bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory Role of IFN-γ-Inducible Lysosomal Thiol Reductase in T Cell Activation
Authors: Barjaktarević Igor , Rahman Ayman , Radoja Sasa , Bogunović Branka , Vollmer Alison , Vukmanović Stanislav , Marić Maja 
Published: April 2014

AbstractIFN-γ-inducible lysosomal thiol reductase (GILT) is a unique thiol reductase with optimal enzymatic activity at low pH. GILT plays a crucial role in unfolding the antigenic proteins in preparation for their proteolytic cleavage and presentation of resulting peptides by MHC class II. In this study, we demonstrate that GILT is expressed in T lymphocytes and that it has an APC-nonrelated role in the regulation of T cell activation. Surprisingly, comparison of wild-type and GILT-deficient T cell activation in vitro revealed stronger responsiveness in the absence of GILT. The effect of GILT in reducing the proliferative and cytotoxic responses was endogenous to T cells and resulted from decreased sensitivity at the individual cell level. Therefore, a molecule with primarily lysosomal localization suppresses T cell activation, a process characterized by signal transmission from plasma membrane to cytoplasm and nucleus.
Induction of Autoimmunity by Expansion of Autoreactive CD4+CD62Llow Cells In Vivo
Authors: Amend Bastian , Doster Hong , Lange Christian , Dubois Evelyn , Kalbacher Hubert , Melms Arthur , Bischof Felix 
Published: April 2014

Abstract
The prerequisites of peripheral activation of self-specific CD4+ T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139–151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IAs/PLP139–151 tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN-γ production by self-specific CD4+ T cells. In addition, PT promoted the generation of CD4+CD62Llow effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4+CD62Lhigh cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c+CD4+ dendritic cells whereas CD11c+CD8α+ dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4+CD62Llow cells and indicate that CD4+CD62Llow effector T cells and CD11c+CD4+ dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.
The Effects of Age, Thymectomy, and HIV Infection on α and β TCR Excision Circles in Naive T Cells
Authors: van den Dool Carline , de Boer Rob J. 
Published: April 2014

AbstractDue to homeostasis total naive T cell numbers remain fairly constant over life despite a gradual involution of the thymus. The contribution of the thymus to maintaining naive T cell pools is typically measured with TCR excision circles (TRECs) that are formed in thymocytes. The mechanisms underlying thymic involution are poorly understood. Some data suggest that thymocytes undergo fewer divisions in old (small) than young (large) thymi, and other data suggest that the number of TRECs per thymocyte is independent of age. If thymic involution were associated with a decreased number of divisions of the thymocytes, this would markedly complicate the interpretation of TREC data. To study this we develop a mathematical model in which the division rate of thymocytes decreases with increasing age. We describe the dilution of TRECs formed during the arrangement of both chains of the TCR by division of thymocytes, recent thymic emigrants, and mature naive T cells. The model behavior is complicated as TREC contents in naive T cells can increase with age due to decreased dilution in the thymus. Because our model is consistent with current data on the effects of age and thymectomy on TRECs in peripheral T cells, we conclude that aging may well affect thymocyte division, which markedly complicates the interpretation of TREC data. It is possible, but more difficult, to let the model be consistent with the rapid changes in α and β TRECs observed shortly after HIV infection.
Host-Derived Langerhans Cells Persist after MHC-Matched Allografting Independent of Donor T Cells and Critically Influence the Alloresponses Mediated by Donor Lymphocyte Infusions
Authors: Durakovic Nadira , Bezak Karl B. , Skarica Mario , Radojcic Vedran , Fuchs Ephraim J. , Murphy George F. , Luznik Leo 
Published: April 2014

Abstract
Mouse models of minor histocompatibility Ag-mismatched bone marrow transplantation were used to study donor dendritic cell (DC) reconstitution after conditioning, variables influencing the persistence of residual host DCs in different compartments, their phenotype, and their role in governing donor lymphocyte infusion (DLI)-mediated alloresponses. Reconstitution of all splenic DC subsets occurred rapidly after bone marrow transplantation and before T cell reconstitution. However, in contrast to MHC-mismatched chimeras, residual host-derived DCs persisted in the cutaneous lymph nodes (CLNs) of MHC-matched chimeras despite the presence or addition of donor T cells to the graft. The phenotype of these residual host-derived DCs in CLNs was consistent with Langerhans’ cells (LCs). We confirmed their skin origin and found near-complete preservation of host-derived LCs in the skin. Host-derived LCs retained their ability to continuously traffic to the CLNs, expressed homogeneously increased levels of costimulatory molecules, and could capture and carry epicutaneously applied Ags. To determine the role of residual host LCs in governing DLI-mediated alloresponses, we administered DLI alone or after topical application of the TLR7 ligand imiquimod, which is known to enhance the LC emigration from the skin. DLI administration resulted in a decrease in host-derived DCs in the CLNs and increased recruitment of donor-derived DCs to the skin, whereas imiquimod augmented their alloreactivity. These results suggest uniqueness of the MHC-matched setting in relation to the persistence of host-derived DCs in the skin and points to a previously unrecognized role of host-derived LCs in the induction of DLI-mediated graft-vs-host alloresponses.
Regulatory Role of γδ T Cells in the Recruitment of CD4+ and CD8+ T Cells to Lung and Subsequent Pulmonary Fibrosis
Authors: Simonian Philip L. , Roark Christina L. , Diaz del Valle Fernando , Palmer Brent E. , Douglas Ivor S. , Ikuta Koichi , Born Willi K. , O’Brien Rebecca L. , Fontenot Andrew P. 
Published: April 2014

AbstractThe mechanisms by which T cells accumulate in the lungs of patients with pulmonary fibrosis are poorly understood. Because the lung is continually exposed to microbial agents from the environment, we repeatedly exposed C57BL/6 mice to the ubiquitous microorganism, Bacillus subtilis, to determine whether chronic exposure to an inhaled microorganism could lead to T cell accumulation in the lungs and subsequent pulmonary fibrosis. C57BL/6 mice repeatedly treated with B. subtilis for 4 consecutive weeks developed a 33-fold increase in the number of CD4+ T cells and a 354-fold increase in γδ T cells in the lung. The γδ T cells consisted almost entirely of Vγ6/Vδ1+ cells, a murine subset bearing an invariant TCR the function of which is still unknown. Treatment of C57BL/6 mice with heat-killed vs live B. subtilis resulted in a 2-fold increase in the number of CD4+ T cells in the lung but no expansion of γδ T cells indicating that γδ cells accumulate in response to live microorganisms. In addition, mice treated with heat-killed B. subtilis developed significantly increased pulmonary fibrosis compared with mice treated with the live microorganism. Mice deficient in Vγ6/Vδ1+ T cells when treated with B. subtilis had a 231-fold increase in lung CD4+ T cells and significantly increased collagen deposition compared with wild-type C57BL/6 mice, consistent with an immunoregulatory role for the Vγ6/Vδ1 T cell subset. These findings indicate that chronic inhalation of B. subtilis can result in T cell accumulation in the lung and fibrosis, constituting a new model of immune-mediated pulmonary fibrosis.
Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses
Authors: Lee Seung-Woo , Park Yunji , Song Aihua , Cheroutre Hilde , Kwon Byoung S. , Croft Michael 
Published: April 2014

AbstractMembers of the TNFR family are thought to deliver costimulatory signals to T cells and modulate their function and survival. In this study, we compare the role of two closely related TNFR family molecules, OX40 and 4-1BB, in generating effector CD8 T cells to Ag delivered by adenovirus. OX40 and 4-1BB were both induced on responding naive CD8 T cells, but 4-1BB exhibited faster and more sustained kinetics than OX40. OX40-deficient CD8 T cells initially expanded normally; however, their accumulation and survival at late times in the primary response was significantly impaired. In contrast, 4-1BB-deficient CD8 T cells displayed hyperresponsiveness, expanding more than wild-type cells. The 4-1BB-deficient CD8 T cells also showed enhanced maturation attributes, whereas OX40-deficient CD8 T cells had multiple defects in the expression of effector cell surface markers, the synthesis of cytokines, and in cytotoxic activity. These results suggest that, in contrast to current ideas, OX40 and 4-1BB can have a clear functional dichotomy in modulating effector CD8 T cell responses. OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses.
CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway
Authors: Sester David P. , Brion Kristian , Trieu Angela , Goodridge Helen S. , Roberts Tara L. , Dunn Jasmyn , Hume David A. , Stacey Katryn J. , Sweet Matthew J. 
Published: April 2014

AbstractBacterial CpG-containing (CpG) DNA promotes survival of murine macrophages and triggers production of proinflammatory mediators. The CpG DNA-induced inflammatory response is mediated via TLR9, whereas a recent study reported that activation of the Akt prosurvival pathway occurs via DNA-dependent protein kinase (DNA-PK) and independently of TLR9. We show, in this study, that Akt activation and survival of murine bone marrow-derived macrophages (BMM) triggered by CpG-containing phosphodiester oligodeoxynucleotides or CpG-containing phosphorothioate oligodeoxynucleotides was completely dependent on TLR9. In addition, survival triggered by CpG-containing phosphodiester oligodeoxynucleotides was not compromised in BMM from SCID mice that express a catalytically inactive form of DNA-PK. CpG DNA-induced survival of BMM was inhibited by the PI3K inhibitor, LY294002, but not by the MEK1/2 inhibitor, PD98059. The effect of LY294002 was specific to survival, because treatment of BMM with LY294002 affected CpG DNA-induced TNF-α production only modestly. Therefore, CpG DNA activates macrophage survival via TLR9 and the PI3K-Akt pathway and independently of DNA-PK and MEK-ERK.
The Majority of Human Peripheral Blood CD4+CD25highFoxp3+ Regulatory T Cells Bear Functional Skin-Homing Receptors
Authors: Hirahara Kazuki , Liu Luzheng , Clark Rachael A. , Yamanaka Kei-ichi , Fuhlbrigge Robert C. , Kupper Thomas S. 
Published: April 2014

Abstract
CD4+CD25+ T regulatory cells (Treg) are thought to be important in the peripheral tolerance. Recent evidence suggests that human peripheral blood CD4+CD25+ T cells are heterogeneous and contain both CD4+CD25high T cells with potent regulatory activity and many more CD4+CD25low/med nonregulatory T cells. In this study, we found that virtually all peripheral blood CD4+CD25highFoxp3+ Treg expressed high levels of the chemokine receptor CCR4. In addition, 80% of Treg expressed cutaneous lymphocyte Ag (CLA) and 73% expressed CCR6. These molecules were functional, as CLA+ Treg showed CD62E ligand activity and demonstrable chemotactic responses to the CCR4 ligands CCL22 and CCL17 and to the CCR6 ligand CCL20. The phenotype and chemotactic response of these Treg were significantly different from those of CD4+CD25med nonregulatory T cells. We further demonstrated that blood CLA+ Treg inhibited CD4+CD25− T cell proliferation induced by anti-CD3. Based on homing receptor profile, CLA+ Treg should enter normal skin. We next isolated CD4+CD25high T cells directly from normal human skin; these cells suppressed proliferation of skin CD4+CD25− T cells. Therefore, the majority of true circulating Treg express functional skin-homing receptors, and human Treg may regulate local immune responses in normal human skin.
Trauma-Hemorrhage Induces Depressed Splenic Dendritic Cell Functions in Mice
Authors: Kawasaki Takashi , Hubbard William J. , Choudhry Mashkoor A. , Schwacha Martin G. , Bland Kirby I. , Chaudry Irshad H. 
Published: April 2014

AbstractAlthough Kupffer cell, splenic, and peritoneal macrophage functions are markedly altered following trauma-hemorrhage (T-H), it remains unclear whether T-H also affects splenic dendritic cell (sDC) functions. We hypothesized that sDC functions will also be compromised following T-H. Male C3H/HeN (6- to 8-wk) mice were randomly assigned to sham operation or T-H. T-H was induced by midline laparotomy and ∼90 min of hemorrhagic shock (blood pressure 35 mmHg), followed by fluid resuscitation (four times the shed blood volume in the form of Ringer’s lactate). Two hours later, the mice were sacrificed; sDC were isolated; and the changes in their apoptosis, MHC class II expression, and ability to produce costimulatory cytokines and Ag presentation were measured. The results indicate that sDC Ag presentation capacity was significantly decreased and MHC class II expression was also significantly decreased following T-H. Moreover, LPS-induced IL-12 production and LPS- or IL-12-induced IFN-γ production following T-H were significantly decreased. Thus, the markedly decreased MHC class II expression and cytokine (IL-12, IFN-γ) production following T-H may be the cause for the depressed sDC Ag presentation under those conditions. This depression in Ag presentation could contribute to the host’s enhanced susceptibility to sepsis following T-H.
STAT1-Independent Cell Type-Specific Regulation of Antiviral APOBEC3G by IFN-α
Authors: Sarkis Phuong Thi Nguyen , Ying Songcheng , Xu Rongzhen , Yu Xiao-Fang 
Published: April 2014

Abstract
APOBEC3G (A3G) has broad antiviral activity against retroviruses and hepatitis B virus. However, the role of IFNs in regulating A3G during innate immunity has not been established. In this study, we show that the A3G gene is uniquely regulated by IFNs in a cell type-dependent manner. A3G was up-regulated by IFN-α in liver cells and macrophages, but not in T lymphoid cells or epithelial 293T cells. In contrast, other IFN-α-stimulated genes such as dsRNA-activated protein kinase were induced in all these cells, suggesting additional cellular factors may regulate IFN-α-induced A3G expression. Consistent with this idea, IFN-α-mediated induction of A3G, but not other IFN-α-stimulated genes, was potently inhibited by the drug Rottlerin, through a mechanism independent of STAT1 activation. The canonical IFN-α-mediated pathway of gene transcription requires both STAT1 and STAT2. Surprisingly, induction of A3G was STAT1 independent, but STAT2 dependent in liver cells. However, STAT1 signaling was functional and required for IFN-γ induction of A3G in these cells. Our results indicate that A3G may participate in antiviral cellular defenses through a novel IFN-mediated signaling pathway.
Intracellular Protein Modification Associated with Altered T Cell Functions in Autoimmunity
Authors: Yang Mei-Ling , Doyle Hester A. , Gee Renelle J. , Lowenson Jonathan D. , Clarke Steven , Lawson Brian R. , Aswad Dana W. , Mamula Mark J. 
Published: April 2014

Abstract
Posttranslational protein modifications influence a number of immunologic responses ranging from intracellular signaling to protein processing and presentation. One such modification, termed isoaspartyl (isoAsp), is the spontaneous nonenzymatic modification of aspartic acid residues occurring at physiologic pH and temperature. In this study, we have examined the intracellular levels of isoAsp residues in self-proteins from MRL+/+, MRL/lpr, and NZB/W F1 mouse strains compared with nonautoimmune B10.BR mice. In contrast to control B10.BR or NZB/W mice, the isoAsp content in MRL autoimmune mice increased and accumulated with age in erythrocytes, brain, kidney, and T lymphocytes. Moreover, T cells that hyperproliferate to antigenic stimulation in MRL mice also have elevated intracellular isoAsp protein content. Protein l-isoaspartate O-methyltransferase activity, a repair enzyme for isoAsp residues in vivo, remains stable with age in all strains of mice. These studies demonstrate a role for the accumulation of intracellular isoAsp proteins associated with T cell proliferative defects of MRL autoimmune mice.
PKB Rescues Calcineurin/NFAT-Induced Arrest of Rag Expression and Pre-T Cell Differentiation
Authors: Patra Amiya K. , Drewes Thomas , Engelmann Swen , Chuvpilo Sergei , Kishi Hiroyuki , Hünig Thomas , Serfling Edgar , Bommhardt Ursula H. 
Published: April 2014

Abstract
Protein kinase B (PKB), an Ag receptor activated serine-threonine kinase, controls various cellular processes including proliferation and survival. However, PKB function in thymocyte development is still unclear. We report PKB as an important negative regulator of the calcineurin (CN)-regulated transcription factor NFAT in early T cell differentiation. Expression of a hyperactive version of CN induces a profound block at the CD25+CD44− double-negative (DN) 3 stage of T cell development. We correlate this arrest with up-regulation of Bcl-2, CD2, CD5, and CD27 proteins and constitutive activation of NFAT but a severe impairment of Rag1, Rag2, and intracellular TCR-β as well as intracellular TCR-γδ protein expression. Intriguingly, simultaneous expression of active myristoylated PKB inhibits nuclear NFAT activity, restores Rag activity, and enables DN3 cells to undergo normal differentiation and expansion. A correlation between the loss of NFAT activity and Rag1 and Rag2 expression is also found in myristoylated PKB-induced CD4+ lymphoma cells. Furthermore, ectopic expression of NFAT inhibits Rag2 promoter activity in EL4 cells, and in vivo binding of NFATc1 to the Rag1 and Rag2 promoter and cis-acting transcription regulatory elements is verified by chromatin immunoprecipitation analysis. The regulation of CN/NFAT signaling by PKB may thus control receptor regulated changes in Rag expression and constitute a signaling pathway important for differentiation processes in the thymus and periphery.
Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF
Authors: Takahashi Kyoko , Hayashi Natsuko , Kaminogawa Shuichi , Ra Chisei 
Published: April 2014

Abstract
The β-chain of the high-affinity receptor for IgE (FcεRI) plays an important role in regulating activation of FcεRI-expressing cells such as mast cells in allergic reactions. We already reported that the transcription factor myeloid zinc finger (MZF) 1 which formed a high m.w. complex including four and a half LIM-only protein (FHL)3 in the nucleus repressed human β-chain gene expression through an element in the fourth intron. We also found that GM-CSF induced expression of MZF-1 and nuclear translocation of FHL3. We screened a human cDNA library and identified NFY which was reported to bind histone deacetylases (HDACs) as a constituent of the complex. The C-subunit of NFY was demonstrated to form a ternary complex with MZF-1/FHL3 and interact with a β-chain gene region including the element in the fourth intron. HDAC1 and HDAC2 were also shown to interact with the fourth intron region of the β-chain gene. In a human mast cell line HMC-1 cultured with GM-CSF, both β-chain expression and acetylation of histones interacting with the fourth intron region of the β-chain gene were decreased. Collectively, these results indicated that HDACs, which were recruited to the β-chain gene through the element in the fourth intron by MZF-1/FHL3/NFY, repressed β-chain gene transcription by deacetylation of histones in the presence of GM-CSF. These mechanisms will be involved in not only the cell type-specific repression of β-chain gene expression in differentiating hemopoietic cells but also the repression of β-chain gene expression in the peripheral cells under specific circumstances.
MHC Class II Molecules Control Murine B Cell Responsiveness to Lipopolysaccharide Stimulation
Authors: Rodo Joana , Gonçalves Lígia A. , Demengeot Jocelyne , Coutinho António , Penha-Gonçalves Carlos 
Published: April 2014

AbstractLPS is a strong stimulator of the innate immune system and inducer of B lymphocyte activation. Two TLRs, TLR4 and RP105 (CD180), have been identified as mediators of LPS signaling in murine B cells, but little is known about genetic factors that are able to control LPS-induced cell activation. We performed a mouse genome-wide screen that aside from identifying a controlling locus mapping in the TLR4 region (logarithm of odds score, 2.77), also revealed that a locus closely linked to the MHC region (logarithm of odds score, 3.4) governed B cell responsiveness to LPS stimulation. Using purified B cells obtained from MHC congenic strains, we demonstrated that the MHCb haplotype is accountable for higher cell activation, cell proliferation, and IgM secretion, after LPS stimulation, when compared with the MHCd haplotype. Furthermore, B cells from MHC class II−/− mice displayed enhanced activation and proliferation in response to LPS. In addition, we showed that the MHC haplotype partially controls expression of RP105 (a LPS receptor molecule), following a pattern that resembles the LPS responsiveness phenotype. Together, our results strongly suggest that murine MHC class II molecules play a role in constraining the B cell response to LPS and that genetic variation at the MHC locus is an important component in controlling B cell responsiveness to LPS stimulation. This work raises the possibility that constraining of B cell responsiveness by MHC class II molecules may represent a functional interaction between adaptive and innate immune systems.