bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice
Authors: Kreuwel Huub T. C. , Biggs Judith A. , Pilip Ingrid M. , Pamer Eric G. , Lo David , Sherman Linda A. 
Published: April 2014

AbstractNonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that involves participation of both CD4+ and CD8+ T cells. Previous studies have demonstrated spontaneous reactivity to self-Ags within the CD4+ T cell compartment in this strain. Whether CD8+ T cells in NOD mice achieve and maintain tolerance to self-Ags has not previously been evaluated. To investigate this issue, we have assessed the extent of tolerance to a model pancreatic Ag, the hemagglutinin (HA) molecule of influenza virus, that is transgenically expressed by pancreatic islet β cells in InsHA mice. Previous studies have demonstrated that BALB/c and B10.D2 mice that express this transgene exhibit tolerance of HA and retain only low-avidity CD8+ T cells specific for the dominant peptide epitope of HA. In this study, we present data that demonstrate a deficiency in peripheral tolerance within the CD8+ T cell repertoire of NOD-InsHA mice. CD8+ T cells can be obtained from NOD-InsHA mice that exhibit high avidity for HA, as measured by tetramer (KdHA) binding and dose titration analysis. Significantly, these autoreactive CD8+ T cells can cause diabetes very rapidly upon adoptive transfer into NOD-InsHA recipient mice. The data presented demonstrate a retention in the repertoire of CD8+ T cells with high avidity for islet Ags that could contribute to autoimmune diabetes in NOD mice.
Cutting Edge: Differential Requirements for Stat4 in Expression of Glycosyltransferases Responsible for Selectin Ligand Formation in Th1 Cells
Authors: White Samuel J. , Underhill Gregory H. , Kaplan Mark H. , Kansas Geoffrey S. 
Published: April 2014

AbstractA role for Stat4 in IL-12-induced up-regulation of selectin ligands on Th1 cells was explored. Th1 cells generated from Stat4−/− mice exhibited no IL-12-inducible P-selectin ligands, no up-regulation of core 2 β1,6-glucosaminyltransferase I (C2GlcNAcT-I), and low levels of the Th1 transcription factor T-bet. In contrast, Stat4−/− Th1 cells exhibited only a partial defect in expression of IL-12-inducible E-selectin ligands and expressed equivalently high levels of α1,3-fucosyltransferase VII (FucT-VII) as wild-type Th1 cells. FucT-VII expression was induced by T cell activation, and was enhanced by IL-12 independently of Stat4, whereas C2GlcNAcT-I up-regulation was mediated exclusively by IL-12, acting through Stat4. These data show that FucT-VII and C2GlcNAcT-I are controlled through distinct pathways and imply the existence of at least one other IL-12-inducible glycosyltransferase required for E-selectin and possibly P-selectin ligand formation in Th1 cells.
Cutting Edge: Integration of Human T Lymphocyte Cytoskeleton by the Cytolinker Plectin
Authors: Brown Martin J. , Hallam John A. , Liu Yin , Yamada Kenneth M. , Shaw Stephen 
Published: April 2014

Abstract
Chemokine-induced polarization of lymphocytes involves the rapid collapse of vimentin intermediate filaments (IFs) into an aggregate within the uropod. Little is known about the interactions of lymphocyte vimentin with other cytoskeletal elements. We demonstrate that human peripheral blood T lymphocytes express plectin, an IF-binding, cytoskeletal cross-linking protein. Plectin associates with a complex of structural proteins including vimentin, actin, fodrin, moesin, and lamin B in resting peripheral blood T lymphocytes. During chemokine-induced polarization, plectin redistributes to the uropod associated with vimentin and fodrin; their spatial distribution indicates that this vimentin-plectin-fodrin complex provides a continuous linkage from the nucleus (lamin B) to the cortical cytoskeleton. Overexpression of the plectin IF-binding domain in the T cell line Jurkat induces the perinuclear aggregation of vimentin IFs. Plectin is therefore likely to serve as an important organizer of the lymphocyte cytoskeleton and may regulate changes of lymphocyte cytoarchitecture during polarization and extravasation.
The Peyer’s Patch Microenvironment Suppresses T Cell Responses to Chemokines and Other Stimuli
Authors: Kellermann Sirid-Aimée , McEvoy Leslie M. 
Published: April 2014

AbstractImmunosurveillance of mucosal sites presents immune cells with challenges not encountered in the periphery. T cells in the gut must distinguish enteric pathogens from innocuous non-self Ag derived from food or commensal bacteria. The mechanisms that regulate T cells in the gut remain incompletely understood. We assessed the effect of the Peyer’s patch microenvironment on T cell responses to chemokines. Chemokines are believed to play an important role during T cell priming by facilitating T cell migration into and within lymphoid tissues as well as T cell encounter and interaction with APCs. We found a profound suppression of chemokine-stimulated T cell chemotaxis and actin polymerization in Peyer’s patch relative to lymph node. Chemokine hyporesponsiveness is imposed upon T cells within hours of their entry into Peyer’s patches and is reversed following their removal. Suppression was not restricted to chemokine stimulation, as T cell responses to Con A and PMA were also suppressed. The global nature of this defect is further underscored by an impairment in calcium mobilization. Evidence indicates that a soluble factor contributes to this hyporesponsiveness, and comparison of Peyer’s patches and lymph nodes revealed striking differences in their chemokine and cytokine constitution, indicating a marked Th2 bias in the Peyer’s patches. The role of the Th2 microenvironment in mediating suppression is suggested by the ability of Nippostrongylus brasiliensis to elicit hyporesponsiveness in lymph node T cells. The suppressive milieu encountered by T cells in Peyer’s patches may be critical for discouraging undesired immune responses and promoting tolerance.
Enforced Expression of GATA-3 in Transgenic Mice Inhibits Th1 Differentiation and Induces the Formation of a T1/ST2-Expressing Th2-Committed T Cell Compartment In Vivo
Authors: Nawijn Martijn C. , Dingjan Gemma M. , Ferreira Rita , Lambrecht Bart N. , Karis Alar , Grosveld Frank , Savelkoul Huub , Hendriks Rudolf W. 
Published: April 2014

AbstractThe transcription factor GATA-3 is essential for early T cell development and differentiation of naive CD4+ T cells into Th2 effector cells. To study the function of GATA-3 during T cell-mediated immune responses in vivo, we investigated CD2-GATA3-transgenic mice in which GATA-3 expression is driven by the CD2 locus control region. Both in the CD4+ and the CD8+ T cell population the proportion of cells exhibiting a CD44highCD45RBlowCD62Llow Ag-experienced phenotype was increased. In CD2-GATA3-transgenic mice, large fractions of peripheral CD4+ T cells expressed the IL-1 receptor family member T1/ST2, indicative of advanced Th2 commitment. Upon in vitro T cell stimulation, the ability to produce IL-2 and IFN-γ was decreased. Moreover, CD4+ T cells manifested rapid secretion of the Th2 cytokines IL-4, IL-5, and IL-10, reminiscent of Th2 memory cells. In contrast to wild-type CD4+ cells, which lost GATA-3 expression when cultured under Th1-polarizing conditions, CD2-GATA3-transgenic CD4+ cells maintained expression of GATA-3 protein. Under Th1 conditions, cellular proliferation of CD2-GATA3-transgenic CD4+ cells was severely hampered, IFN-γ production was decreased and Th2 cytokine production was increased. Enforced GATA-3 expression inhibited Th1-mediated in vivo responses, such as Ag-specific IgG2a production or a delayed-type hypersensitivity response to keyhole limpet hemocyanin. Collectively, these observations indicate that enforced GATA-3 expression selectively inhibits Th1 differentiation and induces Th2 differentiation. The increased functional capacity to secrete Th2 cytokines, along with the increased expression of surface markers for Ag-experienced Th2-committed cells, would argue for a role of GATA-3 in Th2 memory formation.
IL-12 Decreases Activation-Induced Cell Death in Human Naive Th Cells Costimulated by Intercellular Adhesion Molecule-1. I. IL-12 Alters Caspase Processing and Inhibits Enzyme Function
Authors: Palmer Ellen M. , Farrokh-Siar Lili , Maguire van Seventer Jean , van Seventer Gijs A. 
Published: April 2014

AbstractTh cells can receive costimulatory signals through the LFA-1/ICAM-1 accessory pathway that are sufficient to induce early Th cell proliferation, but not subsequent cell expansion and maintenance of cell viability. To investigate the regulatory role for IL-12 in ICAM-1-mediated costimulation, human naive Th cells were stimulated with coimmobilized anti-CD3 mAb and ICAM-1 Ig in the presence or absence of IL-12. The ICAM-1-mediated costimulatory signals in this model resulted in early Th cell proliferation followed by cell death that was partially mediated by Fas and involved loss of mitochondrial membrane potential, processing of procaspase-9 and -3, and activation of caspase-3. Addition of IL-12 prevented activation-induced cell death and promoted late proliferation. ICAM-1 + IL-12-costimulated Th cells were resistant to Fas-mediated cell death through a mechanism that did not appear to involve a decrease in either Fas or Fas ligand expression. IL-12 did not inhibit the loss of mitochondrial membrane potential induced by ICAM-1-mediated costimulation, and this finding was consistent with the inability of IL-12 to increase expression of the antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-xL. Interestingly, IL-12 promoted an altered processing of procaspase-9 and -3 and a decrease in the percentage of cells displaying caspase-3 catalytic function. In conclusion, we now describe a novel regulatory function for IL-12 in preventing Th cell death and, as a result, in greatly increasing Th cell viability and expansion. Together, our findings indicate that IL-12 may perform this regulatory role by preventing Fas-mediated activation-induced cell death through inhibition of caspase-3 enzyme activity.
The Binding of Thymus Leukemia (TL) Antigen Tetramers to Normal Intestinal Intraepithelial Lymphocytes and Thymocytes
Authors: Tsujimura Kunio , Obata Yuichi , Matsudaira Yasue , Ozeki Satoshi , Yoshikawa Kazuhiro , Saga Shinsuke , Takahashi Toshitada 
Published: April 2014

AbstractThymus leukemia (TL) Ags belong to the family of nonclassical MHC class I Ags and can be recognized by both TCRαβ and TCRγδ CTL with TL, but not H-2 restriction. We previously reported that the CTL epitope is TAP independent, but the antigenic molecule(s) presented by TL has yet to be determined. In the present study, TL tetramers were prepared with T3b-TL and murine β2-microglobulin, not including antigenic peptides, and binding specificity was studied. CTL clones against TL Ags were stained with the T3b-TL tetramer, and the binding shown to be CD3 and CD8 dependent. Normal lymphocytes from various origins were also studied. Surprisingly, most CD8+ intraepithelial lymphocytes derived from the small intestines (iIEL), as well as CD8+ and CD4+CD8+ thymocytes, were stained, while only very minor populations of CD8+ cells derived from other peripheral lymphoid tissues, such as spleen and lymph nodes, were positive. The binding of T3b-TL tetramers to CD8+ iIEL and thymocytes was CD8 dependent, but CD3 independent, in contrast to that to TL-restricted CTL. These results altogether showed that TL-restricted CTL can be monitored by CD3-dependent binding of T3b-TL tetramers. In addition, CD3-independent T3b-TL tetramer binding to iIEL and thymocytes may imply that TL expressed on intestinal epithelium and cortical thymocytes has a physiological function interacting with these tetramer+CD8+ T lymphocytes.
Wnt Signaling Regulates Hemopoiesis Through Stromal Cells
Authors: Yamane Toshiyuki , Kunisada Takahiro , Tsukamoto Hirotake , Yamazaki Hidetoshi , Niwa Hitoshi , Takada Shinji , Hayashi Shin-Ichi 
Published: April 2014

Abstract
Hemopoietic cells develop in a complex milieu that is made up of diverse components, including stromal cells. Wnt genes, which are known to regulate the fate of the cells in a variety of tissues, are expressed in hemopoietic organs. However, their roles in hemopoiesis are not well characterized. In this study, we examined the roles of Wnt proteins in hemopoiesis using conditioned medium containing Wnt-3a. This conditioned medium dramatically reduced the production of B lineage cells and myeloid lineage cells, except for macrophages in the long-term bone marrow cultures grown on stromal cells, although the sensitivity to the conditioned medium differed, depending on the hemopoietic lineage. In contrast, the same conditioned medium did not affect the generation of B lineage or myeloid lineage cells in stromal cell-free conditions. These results suggested that Wnt proteins exert their effects through stromal cells. Indeed, these effects were mimicked by the expression of a stabilized form of β-catenin in stromal cells. In this study, we demonstrated that Wnt signaling regulates hemopoiesis through stromal cells with selectivity and different degrees of the effect, depending on the hemopoietic lineage in the hemopoietic microenvironment.
Regulation of TGF-β Response During T Cell Activation Is Modulated by IL-10
Authors: Cottrez Françoise , Groux Hervé 
Published: April 2014

AbstractTGF-β1 is an important pleiotropic cytokine that has been described to have both stimulatory and inhibitory effects on cell growth and differentiation. For several cell types, the effect of TGF-β1 was found to correlate with the differentiation stage of the cells and the presence of other cytokines. In this report, we address the influence of TGF-β1 on CD4+ T cell activation by evaluating the effect of TGF-β1 on the proliferative and cytokine responses of purified resting and activated human or mouse CD4+ T cells. TGF-β1 inhibits proliferation and cytokine secretion on resting CD4+ T cells but has no inhibitory effect on activated T cells. Moreover, TGF-β1 unresponsiveness of activated T cells was correlated with a down-regulation in the expression of the TGF-β receptor type II. Interestingly, IL-10 addition enhances TGF-β receptor type II expression and restores TGF-β responsiveness on activated T cells. These results indicated that TGF-β responsiveness is sequentially regulated on T cells by the modulation of the of TGF-β receptor type II chain expression. Moreover, we have identified a novel regulatory role of IL-10 on TGF-β-dependent T cell growth that can explain the control of T cell activation on chronic vs acute inflammatory sites.
A Role for IL-12 Receptor Expression and Signal Transduction in Host Defense in Leprosy
Authors: Kim Jenny , Uyemura Koichi , Van Dyke Melissa K. , Legaspi Annaliza J. , Rea Thomas H. , Shuai Ke , Modlin Robert L. 
Published: April 2014

AbstractThe generation of cell-mediated immunity against intracellular infection involves the production of IL-12, a critical cytokine required for the development of Th1 responses. The biologic activities of IL-12 are mediated through a specific, high affinity IL-12R composed of an IL-12Rβ1/IL-12Rβ2 heterodimer, with the IL-12Rβ2 chain involved in signaling via Stat4. We investigated IL-12R expression and function in human infectious disease, using the clinical/immunologic spectrum of leprosy as a model. T cells from tuberculoid patients, the resistant form of leprosy, are responsive to IL-12; however, T cells from lepromatous patients, the susceptible form of leprosy, do not respond to IL-12. We found that the IL-12Rβ2 was more highly expressed in tuberculoid lesions compared with lepromatous lesions. In contrast, IL-12Rβ1 expression was similar in both tuberculoid and lepromatous lesions. The expression of IL-12Rβ2 on T cells was up-regulated by Mycobacterium leprae in tuberculoid but not in lepromatous patients. Furthermore, IL-12 induced Stat4 phosphorylation and DNA binding in M. leprae-activated T cells from tuberculoid but not from lepromatous patients. Interestingly, IL-12Rβ2 in lepromatous patients could be up-regulated by stimulation with M. tuberculosis. These data suggest that Th response to M. leprae determines IL-12Rβ2 expression and function in host defense in leprosy.
Engagement of FcεRI on Human Monocytes Induces the Production of IL-10 and Prevents Their Differentiation in Dendritic Cells
Authors: Novak Natalija , Bieber Thomas , Katoh Norito 
Published: April 2014

AbstractThe local cytokine environment and the presence of stimulatory signals determine whether circulating monocytes will finally acquire characteristics of dendritic cells (DCs) or macrophages. Because FcεRI expressed on professional APCs, e.g., monocytes and DCs, has been suggested to play a key role in the pathophysiology of atopic diseases, we evaluated the effect of receptor ligation on the generation of monocyte-derived DCs (MoDCs). Aggregation of FcεRI at the initiation of the IL-4-GM-CSF-driven differentiation resulted in the emergence of macrophage-like cells with a strong expression of the mannose receptor and a low level of CD1a and the DC-specific markers CD83 and the actin-bundling protein (p55). These cells sustained the ability to take up FITC-labeled Escherichia coli by phagocytosis and were significantly less efficient in stimulating purified allogeneic T cells. In addition, receptor ligation of FcεRI at the beginning of the culture prevented the generation of MoDCs, mainly due to a dramatic increase in the IL-10 production. These results suggest that FcεRI aggregation prevents the generation of CD1a+ MoDCs and imply a novel pivotal function of this receptor in modulating the differentiation of monocytes.
Peripheral T Cells Become Sensitive to Glucocorticoid- and Stress-Induced Apoptosis in Transgenic Mice Overexpressing SRG3
Authors: Han Sunmi , Choi Heonsik , Ko Myung-gon , Choi Young I. , Sohn Dong H. , Kim Joong K. , Shin Dongho , Chung Heekyoung , Lee Han W. , Kim Jae-B. , Park Sang D. , Seong Rho H. 
Published: April 2014

AbstractImmature double-positive thymocytes are sensitive to glucocorticoid (GC)-induced apoptosis, whereas mature single-positive T cells are relatively resistant. Thymocytes seem to acquire resistance to GCs during differentiation into mature single-positive thymocytes. However, detailed knowledge concerning what determines the sensitivity of thymocytes to GCs and how GC sensitivity is regulated in thymocytes during development is lacking. We have previously reported that the murine SRG3 gene (for SWI3-related gene) is required for GC-induced apoptosis in a thymoma cell line. Herein, we provide results suggesting that the expression level of SRG3 protein determines the GC sensitivity of T cells in mice. SRG3 associates with the GC receptor in the thymus, but rarely in the periphery. Transgenic overexpression of the SRG3 protein in peripheral T cells induces the formation of the complex and renders the cells sensitive to GC-induced apoptosis. Our results also show that blocking the formation of the SRG3-GC receptor complex with a dominant negative mutant form of SRG3 decreases GC sensitivity in thymoma cells. In addition, mice overexpressing the SRG3 protein appear to be much more susceptible to stress-induced deletion of peripheral T cells than normal mice, which may result in an immunosuppressive state in an animal.
Monomeric Class I Molecules Mediate TCR/CD3ε/CD8 Interaction on the Surface of T Cells
Authors: Block Matthew S. , Johnson Aaron J. , Mendez-Fernandez Yanice , Pease Larry R. 
Published: April 2014

Abstract
Both CD8 and the TCR bind to MHC class I molecules during physiologic T cell activation. It has been shown that for optimal T cell activation to occur, CD8 must be able to bind the same class I molecule that is bound by the TCR. However, no direct evidence for the class I-dependent association of CD8 and the TCR has been demonstrated. Using fluorescence resonance energy transfer, we show directly that a single class I molecule causes TCR/CD8 interaction by serving as a docking molecule for both CD8 and the TCR. Furthermore, we show that CD3ε is brought into close proximity with CD8 upon TCR/CD8 association. These interactions are not dependent on the phosphorylation events characteristic of T cell activation. Thus, MHC class I molecules, by binding to both CD8 and the TCR, mediate the reorganization of T cell membrane components to promote cellular activation.
Signal Transduction by Human-Restricted FcγRIIa Involves Three Distinct Cytoplasmic Kinase Families Leading to Phagocytosis
Authors: Cooney Damon S. , Phee Hyewon , Jacob Anand , Coggeshall K. Mark 
Published: April 2014

AbstractRecent experiments indicate an important role for Src family and Syk protein tyrosine kinases and phosphatidylinositol 3-kinase in the signal transduction process initiated by mouse receptors for IgG and leading to phagocytosis. Considerably less is known regarding signal transduction by the human-restricted IgG receptor, FcγRIIa. Furthermore, the relationship among the Src family, Syk, and phosphatidylinositol 3-kinase in phagocytosis is not understood. Here, we show that FcγRIIa is phosphorylated by an Src family member, which results in recruitment and concomitant activation of the distal enzymes Syk and phosphatidylinositol 3-kinase. Using a FcγRI-p85 receptor chimera cotransfected with kinase-inactive mutants of Syk or application of a pharmacological inhibitor of Syk, we show that Syk acts in parallel with phosphatidylinositol 3-kinase. Our results indicate that FcγRIIa-initiated monocyte or neutrophil phagocytosis proceeds from the clustered IgG receptor to Src to phosphatidylinositol 3-kinase and Syk.
Chromatin Remodeling at the Ig Loci Prior to V(D)J Recombination
Authors: Maës Jérôme , O’Neill Laura P. , Cavelier Patricia , Turner Bryan M. , Rougeon François , Goodhardt Michele 
Published: April 2014

AbstractRearrangement of Ig H and L chain genes is highly regulated and takes place sequentially during B cell development. Several lines of evidence indicate that chromatin may modulate accessibility of the Ig loci for V(D)J recombination. In this study, we show that remodeling of V and J segment chromatin occurs before V(D)J recombination at the endogenous H and κ L chain loci. In recombination-activating gene-deficient pro-B cells, there is a reorganization of nucleosomal structure over the H chain JH cluster and increased DNase I sensitivity of VH and JH segments. The pro-B/pre-B cell transition is marked by a decrease in the DNase I sensitivity of VH segments and a reciprocal increase in the nuclease sensitivity of Vκ and Jκ segments. In contrast, JH segments remain DNase I sensitive, and their nucleosomal organization is maintained in μ+ recombination-activating gene-deficient pre-B cells. These results indicate that initiation of rearrangement is associated with changes in the chromatin structure of both V and J segments, whereas stopping recombination involves changes in only V segment chromatin. We further find an increase in histone H4 acetylation at both the H and κ L chain loci at the pro-B cell stage. Although histone H4 acetylation appears to be an early change associated with B cell commitment, acetylation alone is not sufficient to promote subsequent modifications in Ig chromatin.