purdie David M. , Chaplin Paul , Suhrbier Andreas 
Published: April 2014

Abstract
Vaccination strategies involving priming with DNA and boosting with a poxvirus vector have emerged as a preferred combination for the induction of protective CD8 T cell immunity. Using IFN-γ ELISPOT and a series of DNA plasmid, peptide, and modified vaccinia Ankara (MVA) vaccine combinations, we demonstrate that the DNA/MVA combination was uniquely able to enhance IFN-γ secretion by Ag-specific CD8 T cells. However, CD8 T cell populations induced by DNA/MVA vaccination failed to show an enhanced capability to mediate protection in an IFN-γ-independent influenza challenge model. The DNA/MVA vaccine strategy was also not unique in its ability to induce high numbers of CD8 T cells, with optimal strategies simply requiring the use of vaccine modalities that individually induce high numbers of CD8 T cells. These experiments argue that rivals to DNA/poxvirus vaccination strategies for the induction of optimal protective CD8 T cell responses are likely to emerge.
Severe Impairment in Early Host Defense Against Listeria monocytogenes in Mice Deficient in Acid Sphingomyelinase
Authors: Utermöhlen Olaf , Karow Ulrike , Löhler Jürgen , Krönke Martin 
Published: April 2014

Abstract
The phagolysosomal compartment is crucial for the defense against infection with intracellular pathogens. Within this compartment, the TNF- and IFN-γ-responsive acid sphingomyelinase (ASMase) generates the signaling molecule ceramide, resulting in the activation of proteases like cathepsin D. To investigate the possible role of ASMase as a mediator of the antibacterial effects of TNF and IFN-γ, ASMase−/− mice were infected with Listeria monocytogenes. ASMase−/− mice showed a dramatically increased susceptibility to L. monocytogenes (LD50 ∼100 CFU) when compared with syngeneic wild-type mice (LD50 ∼10,000 CFU). In L. monocytogenes-challenged ASMase−/− mice, IFN-γ serum levels as well as IL-1β and IL-6 secretion by macrophages were similar to those observed in wild-type C57BL/6 mice. Although macrophages and granulocytes from ASMase−/− mice showed intact production of reactive nitrogen intermediates and oxidative burst, ASMase−/− macrophages proved completely incapable of restricting the growth of L. monocytogenes in vitro. The results of this study suggest that ASMase is crucially required for the intracellular control of L. monocytogenes in macrophages and granulocytes by nonoxidative mechanisms.
Synthesis and Secretion of Monocyte Chemotactic Protein-1 Stimulated by the High Affinity Receptor for IgE
Authors: Eglite Santa , Morin Juan M. , Metzger Henry 
Published: April 2014

Abstract
In prior studies aggregation of the high affinity receptors for IgE, FcεRI, on a rat mast cell line, RBL-2H3, stimulated transcription of the gene for monocyte chemotactic protein-1 (MCP-1) and secretion of the protein. Unexpectedly, those delayed events appeared much less constrained by kinetic proofreading than had been documented for other receptor-initiated responses. The results of the present experiments are consistent with the proposal that the biosynthesis and secretion of MCP-1 result from a soluble messenger formed in the reaction cascades initiated by the receptor, and that Ca2+ could serve as that messenger. Interestingly, whereas receptor-mediated signals were required for transcription of the gene for MCP-1 and secretion of the chemokine, such signals were not required for the intervening step of translation of its mRNA.