bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Peyer’s Patch T Cells Are Sensitized to Dietary Antigen and Display a Th Cell Type 1 Cytokine Profile
Authors: Nagata Satoru , McKenzie Catriona , Pender Sylvia L. F. , Bajaj-Elliott Mona , Fairclough Peter D. , Walker-Smith John A. , Monteleone Giovanni , MacDonald Thomas T. 
Published: April 2014

AbstractAnimal studies have demonstrated that feeding Ags induces regulatory (Th2, Th3) cells in Peyer’s patches (PP), which migrate to the periphery and produce immunomodulatory cytokines such as IL-4, IL-10, or TGF-β. In this work we have attempted to extend this paradigm to man by analyzing the response of human PP T cells to in vitro challenge with the common dietary Ag β-lactoglobulin (βlg) of cow’s milk. PP T cells stimulated with βlg showed enhanced proliferation compared with blood T cells from the same patient. Increased expression of CD25 and the Th1-associated chemokine receptor CCR5 was also seen on CD4+ and CD8+ PP T cells, but not blood T cells, stimulated with βlg. By enzyme-linked immunospot assay and RT-PCR, the PP T cell recall response to βlg and casein was dominated by IFN-γ, with negligible IL-4, IL-5, IL-10, or TGF-β. To help explain the PP T cell response to βlg, we examined IL-12 expression. Both IL-12p40 and -p35 transcripts were abundantly expressed in PP, but not in adjacent normal ileal mucosa. Immunoreactive IL-12p40-containing cells were present below the PP dome epithelium. Furthermore, in culture, PP, but not paired PBMC, spontaneously released IL-12p70. These results suggest that the human response to oral Ags in the gut may be different from that in rodents.
Anti-SSA/Ro and Anti-SSB/La Autoantibodies Bind the Surface of Apoptotic Fetal Cardiocytes and Promote Secretion of TNF-α by Macrophages
Authors: Miranda-Carús Maria-Eugenia , Askanase Anca Dinu , Clancy Robert M. , Di Donato Francis , Chou Tseng-Ming , Libera Matthew R. , Chan Edward K. L. , Buyon Jill P. 
Published: April 2014

Abstract
Despite the near universal association of congenital heart block and maternal Abs to SSA/Ro and SSB/La, the intracellular location of these Ags has made it difficult to substantiate their involvement in pathogenicity. To define whether components of the SSA/Ro-SSB/La complex, which translocate during apoptosis, are indeed accessible to extracellular Abs, two approaches were taken: immunoprecipitation of surface biotinylated proteins and scanning electron microscopy. Human fetal cardiocytes from 16–24-wk abortuses were cultured and incubated with staurosporine to induce apoptosis. Surface biotinylated 48-kDa SSB/La was reproducibly immunoprecipitated from apoptotic, but not nonapoptotic cardiocytes. Surface expression of SSA/Ro and SSB/La was further substantiated by scanning electron microscopy. Gold particles (following incubation with gold-labeled sera containing various specificities of anti-SSA/Ro-SSB/La Abs and murine mAb to SSB/La and 60-kDa SSA/Ro) were consistently observed on early and late apoptotic cardiocytes. No particles were seen after incubation with control antisera. To evaluate whether opsonized apoptotic cardiocytes promote inflammation, cells were cocultured with macrophages. Compared with nonapoptotic cardiocytes or apoptotic cardiocytes incubated with normal sera, apoptotic cardiocytes preincubated with affinity-purified Abs to SSB/La, 52-kDa SSA/Ro, or 60-kDa SSA/Ro increased the secretion of TNF-α from cocultured macrophages. In summary, apoptosis results in surface accessibility of all SSA/Ro-SSB/La Ags for recognition by circulating maternal Abs. It is speculated that in vivo such opsonized apoptotic cardiocytes promote an inflammatory response by resident macrophages with damage to surrounding conducting tissue.
Cell Division Is Not a “Clock” Measuring Acquisition of Competence to Produce IFN-γ or IL-4
Authors: Ben-Sasson Shlomo Z. , Gerstel Regina , Hu-Li Jane , Paul William E. 
Published: April 2014

AbstractNaive CD4 T cells acquire the potential to produce IFN-γ and IL-4 by culture in the presence of their cognate Ag, APC, and appropriate cytokines. In this study, we show that commitment to IFN-γ production on the part of rigorously purified naive CD4 T cells can occur without cell division. Indeed, even entry into S phase is not essential. Moreover, both CD4 and CD4/CD8 thymocytes from TCR-transgenic mice (5CC7 mice) on a Rag2−/− background can acquire IFN-γ-producing capacity when stimulated by peptide, APC, and IL-12. These cells can do so without dividing and some acquire IFN-γ-producing activity without entry into S phase. Not only is cell division not required for acquisition of cytokine-producing potential, cell populations that have undergone the same numbers of divisions can have quite different proportions of IFN-γ- or IL-4-producing cells, depending on the duration of priming or, in the case of IL-4, on the concentration of peptide. Thus, cell division is not a clock for the expression of these cytokines. Factors associated with priming conditions including strength of stimulation, duration of priming, and number of divisions each play a role.
IL-6 Secretion by a Rat T9 Glioma Clone Induces a Neutrophil-Dependent Antitumor Response with Resultant Cellular, Antiglioma Immunity
Authors: Graf Martin R. , Prins Robert M. , Merchant Randall E. 
Published: April 2014

AbstractPreviously, we reported that IL-6 transduction attenuates tumor formation of a rat T9 glioma clone (termed T9.F). This study focuses on the mechanisms of the antitumor response elicited by IL-6 and the generation of glioma immunity. Ten days post s.c. inoculation of T9.F- or IL-6-secreting T9.F cells (T9.F/IL6/hi), tumor nodules were removed and their leukocytic infiltrate was analyzed by FACS with Ab markers for T cells, B cells, granulocytes, and monocytes. T9.F/IL6/hi tumors showed a marked increase in granulocytes as compared with parental T9.F tumors, and histological examination revealed that the granulocytes were neutrophils. Animals made neutropenic failed to reject T9.F/IL6/hi tumors. FACS analysis of 17-day T9.F/IL6/hi regressing tumors and T9.F progressing tumors did not reveal any significant differences in the leukocytic infiltrates. Tumor-specific effector cells were detected in the spleens harvested from animals bearing 17-day, regressing, T9.F/IL6/hi tumors. In vitro, these effector cells lysed T9.F cells, proliferated in response to T9.F stimulator cells, and produced Th1 cytokines (IL-2 and IFN-γ) but not the Th2 cytokine, IL-4, when cocultured with T9.F stimulator cells. Rats that had rejected s.c. T9.F/IL6/hi tumors displayed a delayed-type hypersensitivity response when injected with viable T9.F cells in the contralateral flank. Passive transfer of spleen cells from these animals transferred glioma immunity to naive recipients and depletion of CD3+ T cells, before transfer, completely abolished immunity, whereas depletion of CD8+ T cells had moderate inhibitory effects on the transfer of immunity.
VCAM-1 Activates Phosphatidylinositol 3-Kinase and Induces p120CblPhosphorylation in Human Airway Smooth Muscle Cells
Authors: Lazaar Aili L. , Krymskaya Vera P. , Das Susan K. P. 
Published: April 2014

AbstractVCAM-1 is a member of the Ig superfamily of receptors the expression of which is up-regulated on human airway smooth muscle (ASM) cells following stimulation with inflammatory mediators. The function of these receptors in adhesion is well known, but there is growing recognition that they also possess “outside-in” signaling functions, such as cytoskeletal reorganization, calcium mobilization, and cytokine release. The present study examined the activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase (PI3K) in ASM cells following VCAM-1 engagement. VCAM-1 ligation activated extracellular signal-regulated kinase 2 and resulted in increased expression of cyclin D1, yet there was neither p27kip1 degradation nor an increase in smooth muscle cell DNA synthesis. VCAM-1 ligation, however, augmented the proliferative response to submitogenic concentrations of epidermal growth factor. VCAM-1 engagement also stimulated a rapid increase in PI3K activity. This was associated with phosphorylation of the adapter protein p120Cbl and an increase in Cbl-associated PI3K activity. These studies suggest that VCAM-1 is linked to multiple signaling pathways in human ASM cells and may function to augment growth factor-induced responses.
IL-7 Enhances the Responsiveness of Human T Cells That Develop in the Bone Marrow of Athymic Mice
Authors: Tsark Eleanor C. , Dao Mo A. , Wang Xiuli , Weinberg Kenneth , Nolta Jan A. 
Published: April 2014

AbstractThe beige/nude/xid/human (bnx/hu) model of human hematopoiesis provides a unique opportunity to study extrathymic human T lymphocyte development in an in vivo system. Purified human hematopoietic stem cells develop into mature T lymphocytes and immature progenitors in the bone marrow of athymic bnx mice. The human T cells are all TCRαβ+ and display a restricted TCRVβ repertoire. In the current studies, we examined the effects of systemic human IL-7 (huIL-7) administration on the phenotype and the activation status of the bnx/hu T cells. In the majority of the mice that did not have huIL-7 administration, a higher frequency of human CD3+/CD8+ than CD3+/CD4+ T cells developed in the bone marrow. This phenomenon is also frequently observed in human bone marrow transplant recipients. Extremely low levels of IL-2 were expressed by human CD3+ cells isolated from these mice, in response to PMA plus ionomycin and to CD3 and CD28 cross-linking. IL-4 was not expressed by cells exposed to either stimulus, demonstrating a profound inability of the bnx/hu T cells to produce this cytokine. Systemic production of huIL-7 from engineered stromal cells transplanted into the mice increased the human CD4 to CD8 ratios, and increased the ratio of memory to naive CD4+ and CD8+ T cells. The human CD3+ cells recovered from mice that had systemic huIL-7 and equivalent numbers of CD3+/CD4+ and CD3+/CD8+ cells in the marrow were still unable to produce IL-4 in response to any condition tested, but were capable of normal levels of IL-2 production following stimulation.
Redirecting Mouse CTL Against Colon Carcinoma: Superior Signaling Efficacy of Single-Chain Variable Domain Chimeras Containing TCR-ζ vs FcεRI-γ
Authors: Haynes Nicole M. , Snook Marie B. , Trapani Joseph A. , Cerruti Loretta , Jane Stephen M. , Smyth Mark J. , Darcy Phillip K. 
Published: April 2014

AbstractThe structurally related TCR-ζ and Fc receptor for IgE (FcεRI)-γ are critical signaling components of the TCR and FcεRI, respectively. Although chimeric Ab receptors containing ζ and γ signaling chains have been used to redirect CTL to tumors, a direct comparison of their relative efficacy has not previously been undertaken. Here, in naive T lymphocytes, we compare the signaling capacities of the ζ and γ subunits within single-chain variable domain (scFv) chimeric receptors recognizing the carcinoembryonic Ag (CEA). Using a very efficient retroviral gene delivery system, high and equivalent levels of scFv-ζ and scFv-γ receptors were expressed in T cells. Despite similar levels of expression and Ag-specific binding to colon carcinoma target cells, ligation of scFv-anti-CEA-ζ chimeric receptors on T cells resulted in greater cytokine production and direct cytotoxicity than activation via scFv-anti-CEA-γ receptors. T cells expressing scFv-ζ chimeric receptors had a greater capacity to control the growth of human colon carcinoma in scid/scid mice or mouse colon adenocarcinoma in syngeneic C57BL/6 mice. Overall, these data are the first to directly compare and definitively demonstrate the enhanced potency of T cells activated via the ζ signaling pathway.
Activated T Lymphocytes Regulate Hyaluronan Binding to Monocyte CD44 Via Production of IL-2 and IFN-γ
Authors: Levesque Marc C. , Haynes Barton F. 
Published: April 2014

AbstractInteractions of the cell surface proteoglycan CD44 with the extracellular matrix glycosaminoglycan hyaluronan (HA) are important during inflammatory immune responses. Our previous studies indicated that monocyte HA binding could be induced by TNF-α. Moreover, monocyte HA binding could be markedly up-regulated by culturing PBMC with anti-CD3 (TCR complex) mAbs. The present study was undertaken to identify soluble factors and/or cell surface molecules of activated T lymphocytes that might regulate HA binding to monocytes. Abs to IL-1α, IL-1β, IL-2, IL-3, IL-10, IL-15, GM-CSF, IFN-γ, and TNF-α were tested for their effects on anti-CD3 mAb-, Con A-, and PMA/ionomycin-mediated monocyte HA binding in PBMC cultures. Anti-TNF-α, anti-IL-2, and anti-IFN-γ Abs, when added together to PBMC cultures, completely blocked Con A- and partially blocked anti-CD3- and PMA/ionomycin-induced monocyte HA binding. Furthermore, when added together to PBMC cultures, IL-2 and TNF-α induced high levels of monocyte HA binding. Likewise, IFN-γ augmented TNF-α-induced monocyte HA binding. To investigate the role of T cell-monocyte direct contact in induction of monocyte HA binding, we studied PMA/ionomycin-activated, paraformaldehyde-fixed CD4+ T cells in these assays. Fixed, PMA/ionomycin-activated CD4+ T lymphocytes induced monocyte HA binding, but direct T cell-monocyte contact was not required. Moreover, anti-IFN-γ and anti-TNF-α Abs blocked fixed PMA/ionomycin-activated CD4+ T cell-induced monocyte HA binding. Taken together, these studies indicate roles for soluble T lymphocyte-derived factor(s), such as IL-2 and IFN-γ, and a role for monocyte-derived TNF-α in Con A-, TCR complex-, and PMA/ionomycin-induced HA binding to monocyte CD44.
Negative-Feedback Regulation of CD28 Costimulation by a Novel Mitogen-Activated Protein Kinase Phosphatase, MKP6
Authors: Marti Francesc , Krause Anja , Post Nicholas H. , Lyddane Clay , Dupont Bo , Sadelain Michel , King Philip D. 
Published: April 2014

Abstract
TCR and CD28 costimulatory receptor-cooperative induction of T cell IL-2 secretion is dependent upon activation of mitogen-activated protein (MAP) kinases. Using yeast-hybrid technology, we cloned a novel CD28 cytoplasmic tail (CD28 CYT) interacting protein, MAP kinase phosphatase-6 (MKP6), which we demonstrate inactivates MAP kinases. Several lines of evidence indicate that MKP6 plays an important functional role in CD28 costimulatory signaling. First, in human peripheral blood T cells (PBT), expression of MKP6 is strongly up-regulated by CD28 costimulation. Second, transfer of dominant-negative MKP6 to PBT with the use of retroviruses primes PBT for the secretion of substantially larger quantities of IL-2, specifically in response to CD28 costimulation. A similar enhancement of IL-2 secretion is observed neither in response to TCR plus CD2 costimulatory receptor engagement nor in response to other mitogenic stimuli such as phorbol ester and ionomycin. Furthermore, this hypersensitivity to CD28 costimulation is associated with CD28-mediated hyperactivation of MAP kinases. Third, a retroviral transduced chimeric receptor with a CD28 CYT that is specifically unable to bind MKP6 costimulates considerably larger quantities of IL-2 from PBT than a similar transduced chimeric receptor that contains a wild-type CD28 CYT. Taken together, these results suggest that MKP6 functions as a novel negative-feedback regulator of CD28 costimulatory signaling that controls the activation of MAP kinases.
Allergen-Specific Th1 Cells Counteract Efferent Th2 Cell-Dependent Bronchial Hyperresponsiveness and Eosinophilic Inflammation Partly Via IFN-γ
Authors: Huang Tung-Jung , MacAry Paul A. , Eynott Paul , Moussavi Artin , Daniel Kenn C. , Askenase Philip W. , Kemeny David M. , Chung K. Fan 
Published: April 2014

AbstractTh2 T cell immune-driven inflammation plays an important role in allergic asthma. We studied the effect of counterbalancing Th1 T cells in an asthma model in Brown Norway rats that favors Th2 responses. Rats received i.v. transfers of syngeneic allergen-specific Th1 or Th2 cells, 24 h before aerosol exposure to allergen, and were studied 18–24 h later. Adoptive transfer of OVA-specific Th2 cells, but not Th1 cells, and OVA, but not BSA exposure, induced bronchial hyperresponsiveness (BHR) to acetylcholine and eosinophilia in a cell number-dependent manner. Importantly, cotransfer of OVA-specific Th1 cells dose-dependently reversed BHR and bronchoalveolar lavage (BAL) eosinophilia, but not mucosal eosinophilia. OVA-specific Th1 cells transferred alone induced mucosal eosinophilia, but neither BHR nor BAL eosinophilia. Th1 suppression of BHR and BAL eosinophilia was allergen specific, since cotransfer of BSA-specific Th1 cells with the OVA-specific Th2 cells was not inhibitory when OVA aerosol alone was used, but was suppressive with OVA and BSA challenge. Furthermore, recipients of Th1 cells alone had increased gene expression for IFN-γ in the lungs, while those receiving Th2 cells alone showed increased IL-4 mRNA. Importantly, induction of these Th2 cytokines was inhibited in recipients of combined Th1 and Th2 cells. Anti-IFN-γ treatment attenuated the down-regulatory effect of Th1 cells. Allergen-specific Th1 cells down-regulate efferent Th2 cytokine-dependent BHR and BAL eosinophilia in an asthma model via mechanisms that depend on IFN-γ. Therapy designed to control the efferent phase of established asthma by augmenting down-regulatory Th1 counterbalancing mechanisms should be effective.
Ocular Immune Privilege Promoted by the Presentation of Peptide on Tolerogenic B Cells in the Spleen. II. Evidence for Presentation by Qa-1
Authors: D’Orazio Thomas J. , Mayhew Elizabeth , Niederkorn Jerry Y. 
Published: April 2014

AbstractOcular immune privilege is the result of several unique features of the eye, including the systemic down-regulation of Th1 immune responses to Ags encountered in the anterior chamber of the eye—a phenomenon termed anterior chamber-associated immune deviation (ACAID). The induction of ACAID requires the participation of three cell populations: the ocular ACAID APC, the splenic B cell, and the splenic T cell. Because B cells have been implicated in tolerogenic Ag presentation in other systems, we hypothesized that B cells were responsible for the induction of regulatory T cells in ACAID. The central hypothesis for this study is that APC from the eye migrate to the spleen where they release antigenic peptides (OVA) that are captured and presented to T cells by splenic B cells. A combination of in vitro and in vivo studies demonstrated that splenic B cells, incubated with ACAID APC in vitro, were capable of inducing ACAID when transferred to naive mice. The induction of ACAID required the normal expression of β2-microglobulin on both the B cell and ACAID APC, but not on the T suppressor cells. Moreover, the induction of ACAID regulatory cells required histocompatibility between the B cells and regulatory T cells at the TL/Qa region. The results indicate that: 1) B cells are necessary for the induction of ACAID; 2) ACAID B cells do not directly suppress the expression of delayed-type hypersensitivity; and 3) the induction of Ag-specific regulatory T cells by ACAID B cells requires histocompatibility at the TL/Qa region.
Control of T Cell Development In Vivo by Subdomains Within the IL-7 Receptor α-Chain Cytoplasmic Tail
Authors: Porter Brian O. , Scibelli Paul , Malek Thomas R. 
Published: April 2014

AbstractIL-7/IL-7R signaling functions in both growth and differentiation during T cell development. In this study, we examined the extent these activities were controlled by signaling associated with distinct IL-7Rα cytoplasmic domains by transgenic expression of wild-type or cytoplasmic deletion mutants of IL-7Rα in the thymi of IL-7Rα−/− mice. We show an essential requirement for the tyrosine-containing carboxyl-terminal T domain in restoring thymic cellularity, pro-/pre-T cell progression, and survival. In contrast, the functional differentiation of TCR αβ cells and the development of TCR γδ cells are partially independent of the T domain. Thus, separate cytoplasmic domains of the IL-7Rα chain differentially control distinct functions during T cell development, whereas normal IL-7R-dependent thymic development requires the integrated activity of all these domains.
Enhanced Secretion of IFN-γ by Activated Th1 Cells Occurs Via Reverse Signaling Through TNF-Related Activation-Induced Cytokine
Authors: Chen Nien-Jung , Huang Mei-Wen , Hsieh Shie-Liang 
Published: April 2014

AbstractGrowing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. TNF-related activation-induced cytokine (TRANCE), a member of TNF superfamily, is preferentially expressed on the surface of activated CD4+ Th1 cells. The soluble receptor activator of NF-κB (RANK).Fc fusion protein suppresses IFN-γ secretion by activated Th1 cells, but does not affect IL-4 secretion by Th2 cells. The suppressive effect on IFN-γ secretion is observed when Th1 cells are activated by APCs, but not by immobilized anti-TCRβ mAb. In contrast, immobilized RANK.Fc fusion protein augments IFN-γ secretion by Th1 cells, indicating the occurrence of reverse signaling through TRANCE during T cell/APC interaction. The enhanced secretion of IFN-γ mediated via TRANCE correlates with the activation of p38 mitogen-activated protein kinase and is blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in activating dendritic cells by binding to the receptor RANK, TRANCE itself can signal the augmentation of IFN-γ secretion via a p38-dependent pathway, and this provides yet another example of reverse signaling by a member of TNF superfamily.
Multiple Signals Required for Cyclic AMP-Responsive Element Binding Protein (CREB) Binding Protein Interaction Induced by CD3/CD28 Costimulation
Authors: Yu Cheng-Tai , Shih Hsiu-ming , Lai Ming-Zong 
Published: April 2014

AbstractThe optimal activation of cAMP-responsive element binding protein (CREB), similar to the full activation of T lymphocytes, requires the stimulation of both CD3 and CD28. Using a reporter system to detect interaction of CREB and CREB-binding protein (CBP), in this study we found that CREB binds to CBP only by engagement of both CD3 and CD28. CD3/CD28-promoted CREB-CBP interaction was dependent on p38 mitogen-activated protein kinase (MAPK) and calcium/calmodulin-dependent protein kinase (CaMK) IV in addition to the previously identified extracellular signal-regulated kinase pathway. Extracellular signal-regulated kinase, CaMKIV, and p38 MAPK were also the kinases involved in CREB Ser133 phosphorylation induced by CD3/CD28. A reconstitution experiment illustrated that optimum CREB-CBP interaction and CREB trans-activation were attained when these three kinase pathways were simultaneously activated in T cells. Our results demonstrate that coordinated activation of different kinases leads to full activation of CREB. Notably, CD28 ligation activated p38 MAPK and CaMKIV, the kinases stimulated by CD3 engagement, suggesting that CD28 acts by increasing the activation extent of p38 MAPK and CaMKIV. These results support the model of a minimum activation threshold for CREB-CBP interaction that can be reached only when both CD3 and CD28 are stimulated.
MIP-2 Recruits NKT Cells to the Spleen During Tolerance Induction
Authors: Faunce Douglas E. , Sonoda Koh-Hei , Stein-Streilein Joan 
Published: April 2014

AbstractPeripheral tolerance occurs after intraocular administration of Ag and is dependent on an increase in splenic NKT cells. New data here show that macrophage inflammatory protein-2 (MIP-2) is selectively up-regulated in tolerance-conferring APCs and serves to recruit NKT cells to the splenic marginal zone, where they form clusters with APCs and T cells. In the absence of the high-affinity receptor for MIP-2 (as in CXCR2-deficient mice) or in the presence of a blocking Ab to MIP-2, peripheral tolerance is prevented, and Ag-specific T regulatory cells are not generated. Understanding the regulation of lymphocyte traffic during tolerance induction may lead to novel therapies for autoimmunity, graft acceptance, and tumor rejection.