bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-4 Influences Apoptosis of Mycobacterium-Reactive Lymphocytes in the Presence of TNF-α
Authors: Seah Geok Teng , Rook Graham A. W. 
Published: April 2014

AbstractT cell apoptosis is associated with defective cell-mediated effector functions in several infectious diseases. In tuberculosis, there is evidence that T cell apoptosis may be cytokine mediated, but the mechanisms are not clearly understood. Type 2 cytokines have recently been associated with disease extent in human tuberculosis, but they have not previously been linked to apoptosis in mycobacterium-reactive T cells. This study presents evidence that PBLs from healthy donors respond to sonicated Mycobacterium tuberculosis Ags with increased IL-4 gene activation, CD30 expression, and apoptosis. The changes were significantly greater than those observed when cells were stimulated with Ags from nonpathogenic Mycobacterium vaccae. A hypothesis linking these observations was tested. CD30 expression and TNF-α-mediated lymphocyte apoptosis were both down-regulated by inhibiting IL-4 in this model. TNFR-associated factor 2 (TRAF2) expression was down-regulated in CD30+ cells, and addition of anti-TNF-α Ab significantly reduced apoptosis in the CD30+ but not the CD30− population. These observations support the hypothesis that increased IL-4 expression in M. tuberculosis-activated lymphocytes promotes CD30 expression, which sensitizes the lymphocytes to TNF-α-mediated apoptosis via TRAF2 depletion. This may be one mechanism by which IL-4 is associated with immunopathological consequences in human tuberculosis.
Human IL-18 Receptor and ST2L Are Stable and Selective Markers for the Respective Type 1 and Type 2 Circulating Lymphocytes
Authors: Chan Woon Ling , Pejnovic Nada , Lee Christine A. , Al-Ali Nadia A. 
Published: April 2014

AbstractCD4+ (Th) and CD8+ (Tc) T and NK lymphocytes can be divided into type 1 and 2 subsets according to their cytokine secretion profile. Studies on the role of lymphocyte subsets in human diseases have been hampered by the lack of stable surface markers to define them. Recently, we reported that ST2L and IL-18R are stably expressed on murine Th2 and Th1 cells, respectively. In this study, we generated Abs to human homologues of ST2L and IL-18R and tested them against Th1/Th2, Tc1/Tc2, and NK1/NK2 lines and PBMCs from healthy individuals. We show for the first time that ST2L and IL-18R are stable selective cell surface markers for human Th2/Tc2/NK2 and Th1/Tc1/NK1 lymphocytes, respectively. We then investigated PBMCs from HIV-infected patients and HIV-negative individuals, to test whether Abs to these two surface markers could be used directly to monitor lymphocyte subset distribution in human diseases. We found a clear Th1 to Th2 shift in the HIV-infected individuals, thus settling a long-standing controversy and include, for the first time, Tc and NK cells as well. Therefore, these cell surface molecules could serve as important determinants of the immune status of human diseases in general, and thereby could be useful for therapeutic monitoring and intervention.
CD4+CD25high Regulatory Cells in Human Peripheral Blood
Authors: Baecher-Allan Clare , Brown Julia A. , Freeman Gordon J. , Hafler David A. 
Published: April 2014

Abstract
Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD+CD25+ T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4+ population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4+CD25+ regulatory cells isolated in mice. With TCR cross-linking, CD4+CD25high cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4+CD25− responder T cells in a contact-dependent manner. The CD4+CD25high regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RBlow on murine CD4+CD25+ regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4+CD25high regulatory cells and CD4+CD25− responder cells. Whereas higher ratios of CD4+CD25high T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.
Processing of Exogenous Antigens for Presentation by Class I MHC Molecules Involves Post-Golgi Peptide Exchange Influenced by Peptide-MHC Complex Stability and Acidic pH
Authors: Chefalo Peter J. , Harding Clifford V. 
Published: April 2014

AbstractVacuolar alternate class I MHC (MHC-I) Ag processing allows presentation of exogenous Ag by MHC-I molecules with binding of antigenic peptides to post-Golgi MHC-I molecules. We investigated the role of previously bound peptides and their dissociation in generating peptide-receptive MHC-I molecules. TAP1-knockout macrophages were incubated overnight with an initial exogenous peptide, producing a large cohort of peptide-Kb complexes that could influence subsequent peptide dissociation/exchange. Initial incubation with FAPGNYPAL, KVVRFDKL, or RGYVYQGL enhanced rather than reduced subsequent binding and presentation of a readout peptide (SIINFEKL or FAPGNYPAL) to T cells. Thus, Kb molecules may be stabilized by an initial (stabilizing) peptide, enhancing their ability to bind readout peptide and implicating peptide dissociation/exchange. In contrast, incubation with SIINFEKL as stabilizing peptide reduced presentation of readout peptide. SIINFEKL-Kb complexes were more stable than other peptide-Kb complexes, which may limit their contribution to peptide exchange. Stabilizing peptides (FAPGNYPAL, KVVRFDKL, or RGYVYQGL) enhanced alternate MHC-I processing of HB101.Crl-OVA (Escherichia coli expressing an OVA fusion protein), indicating that alternate MHC-I Ag processing involves peptide dissociation/exchange. Stabilizing peptide enhanced processing of HB101.Crl-OVA more than presentation of exogenous OVA peptide (SIINFEKL), suggesting that peptide dissociation/exchange may be enhanced in the acidic phagosomal processing environment. Furthermore, exposure of cells to acidic pH increased subsequent binding and presentation of readout peptide. Thus, peptide dissociation/exchange contributes to alternate MHC-I Ag processing and may be influenced by both stability of peptide-MHC-I complexes and pH.
Heterogeneity of Channel Catfish CTL with Respect to Target Recognition and Cytotoxic Mechanisms Employed
Authors: Zhou He , Stuge Tor B. , Miller Norman W. , Bengten Eva , Naftel John P. , Bernanke Jayne M. , Chinchar V. Gregory , Clem L. William , Wilson Melanie 
Published: April 2014

Abstract
Two types of catfish alloantigen-dependent cytotoxic T cells were cloned from PBL from a fish immunized in vivo and stimulated in vitro with the allogeneic B cell line 3B11. Because these are the first clonal cytotoxic T cell lines derived from an ectothermic vertebrate, studies were undertaken to characterize their recognition and cytotoxic mechanisms. The first type of CTL (group I) shows strict alloantigen specificity, i.e., they specifically kill and proliferate only in response to 3B11 cells. The second type (group II) shows broad allogeneic specificity, i.e., they kill and proliferate in response to several different allogeneic cells in addition to 3B11. “Cold” target-inhibition studies suggest that group II CTL recognize their targets via a single receptor, because the killing of one allotarget can be inhibited by a different allotarget. Both types of catfish CTL form conjugates with and kill targets by apoptosis. Killing by Ag-specific cytotoxic T cells (group I) was completely inhibited by treatment with EGTA or concanamycin A, and this killing is sensitive to PMSF inhibition, suggesting that killing was mediated exclusively by the secretory perforin/granzyme mechanism. In contrast, killing by the broadly specific T cytotoxic cells (group II) was only partially inhibited by either EGTA or concanamycin A, suggesting that these cells use a cytotoxic mechanism in addition to that involving perforin/granzyme. Consistent with the presumed use of a secretory pathway, both groups of CTL possess putative lytic granules. These results suggest that catfish CTL show heterogeneity with respect to target recognition and cytotoxic mechanisms.
The Role of p53 in Regulating Antiviral T Cell Responses
Authors: Grayson Jason M. , Lanier J. Gibson , Altman John D. , Ahmed Rafi 
Published: April 2014

AbstractIt is now well established that viral infections can induce large expansions of Ag-specific CD8+ T cells. These cells divide very rapidly with an estimated doubling time of ∼6 h. When virus is cleared, the vast majority of these effector CD8 T cells undergo apoptosis. The remaining memory cells persist at constant levels and provide the basis for the accelerated recall response upon rechallenge. The molecular mechanisms that control the rapid proliferation and death of Ag-specific T cells are poorly understood. Because of its important role in controlling cell proliferation and death, we examined antiviral immune responses in p53−/− mice using lymphocytic choriomeningitis virus. We found that effector CD8 and CD4 responses were comparable but that memory levels were slightly higher in −/− mice compared with +/+ mice. The lack of a major difference in virus-specific T cell responses between +/+ and −/− mice suggests that p53 only plays a minor role in regulating the proliferation, apoptosis, and maintenance of Ag-specific T cells. Thus, it appears that the primary function of p53 is in controlling “illegitimate” proliferation and tumor development and not in regulating Ag-specific T cell responses.
Transgenic Expression of CD95 Ligand on Thyroid Follicular Cells Confers Immune Privilege upon Thyroid Allografts
Authors: Tourneur Léa , Malassagne Benoit , Batteux Frédéric , Fabre Monique , Mistou Sylvie , Lallemand Eliette , Lores Patrick , Chiocchia Gilles 
Published: April 2014

AbstractConstitutive Fas ligand (FasL) expression by specialized cells in the body participates in the immune privilege status of tissues containing these cells. This property has been used to prevent rejection of allogeneic grafts. Nevertheless, the mechanism responsible for such protection has not been fully elucidated. Unfortunately, grafting of FasL transgenic (TG) tissues has been unsuccessful. We have generated TG mice expressing FasL (soluble + membrane bound) on thyroid follicular cells (TFC), and used them to show that ectopic FasL expression prevents thyroid allograft rejection. FasL expression on TFC led to markedly decreased anti-allogeneic, cytotoxic, and helper T lymphocyte activities. The alloantibody response in TG thyroid recipients was either completely inhibited or switched toward a T2-Ab response. Surprisingly, the beneficial effect of FasL on TG thyroid grafts was abolished by host CD4+ T cell depletion. Host CD8+ T cell depletion improved nontransgenic (NTG), but not TG graft survival. Altogether, our results suggest that FasL-induced tolerance is concomitant with a move away from a T1 type response, and a CD4 T cell-mediated regulation of the allocytotoxic T cell response. These results were dependent upon the level of FasL expression on TFC, in that low expression of FasL led to a less marked effect compared with the effect observed with high expression of FasL. These results provide some insight into the role of FasL in regulating destructive alloimmune responses in the case of whole organ grafting, and they have important implications for the development of FasL-based immunotherapy in organ transplantation.
A Common Pathway for Dendritic Cell and Early B Cell Development
Authors: Izon David , Rudd Kristina , DeMuth William , Pear Warren S. , Clendenin Cynthia , Lindsley R. Coleman , Allman David 
Published: April 2014

AbstractB cells and dendritic cells (DCs) each develop from poorly described progenitor cells in the bone marrow (BM). Although a subset of DCs has been proposed to arise from lymphoid progenitors, a common developmental pathway for B cells and BM-derived DCs has not been clearly identified. To address this possibility, we performed a comprehensive analysis of DC differentiative potential among lymphoid and B lymphoid progenitor populations in adult mouse BM. We found that both the common lymphoid progenitors (CLPs), shown here and elsewhere to give rise exclusively to lymphocytes, and a down-stream early B-lineage precursor population devoid of T and NK cell precursor potential each give rise to DCs when exposed to the appropriate cytokines. This result contrasts with more mature B-lineage precursors, all of which failed to give rise to detectable numbers of DCs. Significantly, both CLP and early B-lineage-derived DCs acquired several surface markers associated with functional DCs, and CLP-derived DCs readily induced proliferation of allogeneic CD4+ T cells. Surprisingly, however, DC differentiation from both lymphoid-restricted progenitors was accompanied by up-regulation of CD11b expression, a cell surface molecule normally restricted to myeloid lineage cells including putative myeloid DCs. Together, these data demonstrate that loss of DC developmental potential is the final step in B-lineage commitment and thus reveals a previously unrecognized link between early B cell and DC ontogeny.
Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells
Authors: Trobonjaca Zlatko , Leithäuser Frank , Möller Peter , Schirmbeck Reinhold , Reimann Jörg 
Published: April 2014

AbstractA prominent subset of the hepatic innate immune system is α-galactosylceramide (αGalCer)-reactive, (CD4+ and CD4−CD8−) CD1d-restricted NKT cells. We investigated in C57BL/6 (B6) mice which hepatic cell type stimulates hepatic NKT cell activation. Surface expression of CD1d but not CD40, CD80, or CD86 costimulator molecules was detected in hepatocytes. Pulsed in vitro or in vivo with αGalCer, hepatocytes triggered IL-4 release by liver NKT cells but required exogenous IL-12 to trigger IFN-γ release by NKT cells. Liver dendritic cells (DC) isolated from nontreated mice showed low surface expression of MHC, CD1d, and CD40, CD80, or CD86 costimulator molecules that were strikingly up-regulated after αGalCer injection. Although liver CD11c+ DC displayed lower CD1d surface expression than hepatocytes, they were potent stimulators of IFN-γ and IL-4 release by liver NKT when pulsed with αGalCer in vitro or in vivo. Liver DC are thus potent stimulators of proinflammatory cytokine release by NKT cells, are activated themselves in the process of NKT cell activation, and express an activated phenotype after the NKT cell population is eliminated following αGalCer stimulation.
Cellular Activation of Leukocyte Function-Associated Antigen-1 and Its Affinity Are Regulated at the I Domain Allosteric Site
Authors: Lupher Mark L. , Harris Edith A. S. , Beals Chan R. , Sui LiMing , Liddington Robert C. , Staunton Donald E. 
Published: April 2014

AbstractThe I domain of the integrin LFA-1 possesses a ligand binding interface that includes the metal ion-dependent adhesion site. Binding of the LFA-1 ligand, ICAM-1 to the metal ion-dependent adhesion site is regulated by the I domain allosteric site (IDAS). We demonstrate here that intracellular signaling leading to activation of LFA-1 binding to ICAM-1 is regulated at the IDAS. Inhibitory mutations in or proximal to the IDAS are dominant to cytoplasmic signals that activate binding to ICAM-1. In addition, mutational activation at the IDAS greatly increases the binding of lymphocyte-expressed LFA-1 to ICAM-1 in response to PMA, but does not result in constitutive binding. Binding of a novel CD18 activation epitope mAb to LFA-1 in response to soluble ICAM-1 binding was also blocked by inhibitory and was enhanced by activating IDAS mutations. Surface plasmon resonance using soluble wild-type LFA-1 and an IDAS mutant of LFA-1 indicate that the IDAS can regulate a 6-fold change in the Kd of ICAM-1 binding. The Kd of wild-type LFA-1 (1.2 × 10−1 s−1) differed with that of the activating IDAS mutant (1.9 × 10−2 s−1), but their Ka values were identical (2.2 × 105 M−1s−1). We propose that IDAS regulates the binding of LFA-1 to ICAM-1 activated by intracellular signals. IDAS can control the affinity state of LFA-1 with concomitant I domain and CD18 conformational changes.
Two Novel IL-1 Family Members, IL-1δ and IL-1ε, Function as an Antagonist and Agonist of NF-κB Activation Through the Orphan IL-1 Receptor-Related Protein 2
Authors: Debets Reno , Timans Jackie C. , Homey Bernhard , Zurawski Sandra , Sana Theodore R. , Lo Sylvia , Wagner Janet , Edwards Gina , Clifford Teresa , Menon Satish , Bazan J. Fernando , Kastelein Robert A. 
Published: April 2014

Abstract
IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1δ and IL-1ε. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1δ and ε. Levels of keratinocyte IL-1δ are ∼10-fold higher than those of IL-1ε. In vitro stimulation of keratinocytes with IL-1β/TNF-α significantly up-regulates the expression of IL-1ε mRNA, and to a lesser extent of IL-1δ mRNA. In NF-κB-luciferase reporter assays, we demonstrated that IL-1δ and ε proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1α and β or IL-18. However, IL-1ε activates NF-κB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1δ, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1ε response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1δ and ε and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1αβ/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.
Genomic Structure and Transcriptional Regulation of the Early B Cell GenechB1
Authors: Goitsuka Ryo , Mamada Hiroshi , Kitamura Daisuke , Cooper Max D. , Chen Chen-lo H. 
Published: April 2014

AbstractThe avian B cell differentiation Ag chB1 is a membrane glycoprotein relative of the mammalian B cell differentiation Ag CD72. Unlike CD72, this C-type lectin is expressed in relatively high levels on immature B cells in the bursa of Fabricius and is down-regulated on mature B cells in the periphery. An immunoreceptor tyrosine-based inhibitory motif in the chB1 cytoplasmic tail suggests a potential regulatory role in intrabursal B cell development. To gain further insight into the selective expression and function of chB1, we determined the genomic organization of chB1 and examined the mechanism of its transcriptional regulation. The 8-exon chB1 gene proved to have very similar organization to that of mouse CD72, further supporting the idea that chB1 is a CD72 relative. As for mouse CD72, the chB1 promoter region lacks a TATA box but contains a conserved initiator element. The 131-bp region (−161 to −30) proximal to the transcriptional start site, which contains a potential early B cell factor binding site, is essential for the B lineage stage-specific transcription of chB1, whereas PU.1 and B cell-specific activator protein/Pax5 have been shown to play important roles in CD72 promoter activity and cell-type specificity. This analysis suggests that differences in transcriptional regulation of these phylogenetically related genes may determine the differences in expression pattern and, therefore, the function of avian chB1 and mammalian CD72 during B cell development.
The Inhibitory Effect of IL-1β on IL-6-Induced α2-Macroglobulin Expression Is Due to Activation of NF-κB
Authors: Bode Johannes G. , Fischer Richard , Häussinger Dieter , Graeve Lutz , Heinrich Peter C. , Schaper Fred 
Published: April 2014

AbstractThe cross-talk between the signal transduction of simultaneous acting cytokines largely determines the final impact of cytokines on their target genes. Both NF-κB and STAT3 are transcription factors well known to be activated by many stimuli and to mediate transcriptional activation by binding to specific enhancer sequences. In this study, it is analyzed how IL-1β inhibits IL-6-induced transcriptional activation of the α2-macroglobulin promoter. It is shown that IL-1β prevents STAT3 binding to the two STAT3-responsive sites within the α2-macroglobulin promoter by association of IL-1β-activated NF-κB to this region. The observation that inhibition of IL-6-induced transcriptional activation of this promoter by IL-1β is reversed by cotransfection with I-κBα provides evidence that NF-κB activation by IL-1β is responsible for inhibition of IL-6-mediated trans activation of the α2-macroglobulin gene. Accordingly, cotransfection of the NF-κB subunits p50 or p65 themselves inhibited activation of the α2-macroglobulin promoter by IL-6. Introduction of point mutations in each of the two NF-κB sites overlapping the two STAT3 binding sites within the α2-macroglobulin promoter provides evidence that each of these two sites counteracts transcriptional activation via STAT3. Most interestingly, at least one functional NF-κB consensus site is essential for the IL-6-induced transcriptional activation of the α2-macroglobulin promoter. Additional data are provided indicating that the activation of NF-κB by IL-1β is also responsible for the inhibition of other IL-6-inducible genes, such as the α1-antichymotrypsin gene as well as the suppressor of cytokine signaling 3 gene, suggesting a more general relevance of this mechanism for transcriptional regulation.