bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-Specific Responses in Lymph Nodes Draining Murine Sarcomas Are Concentrated in Cells Expressing P-Selectin Binding Sites
Authors: Tanigawa Keishi , Takeshita Nobuhiro , Craig Ronald A. , Phillips Katie , Knibbs Randall N. , Chang Alfred E. , Stoolman Lloyd M. 
Published: April 2014

AbstractTumor-draining lymph node (TDLN) cells develop substantial antitumor activity after activation on immobilized αCD3 and culture in low-dose IL-2. This study found that the minor subset of TDLN T cells expressing binding sites for the adhesion receptor P-selectin (Plighigh T cells) produced T lymphoblasts with the most tumor-specific IFN-γ synthesis in vitro and antitumor activity following adoptive transfer in vivo. The Plighigh T cells constituted &lt;25% of the cells with the phenotype of recently activated cells including high levels of CD69, CD44, or CD25, and low levels of CD62L. The cultured Plighigh TDLN were 10- to 20-fold more active against established pulmonary micrometastases than cultured unfractionated TDLN, and &gt;30-fold more active than cultured TDLN cells depleted of the Plighigh fraction before expansion (Pliglow cells). Tumor-specific IFN-γ synthesis in vitro paralleled the antitumor activities of the cultured fractions in vivo, implying that increased Tc1 and Th1 effector functions contributed to the tumor suppression. Neither nonspecific interaction with the P-selectin chimera used for sorting nor endogenous costimulatory activity in the Plighigh fraction accounted for the marked increase in antitumor activities after culture. The cultured Plighigh fraction contained a variety of potential effector cells; however, the CD8 and CD4 subsets of αβ T cells accounted for 95–97% of its antitumor activity. The authors propose that P-selectin sorting increased antitumor activities by concentrating Tc1 and Th1 pre-effector/effector cells before culture.
Human Endothelial-Cell Specific Molecule-1 Binds Directly to the Integrin CD11a/CD18 (LFA-1) and Blocks Binding to Intercellular Adhesion Molecule-1
Authors: Béchard David , Scherpereel Arnaud , Hammad Hamida , Gentina Thibaut , Tsicopoulos Anne , Aumercier Marc , Pestel Jöel , Dessaint Jean-Paul , Tonnel André-Bernard , Lassalle Philippe 
Published: April 2014

AbstractICAMs are ligands for LFA-1, a major integrin of mononuclear cells involved in the immune and inflammatory processes. We previously showed that endothelial cell specific molecule-1 (ESM-1) is a proteoglycan secreted by endothelial cells under the control of inflammatory cytokines. Here, we demonstrate that ESM-1 binds directly to LFA-1 onto the cell surface of human blood lymphocytes, monocytes, and Jurkat cells. The binding of ESM-1 was equally dependent on Ca2+, Mg2+, or Mn2+ divalent ions, which are specific, saturable, and sensitive to temperature. An anti-CD11a mAb or PMA induced a transient increase in binding, peaking 5 min after activation. Direct binding of ESM-1 to LFA-1 integrin was demonstrated by specific coimmunoprecipitation by CD11a and CD18 mAbs. A cell-free system using a Biacore biosensor confirmed that ESM-1 and LFA-1 dynamically interacted in real time with high affinity (Kd = 18.7 nM). ESM-1 consistently inhibited the specific binding of soluble ICAM-1 to Jurkat cells in a dose-dependent manner. These results suggest that ESM-1 and ICAM-1 interact with LFA-1 on binding sites very close to but distinct from the I domain of CD11a. Through this mechanism, ESM-1 could be implicated in the regulation of the LFA-1/ICAM-1 pathway and may therefore influence both the recruitment of circulating lymphocytes to inflammatory sites and LFA-1-dependent leukocyte adhesion and activation.
Differentiation of Regulatory T Cells 1 Is Induced by CD2 Costimulation
Authors: Wakkach Abdelilah , Cottrez Françoise , Groux Hervé 
Published: April 2014

AbstractInduction and maintenance of peripheral tolerance is an important phenomenon for the control of homeostasis in the immune system. There is now compelling evidence for CD4+ T cells that prevent immune pathology, both in autoimmunity and in transplantation. However, the mechanisms involved in the specific differentiation of these T cells are unknown. We had previously shown that repetitive stimulations of naive T cells in the presence of IL-10 induce the differentiation of T regulatory cells 1. We further dissected the mechanism of IL-10 function and demonstrated that IL-10 acts by the down-regulation of most costimulatory molecules without modifying the expression of CD58. Using artificial APCs expressing various costimulatory molecules, we demonstrated that, in contrast to other costimulation patterns, costimulation via CD2 alone, in the absence of costimulations through CD28- or LFA-1, induced T cell anergy in an IL-10-independent pathway along with the differentiation of Ag-specific regulatory T cells. T regulatory cell-1 differentiation via CD2 was very efficient as both high IL-10 secretion and regulatory function were observed after the first stimulation of naive T cells with CD32-CD58 L cells. The possibility to rapidly induce the differentiation of Ag-specific regulatory T cells will certainly accelerate their characterization and their potential use as regulators of T cell-mediated diseases.
Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells
Authors: Metelitsa Leonid S. , Naidenko Olga V. , Kant Anita , Wu Hong-Wei , Loza Matthew J. , Perussia Bice , Kronenberg Mitchell , Seeger Robert C. 
Published: April 2014

Abstractα-Galactosylceramide (αGalCer) stimulates NKT cells and has antitumor activity in mice. Murine NKT cells may directly kill tumor cells and induce NK cell cytotoxicity, but the mechanisms are not well defined. Newly developed human CD1d/αGalCer tetrameric complexes were used to obtain highly purified human αGalCer-reactive NKT cell lines (&gt;99%), and the mechanisms of NKT cell cytotoxicity and activation of NK cells were investigated. Human NKT cells were cytotoxic against CD1d− neuroblastoma cells only when they were rendered CD1d+ by transfection and pulsed with αGalCer. Four other CD1d− tumor cell lines of diverse origin were resistant to NKT cells, whereas Jurkat and U937 leukemia cell lines, which are constitutively CD1d+, were killed. Killing of the latter was greatly augmented in the presence of αGalCer. Upon human CD1d/αGalCer recognition, NKT cells induced potent cytotoxicity of NK cells against CD1d− neuroblastoma cell lines that were not killed directly by NKT cells. NK cell activation depended upon NKT cell production of IL-2, and was enhanced by secretion of IFN-γ. These data demonstrate that cytotoxicity of human NKT cells can be CD1d and ligand dependent, and that TCR-stimulated NKT cells produce IL-2 that is required to induce NK cell cytotoxicity. Thus, NKT cells can mediate potent antitumor activity both directly by targeting CD1d and indirectly by activating NK cells.
CD28 Is Not Required for c-Jun N-Terminal Kinase Activation in T Cells
Authors: Rivas Fabiola V. , O’Herrin Sean , Gajewski Thomas F. 
Published: April 2014

Abstract
Studies in Jurkat cells have shown that combined stimulation through the TCR and CD28 is required for activation of c-Jun N-terminal kinase (JNK), suggesting that JNK activity may mediate the costimulatory function of CD28. To examine the role of JNK signaling in CD28 costimulation in normal T cells, murine T cell clones and CD28+/+ or CD28−/− TCR transgenic T cells were used. Although ligation with anti-CD28 mAb augmented JNK activation in Th1 and Th2 clones stimulated with low concentrations of anti-CD3 mAb, higher concentrations of anti-CD3 mAb alone were sufficient for JNK activation even in the absence of anti-CD28. JNK activity was comparably induced in both CD28+/+ and CD28−/− 2C/recombinase-activating gene 2(RAG2)−/− T cells stimulated with anti-CD3 mAb alone, and with Ld/peptide dimers, a direct αβ TCR ligand. Moreover, JNK activation was also detected in 2C/RAG2−/− T cells stimulated with P815 cells that express the relevant alloantigen Ld whether or not B7-1 was coexpressed. However, IL-2 production by both Th1 clones and CD28+/+ 2C/RAG2−/− T cells was detected only upon TCR and CD28 coengagement. Thus, CD28 coligation is not necessary, and stimulation through the TCR is sufficient, for JNK activation in normal murine T cells. The concept that JNK mediates the costimulatory function of CD28 needs to be reconsidered.
Selective Expansion and Partial Activation of Human NK Cells and NK Receptor-Positive T Cells by IL-2 and IL-15
Authors: Dunne Jean , Lynch Sara , O’Farrelly Cliona , Todryk Stephen , Hegarty John E. , Feighery Conleth , Doherty Derek G. 
Published: April 2014

AbstractIL-2 and IL-15 are lymphocyte growth factors produced by different cell types with overlapping functions in immune responses. Both cytokines costimulate lymphocyte proliferation and activation, while IL-15 additionally promotes the development and survival of NK cells, NKT cells, and intraepithelial lymphocytes. We have investigated the effects of IL-2 and IL-15 on proliferation, cytotoxicity, and cytokine secretion by human PBMC subpopulations in vitro. Both cytokines selectively induced the proliferation of NK cells and CD56+ T cells, but not CD56− lymphocytes. All NK and CD56+ T cell subpopulations tested (CD4+, CD8+, CD4−CD8−, αβTCR+, γδTCR+, CD16+, CD161+, CD158a+, CD158b+, KIR3DL1+, and CD94+) expanded in response to both cytokines, whereas all CD56− cell subpopulations did not. Therefore, previously reported IL-15-induced γδ and CD8+ T cell expansions reflect proliferations of NK and CD56+ T cells that most frequently express these phenotypes. IL-15 also expanded CD8α+β− and Vα24Vβ11 TCR+ T cells. Both cytokines stimulated cytotoxicity by NK and CD56+ T cells against K562 targets, but not the production of IFN-γ, TNF-α, IL-2, or IL-4. However, they augmented cytokine production in response to phorbol ester stimulation or CD3 cross-linking by inducing the proliferation of NK cells and CD56+ T cells that produce these cytokines at greater frequencies than other T cells. These results indicate that IL-2 and IL-15 act at different stages of the immune response by expanding and partially activating NK receptor-positive lymphocytes, but, on their own, do not influence the Th1/Th2 balance of adaptive immune responses.
Regulation of IgE Production Requires Oligomerization of CD23
Authors: Kilmon Michelle A. , Ghirlando Rodolfo , Strub Marie-Paule , Beavil Rebecca L. , Gould Hannah J. , Conrad Daniel H. 
Published: April 2014

AbstractHere we describe the production of a rabbit polyclonal Ab (RAS1) raised against the stalk of murine CD23. RAS1 inhibits release of CD23 from the surface of both M12 and B cells resulting in an increase of CD23 on the cell surface. Despite this increase, these cells are unable to bind IgE as determined by FACS. CD23 has previously been shown to bind IgE with both a high (4–10 × 107 M−1) and low (4–10 × 106 M−1) affinity. Closer examination by direct binding of 125I-IgE revealed that RAS1 blocks high affinity binding while having no effect on low affinity binding. These data support the model proposing that oligomers of CD23 mediate high affinity IgE binding. These experiments suggest that RAS1 binding to cell surface CD23 results in a shift from oligomers to monomers, which, according to the model, only bind IgE with low affinity. These experiments also suggest that high affinity binding of IgE is required for IgE regulation by CD23 and is demonstrated by the fact that treatment of Ag/Alum-immunized mice treated with RAS1 results in a significant increase in IgE production similar to the levels seen in CD23-deficient mice. These mice also had significantly decreased levels of serum soluble CD23 and Ag-specific IgG1. RAS1 had no effect on IgE or Ag-specific IgG1 production in CD23-deficient mice.
Eosinophils Promote Allergic Disease of the Lung by Regulating CD4+ Th2 Lymphocyte Function
Authors: MacKenzie Jason R. , Mattes Joerg , Dent Lindsay A. , Foster Paul S. 
Published: April 2014

AbstractEosinophils are primarily thought of as terminal effectors of allergic responses and of parasite elimination. However, limited studies suggest a more discrete immunomodulatory role for this leukocyte during these inflammatory responses. In this investigation, we highlight the potential of eosinophils to act as APCs and thus modulators of allergic responses by influencing Th2 cell function. In response to Ag provocation of the allergic lung, eosinophils rapidly trafficked to sites of Ag deposition (airways lumen) and presentation (lung-associated lymph nodes and T cell-rich paracortical zones). Eosinophils from the allergic lung expressed class II MHC peptides, T cell costimulatory molecules (CD80 and CD86), and rapidly internalized and processed Ag that was sampled from within the airway lumen. Ag-loaded eosinophils promoted the production of IL-4, IL-5, and IL-13 in cocultures with in vitro-polarized Th2 cells and induced IL-5 production in a dose-dependent manner from Ag-specific CD4+ T cells isolated from allergic mice. In addition, Ag-loaded eosinophils primed for Th2 cell-driven allergic disease of the lung when transferred to naive mice. Thus, eosinophils have the potential to not only activate Th2 cells to release disease-modulating cytokines but also to assist in priming the immune system for allergic responses. This investigation highlights the potential of eosinophils to not only act as terminal effector cells but also to actively modulate allergic inflammation by amplifying Th2 cell responses.
A New IFN-Like Cytokine, Limitin Modulates the Immune Response Without Influencing Thymocyte Development
Authors: Takahashi Isao , Kosaka Hiroshi , Oritani Kenji , Heath William R. , Ishikawa Jun , Okajima Yu , Ogawa Megumu , Kawamoto Sin-ichiro , Yamada Masahide , Azukizawa Hiroaki , Itami Satoshi , Yoshikawa Kunihiko , Tomiyama Yoshiaki , Matsuzawa Yuji 
Published: April 2014

AbstractA novel IFN-like molecule, limitin, was recently identified and revealed to suppress B lymphopoiesis through the IFN-αβ receptor, although it lacked growth suppression on myeloid and erythroid progenitors. Here we have studied diverse effects of limitin on T lymphocytes and compared limitin with previously known IFNs. Like IFN–α and -β, limitin modified immunity in the following responses. It suppressed mitogen- and Ag-induced T cell proliferation through inhibiting the responsiveness to exogenous IL-2 rather than suppressing the production of IL-2. In contrast, limitin enhanced cytotoxic T lymphocyte activity associated with the perforin-granzyme pathway. To evaluate the effect of limitin in vivo, a lethal graft-versus-host disease assay was established. Limitin-treatment of host mice resulted in the enhancement of graft-versus-host disease. Limitin did not influence thymocyte development either in fetal thymus organ cultures or in newborn mice injected with limitin-Ig, suggesting that limitin is distinguishable from IFN-α and -β. From these findings, it can be speculated that the human homolog of limitin may be applicable for clinical usage because of its IFN-like activities with low adverse effects on, for example, T lymphopoiesis, erythropoiesis, and myelopoiesis.
Disruption of NF-κB Signaling Reveals a Novel Role for NF-κB in the Regulation of TNF-Related Apoptosis-Inducing Ligand Expression
Authors: Baetu Tudor M. , Kwon Hakju , Sharma Sonia , Grandvaux Nathalie , Hiscott John 
Published: April 2014

AbstractThe NF-κB family of transcription factors functions broadly in the host control of immunoregulatory gene expression, inflammation, and apoptosis. Using Jurkat T cells engineered to inducibly express a transdominant repressor of IκBα, we examined the role of NF-κB in the regulation of cytokine and apoptotic gene expression. In this T cell model, as well as in primary T lymphocytes, expression of TNF-related apoptosis-inducing ligand (TRAIL) apoptotic signaling protein was dramatically down-regulated by inhibition of NF-κB binding activity. TRAIL acts through membrane death receptors to induce apoptosis of activated T lymphocytes and can be up-regulated by a variety of physiological and pharmacological inducers. However, regulation of TRAIL gene expression has not been defined. Treatment with TCR mimetics (PMA/ionomycin, PHA, and anti-CD3/CD28 Abs) resulted in a rapid increase in the expression of TRAIL mRNA and cell surface TRAIL protein. Induction of the transdominant repressor of IκBα dramatically down-regulated surface expression of TRAIL, indicating an essential role for NF-κB in the regulation of TRAIL. The induced expression of TRAIL was linked to a c-Rel binding site in the proximal TRAIL promoter at position −256 to −265; mutation of this site or an adjacent κB site resulted in a complete loss of the inducibility of the TRAIL promoter. The regulation of TRAIL expression by NF-κB may represent a general mechanism that contributes to the control of TRAIL-mediated apoptosis in T lymphocytes.
Signaling Lymphocytic Activation Molecule Is Expressed on CD40 Ligand-Activated Dendritic Cells and Directly Augments Production of Inflammatory Cytokines
Authors: Bleharski Joshua R. , Niazi Kayvan R. , Sieling Peter A. , Cheng Genhong , Modlin Robert L. 
Published: April 2014

AbstractDendritic cells (DC) comprise a key part of the innate immune system that, upon activation, profoundly influences the nature of the adaptive T cell response. In this study, we present evidence that signaling lymphocytic activation molecule (SLAM), a molecule first identified in activated T and B cells, is strongly up-regulated in DC activated through CD40, as well as in response to inflammatory stimuli, including polyinosinic polycytidylic acid and LPS. mRNA encoding both membrane-bound and soluble secreted isoforms of SLAM was detected in CD40 ligand-activated DC, comprising two of the four known SLAM isoforms. Expression of membrane-bound SLAM protein peaked at 12 h poststimulation with CD40 ligand, gradually returning to baseline levels after 6 days. SLAM up-regulation appears to be a direct result of the induction of DC maturation, as inflammatory cytokines released during this process do not affect SLAM expression. Functionally, engagement of SLAM enhances DC production of IL-12 and IL-8, while having no effect on production of IL-10. Because SLAM is involved in the activation of T cells, the expression of SLAM on DC may provide a bidirectional signaling mechanism in which interacting DC and T cells are simultaneously and synergistically activated to mount proinflammatory Th1 responses.
Pituitary Adenylate Cyclase-Activating Polypeptide Inhibits Collagen-Induced Arthritis: An Experimental Immunomodulatory Therapy
Authors: Abad Catalina , Martinez Carmen , Leceta Javier , Gomariz Rosa P. , Delgado Mario 
Published: April 2014

AbstractRheumatoid arthritis is a chronic, systemic, autoimmune, and inflammatory disorder that affects the synovial lining of the joints. We describe the beneficial effects of the pituitary adenylate cyclase-activating polypeptide (PACAP) in the collagen-induced arthritis experimental murine model being proposed as a novel therapeutic approach in the treatment of rheumatoid arthritis. PACAP greatly decreases arthritis frequency and severity in the studied mice by improving clinical symptoms, ameliorating joint damage, and blocking both the inflammatory and autoimmune mediators which are the main keys of the pathogenesis of this disease. With this study, PACAP emerges as a promising candidate for the treatment of a pathology with a high world incidence but currently no effective treatment.
CD19 Can Regulate B Lymphocyte Signal Transduction Independent of Complement Activation
Authors: Hasegawa Minoru , Fujimoto Manabu , Poe Jonathan C. , Steeber Douglas A. , Tedder Thomas F. 
Published: April 2014

AbstractB lymphocytes are critically regulated by signals transduced through the CD19-CD21 cell surface receptor complex, where complement C3d binding to CD21 supplies an already characterized ligand. To determine the extent that CD19 function is controlled by complement activation, CD19-deficient mice (that are hyporesponsive to transmembrane signals) and mice overexpressing CD19 (that are hyperresponsive) were crossed with CD21- and C3-deficient mice. Cell surface CD19 and CD21 expression were significantly affected by the loss of CD21 and C3 expression, respectively. Mature B cells from CD21-deficient littermates had ∼36% higher cell surface CD19 expression, whereas CD21/35 expression was increased by ∼45% on B cells from C3-deficient mice. Negative regulation of CD19 and CD21 expression by CD21 and C3, respectively, may be functionally significant because small increases in cell surface CD19 overexpression can predispose to autoimmunity. Otherwise, B cell development and function in CD19-deficient and -overexpressing mice were not significantly affected by a simultaneous loss of CD21 expression. Although CD21-deficient mice were found to express a hypomorphic cell surface CD21 protein at low levels that associated with mouse CD19, C3 deficiency did not significantly affect B cell development and function in CD19-deficient or -overexpressing mice. These results, and the severe phenotype exhibited by CD19-deficient mice compared with CD21- or C3-deficient mice, collectively demonstrate that CD19 can regulate B cell signaling thresholds independent of CD21 engagement and complement activation.
Vaccination with Cytoplasmic ErbB-2 DNA Protects Mice from Mammary Tumor Growth Without Anti-ErbB-2 Antibody
Authors: Pilon Shari A. , Piechocki Marie P. , Wei Wei-Zen 
Published: April 2014

Abstract
Wild-type ErbB-2 (E2) positive D2F2/E2 tumors are rejected by active vaccination with ErbB-2 DNA. However, anti-ErbB-2 Ab response can cause cardiac toxicity or interfere with cellular immunity. It will be advantageous to induce only cellular immunity by active vaccination. A panel of E2 DNA vaccines were constructed, and their vaccination efficacy was ranked as E2 &gt; tyrosine kinase-deficient ErbB-2 (E2A) &gt; full-length ErbB-2 targeted to the cytoplasm (cytE2) &gt; tyrosine kinase-deficient cytE2 (cytE2A). E2A is a tyrosine kinase-deficient mutant containing a single residue substitution. CytE2 or cytE2A encodes a full-length protein that is targeted to and rapidly degraded in the cytosol by the proteasomes. Covaccination with cytE2A and GM-CSF or IL-2 DNA resulted in equivalent anti-tumor activity as E2. However, anti-ErbB-2 Ab was induced by E2 or E2A, but not cytE2 or cytE2A. Therefore, cytE2A appears to induce anti-tumor immunity without an Ab response. ErbB-2-specific CTL were detected in mice immunized with cytE2A and GM-CSF and have rejected tumor challenge. Depletion of CD8, but not CD4 T cells reduced anti-tumor immunity, indicating CTL as the effector cells. Covaccination with E2A and cytE2A induced synergistic anti-tumor activity, supporting enhanced peptide presentation from cytE2A, which was further evidenced by superior CTL activation using APCs expressing cytE2 vs E2. Taken together, cytoplasmic ErbB-2 DNA induced anti-tumor CTL, but not humoral response, demonstrating the feasibility of eliciting individual effector mechanism by targeted DNA vaccine.