bluuebunny/crossref_metadata_2025_split huggingface dataset:
T and B Cell Recovery in Arthritis Adoptively Transferred to SCID Mice: Antigen-Specific Activation Is Required for Restoration of Autopathogenic CD4+ Th1 Cells in a Syngeneic System
Authors: Bárdos Tamás , Mikecz Katalin , Finnegan Alison , Zhang Jian , Glant Tibor T. 
Published: April 2014

AbstractT cell homeostasis is a physiological function of the immune system that maintains a balance in the numbers and ratios of T cells at the periphery. A self-MHC/self-peptide ligand can induce weak (covert) signals via the TCR, thus providing an extended lifespan for naive T cells. A similar mechanism is responsible for the restoration of immune homeostasis in severe lymphopenic conditions such as those following irradiation or chemotherapy, or upon transfer of lymphocytes to nu/nu or SCID mice. To date, the genetic backgrounds of donor and recipient SCID mice were unmatched in all autoimmune arthritis transfer experiments, and the recovery of lymphoid cells in the host has not been followed. In this study, we present the adoptive transfer of proteoglycan (PG)-induced arthritis using unseparated and T or B cell-depleted lymphocytes from arthritic BALB/c donors to genetically matched syngeneic SCID recipient mice. We demonstrate that selectively recovered lymphoid subsets determine the clinical and immunological status of the recipient. We found that when T cells were depleted (&gt;98% depleted), B cells did not produce PG-specific anti-mouse (auto) Abs unless SCID mice received a second Ag (PG) injection, which promoted the recovery of Ag-specific CD4+ Th1 cells. Reciprocally, as a result of B cell recovery, high levels of serum anti-PG Abs were found in SCID mice that received B cell-depleted (&gt;99% depleted) T lymphocytes. Our results indicate a selective and highly effective cooperation between CD4+ T cells and B lymphocytes that is required for the restoration of pathological homeostasis and development of autoimmune arthritis in SCID mice.
Dynamic Regulation of T Cell Immunity by CD43
Authors: Onami Thandi M. , Harrington Laurie E. , Williams Matthew A. , Galvan Marisa , Larsen Christian P. , Pearson Thomas C. , Manjunath N. , Baum Linda G. , Pearce Brad D. , Ahmed Rafi 
Published: April 2014

AbstractDuring a viral response, Ag-specific effector T cells show dramatically increased binding by the mAb 1B11 and the lectin peanut agglutinin (PNA). We investigated the contribution of CD43 expression to 1B11 and PNA binding as well as its role in generation and maintenance of a CD8 T cell response. Analysis of CD43−/− mice revealed no increased 1B11 binding and reduced PNA binding on virus-specific CD8 T cells from −/− mice compared with +/+ mice. Furthermore, we examined the role of CD43 in the kinetics of an immune response. We show that CD43 expression modestly effects generation of a primary virus-specific CD8 T cell response in vivo but plays a more significant role in trafficking of CD8 T cells to tissues such as the brain. More interestingly, CD43 plays a role in the contraction of the immune response, with CD43−/− mice showing increased numbers of Ag-specific CD8 T cells following initial expansion. Following the peak of expansion, Ag-specific CD8 T cells from −/− mice show similar proliferation but demonstrate increased Bcl-2 levels and decreased apoptosis of Ag-specific effector CD8 T cells in vitro. Consistent with a delay in the down-modulation of the immune response, following chronic viral infection CD43−/− mice show increased morbidity. These data suggest a dynamic role of CD43 during an immune response: a positive regulatory role in costimulation and trafficking of T cells to the CNS and a negative regulatory role in the down-modulation of an immune response.
Antiviral Immune Responses in the Absence of Organized Lymphoid T Cell Zones inplt/pltMice
Authors: Junt Tobias , Nakano Hideki , Dumrese Tilman , Kakiuchi Terutaka , Odermatt Bernhard , Zinkernagel Rolf M. , Hengartner Hans , Ludewig Burkhard 
Published: April 2014

AbstractThe paucity of lymph node (LN) T cells (plt) mutation in mice results in strongly reduced T cell numbers in LNs and homing defects of both dendritic cells (DCs) and naive T cells. In this study, we investigated the functional significance of the plt phenotype for the generation of antiviral immune responses against cytopathic and noncytopathic viruses. We found that DC-CD8+ T cell contacts and the initial priming of virus-specific T cells in plt/plt mice occurred mainly in the marginal zone of the spleen and in the superficial cortex of LNs. The magnitude of the initial response and the maintenance of protective memory responses in plt/plt mice was only slightly reduced compared with plt/+ controls. Furthermore, plt/plt mice mounted rapid neutralizing antiviral B cell responses and displayed normal Ig class switch. Our data indicate that the defective homing of DCs and naive T cells resulting from the plt/plt mutation results in a small, but not significant, effect on the induction of protective antiviral T and B cell immunity. Overall, we conclude that the spatial organization of secondary lymphoid T cell zones via the CCR7-CC chemokine ligand 19/CC chemokine ligand 21 pathway is not an absolute requirement for the initial priming and the maintenance of protective antiviral T and B cell responses.
CD36 or αvβ3 and αvβ5 Integrins Are Not Essential for MHC Class I Cross-Presentation of Cell-Associated Antigen by CD8α+ Murine Dendritic Cells
Authors: Schulz Oliver , Pennington Daniel J. , Hodivala-Dilke Kairbaan , Febbraio Maria , Reis e Sousa Caetano 
Published: April 2014

AbstractCross-presentation of cell-associated Ag is thought to involve receptor-mediated uptake of apoptotic cells by dendritic cells (DC), and studies with human DC strongly implicate the endocytic receptor CD36 and the integrins αvβ3 and/or αvβ5 in this process. In the mouse, cross-presentation was recently shown to be a function of CD8α+ DC. Here we report that CD36 is expressed on CD8α+, but not on CD8α−, DC. To address the role of CD36 in cross-presentation we compared CD36−/− and CD36+/+ H-2b DC for their ability to stimulate naive OT-1 T cells specific for OVA plus H-2Kb in the presence of OVA-loaded MHC-mismatched splenocytes as a source of cell-associated Ag for cross-presentation. Surprisingly, no difference was seen between CD36−/− and CD36+/+ CD8α+ DC in their ability to cross-present cell-associated OVA or to capture OVA-bearing cells. Furthermore, the proliferation of CFSE-labeled OT-1 cells in response to OVA cross-presentation in vivo was normal in CD36−/− bone marrow chimeras, also arguing against a necessary role for CD36 in cross-presentation by DC or other APC. DC doubly deficient for β3 and β5 integrins were similarly unimpaired in their ability to cross-present OVA-bearing cells in vitro. These data demonstrate that in the mouse, receptors other than CD36 or β3 and β5 integrins can support the specialized cross-presenting function of CD8α+ DC.
Apoptosis Mediated Through CD45 Is Independent of Its Phosphatase Activity and Association with Leukocyte Phosphatase-Associated Phosphoprotein
Authors: Fortin Marylène , Steff Ann-Muriel , Felberg Jackie , Ding Isabelle , Schraven Burkhart , Johnson Pauline , Hugo Patrice 
Published: April 2014

AbstractBesides the well-recognized role of CD45 as a major player in TCR signaling, we and others have demonstrated that cross-linking of CD45 with mAbs can induce cell death in T lymphocytes. To investigate the role of CD45 phosphatase activity in apoptosis induction, we expressed either wild-type or phosphatase-dead CD45 molecules in a CD45-deficient BW5147 T cell line. We show here that the phosphatase activity of CD45 was not required for apoptosis triggering after cross-linking of the molecule. It is noteworthy that a revertant of the CD45-negative BW5147 cell line, expressing a truncated form of CD45 lacking most of the cytoplasmic domain, was also susceptible to CD45-mediated death. Moreover, we also demonstrate that leukocyte phosphatase-associated phosphoprotein expression is totally dispensable for CD45-mediated apoptosis to occur. Taken together, these results strongly suggest a role for the extracellular and/or the transmembrane portion of CD45 in apoptosis signaling, which contrasts with the previously reported functions for CD45 in T lymphocytes.
IL-2 and IL-12 Alter NK Cell Responsiveness to IFN-γ-Inducible Protein 10 by Down-Regulating CXCR3 Expression
Authors: Hodge Deborah L. , Schill William B. , Wang Ji Ming , Blanca Isaac , Reynolds Della A. , Ortaldo John R. , Young Howard A. 
Published: April 2014

AbstractCytokine treatment of NK cells results in alterations in multiple cellular responses that include cytotoxicity, cytokine production, proliferation, and chemotaxis. To understand the molecular mechanisms underlying these responses, microarray analysis was performed and the resulting gene expression patterns were compared between unstimulated, IL-2, IL-2 plus IL-12, and IL-2 plus IL-18-stimulated NK92 cells. RNase protection assays and RT-PCR confirmed microarray predictions for changes in mRNA expression for nine genes involved in cell cycle progression, signal transduction, transcriptional activation, and chemotaxis. Multiprobe RNase protection assay also detected changes in the expression of CCR2 mRNA, a gene that was not imprinted on the microarray. We subsequently expanded our search for other chemokine receptor genes absent from the microarray and found an IL-2- and IL-12-dependent decrease in CXCR3 receptor mRNA expression in NK92 cells. A detailed analysis of CXCR3 expression in primary NK cells revealed that an IL-2 and an IL-12 together significantly decreased the CXCR3 receptor mRNA and receptor surface expression by 6 and 24 h of treatment, respectively. This decrease in receptor expression was associated with a significant reduction in chemotaxis in the presence of IFN-γ-inducible protein-10. The decline in CXCR3 mRNA was due to transcriptional and posttranscriptional mechanisms as the addition of actinomycin D to IL-2- and IL-12-treated NK92 slightly altered the half-life of the CXCR3 mRNA. Collectively, these data suggest that IL-2 and IL-12 directly affect NK cell migratory ability by rapid and direct down-regulation of chemokine receptor mRNA expression.
CD4-Lck Through TCR and in the Absence of Vav Exchange Factor Induces Bax Increase and Mitochondrial Damage
Authors: Tuosto Loretta , Marinari Barbara , Piccolella Enza 
Published: April 2014

AbstractIn the present study, we aimed to demonstrate that CD4 may represent a critical turning point that governs the apoptotic and survival programs in T cells, without modifying the physical association with the TCR-CD3 complex. To address this issue, we have explored the possibility that the activation of CD4 may transduce apoptotic signals unless signaling effectors neutralize them. Our data show that in Jurkat T cells CD4 engagement by Leu3a mAb results in a rapid and strong increase of Lck kinase activity, subsequent alterations of mitochondrial membrane potential, and apoptosis. Critical parameters are coassociation of CD4/Lck with TCR/CD3 and up-regulation of the proapoptotic protein Bax. Indeed, Leu3a-mediated Lck activation failed to induce apoptotic features in Jurkat cells either defective for TCR/CD3 or overexpressing the antiapoptotic protein Bcl-2. Furthermore, we demonstrate that Leu3a treatment of Jurkat cells overexpressing Vav results in the inhibition of mitochondrial damage and apoptosis; this rescue effect is accompanied with a significant decrease of Bax expression observed in apoptotic cells. Our evidence that the activation of Lck activates in T cells apoptotic pathways which are counteracted by Vav, a signaling molecule that cooperates with CD28 to boost TCR signals, suggests a novel role for costimulation in protecting T cells from CD4-mediated cell death.
Early Antigen-Specific Response by Naive CD8 T Cells Is Not Altered with Aging
Authors: Li Shaokang P. , Cai Zeling , Shi Weixing , Brunmark Anders , Jackson Michael , Linton Phyllis-Jean 
Published: April 2014

AbstractBoth a dramatic decline in CD8 responses and a switch to memory T cell predominance occur with aging. The extent to which the loss of responsiveness is the consequence of the accumulation of more differentiated vs intrinsically defective T cells (or both) has been unclear. Using similar conditions of Ag stimulation, we have examined the responses generated by CD8+ cells isolated from aged TCR transgenic mice. We found that the naive transgene+ CD8+ cells from aged 2C mice expressed activation markers, produced IL-2, proliferated, and differentiated into cytotoxic T cells as efficiently as their young counterparts. The extent of responsiveness and the level of the responses were comparable in both age groups regardless of the stimulatory conditions used, i.e., partial costimulation/adhesion molecule expression on APCs, or presentation of lower affinity peptide or diminished peptide concentrations. By day 4 after Ag stimulation, no significant age-related differences were observed in the number of effector cells generated nor in the levels of secreted IL-2 or IFN-γ. Upon restimulation of effector cells, IL-2 secretion and to a lesser extent TNF-α expression, but not IFN-γ secretion, were diminished with age. These findings suggest that age-associated alterations in naive CD8 cell function are not found after primary stimulation, but may become apparent upon restimulation.
Lipopolysaccharide- and Lipoteichoic Acid-Induced Tolerance and Cross-Tolerance: Distinct Alterations in IL-1 Receptor-Associated Kinase
Authors: Jacinto Randy , Hartung Thomas , McCall Charles , Li Liwu 
Published: April 2014

Abstract
Human Toll-like receptor (TLR) 4 and TLR2 receptors recognize LPS or lipoteichoic acid (LTA), respectively. Prolonged exposure of human macrophages/monocytes to bacterial LPS induces a state of adaptation/tolerance to subsequent LPS challenge. Inflammatory gene expressions such as IL-1β and TNF-α are selectively repressed, while certain anti-inflammatory genes such as secretory IL-1R antagonist are still induced in LPS-adapted/tolerant cells. In this report, we demonstrate that LPS-tolerized human promonocytic THP-1 cells develop cross-tolerance and no longer respond to LTA-induced IL-1β/TNF-α production, indicating that disruption of common intracellular signaling is responsible for the decreased IL-1β/TNF-α production. We observe that down-regulation of IL-1R-associated kinase (IRAK) protein level and kinase activity closely correlates with the development of cross-tolerance. IRAK protein levels and kinase activities in LPS-tolerized cells remain low and hyporesponsive to subsequent LPS or LTA challenges. We also demonstrate that THP-1 cells with prolonged LTA treatment develop LTA tolerance and do not express IL-1β/TNF-α upon further LTA challenge. Strikingly, cells tolerized with LTA are only refractory to subsequent LTA challenge and can still respond to LPS stimulation. Correspondingly, stimulation of TLR2 by LTA, although activating IRAK, does not cause IRAK degradation. IRAK from LTA-tolerized cells can be subsequently activated and degraded by further LPS challenge, but not LTA treatment. Our studies reveal that LTA-induced tolerance is distinct compared with that of LPS tolerance, and is likely due to disruption of unique TLR2 signaling components upstream of MyD88/IRAK.
Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression
Authors: Smeltz Ronald B. , Chen June , Ehrhardt Rolf , Shevach Ethan M. 
Published: April 2014

AbstractTwo key events occur during the differentiation of IFN-γ-secreting Th1 cells: up-regulation of IL-12Rβ2 and IL-12-driven up-regulation of IL-18Rα. We previously demonstrated that IL-12-driven up-regulation of IL-18Rα expression is severely impaired in IFN-γ−/− mice. However, it was unclear from these studies how IFN-γ influenced IL-18Rα since IFN-γ alone had no direct effect on IL-18Rα expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Rα/IL-12Rβ2 was independent of IFN-γ. However, in the presence of IL-4, IFN-γ functions to limit the negative effects of IL-4 on both IL-18Rα and IL-12Rβ2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18Rα/IL-12Rβ2 in an IFN-γ-independent fashion. In the absence of both IL-12 and IL-4, IFN-γ up-regulates IL-12β2 expression and primes IFN-γ-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Rα or the IL-12Rβ2 and the capacity of these cells to produce IFN-γ, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-γ in regulation of IL-18Rα/IL-12Rβ2 during both IL-12-dependent and IL-12-independent Th1 differentiation.
Dual Functions of Fractalkine/CX3C Ligand 1 in Trafficking of Perforin+/Granzyme B+ Cytotoxic Effector Lymphocytes That Are Defined by CX3CR1 Expression
Authors: Nishimura Miyuki , Umehara Hisanori , Nakayama Takashi , Yoneda Osamu , Hieshima Kunio , Kakizaki Mayumi , Dohmae Naochika , Yoshie Osamu , Imai Toshio 
Published: April 2014

AbstractFractalkine/CX3C ligand 1 and its receptor CX3CR1 are known to mediate both cell adhesion and cell migration. Here we show that CX3CR1 defines peripheral blood cytotoxic effector lymphocytes commonly armed with intracellular perforin and granzyme B, which include NK cells, γδ T cells, and terminally differentiated CD8+ T cells. In addition, soluble fractalkine preferentially induced migration of cytotoxic effector lymphocytes. Furthermore, interaction of cytotoxic effector lymphocytes with membrane-bound fractalkine promoted subsequent migration to the secondary chemokines, such as macrophage inflammatory protein-1β/CC ligand 4 or IL-8/CXC ligand 8. Thus, fractalkine expressed on inflamed endothelium may function as a vascular regulator for cytotoxic effector lymphocytes, regardless of their lineage and mode of target cell recognition, through its ability to capture them from blood flow and to promote their emigration in response to other chemokines.
A Decaepitope Polypeptide Primes for Multiple CD8+ IFN-γ and Th Lymphocyte Responses: Evaluation of Multiepitope Polypeptides as a Mode for Vaccine Delivery
Authors: Alexander Jeff , Oseroff Carla , Dahlberg Carol , Qin Mingsheng , Ishioka Glenn , Beebe Melanie , Fikes John , Newman Mark , Chesnut Robert W. , Morton Phillip A. , Fok Kam , Appella Ettore , Sette Alessandro 
Published: April 2014

AbstractProteins are generally regarded as ineffective immunogens for CTL responses. We synthesized a 100-mer decaepitope polypeptide and tested its capacity to induce multiple CD8+ IFN-γ and Th lymphocyte (HTL) responses in HLA transgenic mice. Following a single immunization in the absence of adjuvant, significant IFN-γ in vitro recall responses were detected for all epitopes included in the construct (six A2.1-, three A11-restricted CTL epitopes, and one universal HTL epitope). Immunization with truncated forms of the decaepitope polypeptide was used to demonstrate that optimal immunogenicity was associated with a size of at least 30–40 residues (3–4 epitopes). Solubility analyses of the truncated constructs were used to identify a correlation between immunogenicity for IFN-γ responses and the propensity of these constructs to form particulate aggregates. Although the decaepitope polypeptide and a pool of epitopes emulsified in IFA elicited similar levels of CD8+ responses using fresh splenocytes, we found that the decaepitope polypeptide more effectively primed for in vitro recall CD8+ T cell responses. Finally, immunogenicity comparisons were also made between the decaepitope polypeptide and a corresponding gene encoding the same polypeptide delivered by naked DNA immunization. Although naked DNA immunization induced somewhat greater direct ex vivo and in vitro recall responses 2 wk after a single immunization, only the polypeptide induced significant in vitro recall responses 6 wk following the priming immunization. These studies support further evaluation of multiepitope polypeptide vaccines for induction of CD8+ IFN-γ and HTL responses.
A Novel Role for IL-3: Human Monocytes Cultured in the Presence of IL-3 and IL-4 Differentiate into Dendritic Cells That Produce Less IL-12 and Shift Th Cell Responses Toward a Th2 Cytokine Pattern
Authors: Ebner Susanne , Hofer Susanne , Nguyen Van Anh , Fürhapter Christina , Herold Manfred , Fritsch Peter , Heufler Christine , Romani Nikolaus 
Published: April 2014

AbstractDendritic cells (DC) derived from plasmacytoid precursors depend on IL-3 for survival and proliferation in culture, and they induce preferentially Th2 responses. Monocytes express not only GM-CSF receptors, but also IL-3Rs. Therefore, we examined whether IL-3 had an effect on the functional plasticity of human monocyte-derived DC generated in a cell culture system that is widely used in immunotherapy. DC were generated with IL-3 (instead of GM-CSF) and IL-4. Yields, maturation, phenotype (surface markers and Toll-like receptors), morphology, and immunostimulatory capacity were similar. Only CD1a was differentially expressed, being absent on IL-3-treated DC. In response to CD40 ligation DC generated in the presence of IL-3 secreted significantly less IL-12 p70 and more IL-10 compared with DC grown with GM-CSF. Coculture of naive allogeneic CD4+ T cells with DC generated in the presence of IL-3 induced T cells to produce significantly more IL-5 and IL-4 and less IFN-γ compared with stimulation with DC generated with GM-CSF. These data extend the evidence that different cytokine environments during differentiation of monocyte-derived DC can modify their Th cell-inducing properties. A hitherto unrecognized effect of IL-3 on DC was defined, namely suppression of IL-12 secretion and a resulting shift from Th1 toward Th2.
KIR2DL4 (CD158d), an NK Cell-Activating Receptor with Inhibitory Potential
Authors: Faure Mathias , Long Eric O. 
Published: April 2014

AbstractKIR2DL4 (CD158d) is an unusual member of the killer cell Ig-like receptor family expressed in all NK cells and some T cells. KIR2DL4 activates the cytotoxicity of NK cells, despite the presence of an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic tail. The role of this ITIM on the activating function of KIR2DL4, and whether it can provide inhibitory signals, is not known. Mutated forms of KIR2DL4 were engineered that lacked either the tyrosine in the ITIM or an arginine-tyrosine motif in the transmembrane region that is required for the activation signal. The activity of the mutated KIR2DL4 molecules was tested in a redirected lysis assay. The ITIM was not necessary for activation of lysis by KIR2DL4. The activation signal of KIR2DL4 was sensitive to inhibition by another ITIM-containing receptor. The activation-deficient mutant of KIR2DL4 inhibited the signal delivered by the activating receptor CD16. In pull-down experiments with GST fusion proteins, the tyrosine-phosphorylated cytoplasmic tail of KIR2DL4 bound the Src homology 2-containing phosphatases 1 and 2, as did the tail of the inhibitory receptor KIR2DL1. Therefore, KIR2DL4 has inhibitory potential in addition to its activating function.