bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Ly49A Inhibits TCR/CD3-Induced Apoptosis and IL-2 Secretion
Authors: Roger Joanne , Chalifour Anick , Lemieux Suzanne , Duplay Pascale 
Published: April 2014

Abstract
To evaluate the importance of Ly49A on TCR-induced cellular events, we established clones of the 1F2 T cell hybridoma expressing either Ly49A or a chimeric version, Ly49A/H, where the Ly49A cytoplasmic domain has been replaced by the Ly49H cytoplasmic domain. Ligation of Ly49A, but not Ly49A/H, with its ligand H-2Dd or anti-Ly49A mAbs caused a specific inhibition of TCR/CD3-induced IL-2 secretion. Moreover, flow cytometry analysis of hypodiploid DNA and annexin V binding revealed that ligation of Ly49A protected cells from apoptosis induced by anti-CD3 mAbs or Ag. In contrast, ligation of the Ly49A/H chimeric receptor had no antiapoptotic effect. In addition, engagement of Ly49A selectively inhibited TCR-induced Fas ligand expression whereas TCR-induced Fas expression was not significantly affected. Expression of Ly49 inhibitory receptors on T cells may represent an important mechanism for the regulation of T cell survival in vivo by inhibiting TCR-induced apoptosis and IL-2 secretion.
Novel Roles of CpG Oligodeoxynucleotides as a Leader for the Sampling and Presentation of CpG-Tagged Antigen by Dendritic Cells
Authors: Shirota Hidekazu , Sano Kunio , Hirasawa Noriyasu , Terui Tadashi , Ohuchi Kazuo , Hattori Toshio , Shirato Kunio , Tamura Gen 
Published: April 2014

AbstractOligodeoxynucleotides containing CpG motifs have been highlighted as potent Th1 activators. We previously reported that Ag and CpG, when conjugated together, synergistically promoted the Ag-specific Th1 development and inhibited the Th2-mediated airway eosinophilia. In this study, we examined the mechanisms underlying the synergism of the covalent conjugation. The CpG-OVA conjugate enhanced the Th1 activation and development. These characteristic features of the conjugate could not be ascribed to the polymerization of OVA, but mirrored the augmented binding of the CpG-tagged Ag to dendritic cells (DCs) in a CpG-guided manner, because phycobiliprotein, R-PE, conjugated to CpG stained a higher proportion of DCs with higher intensity than the mixture. R-PE fluorescence was emitted from cytoplasmic portions of the DCs, which simultaneously expressed costimulatory molecules and IL-12. The CpG-conjugated R-PE trafficking described above actually served as a potent Ag. These results indicate that CpG conjugated to Ag exhibit novel joint properties as promoters of Ag uptake and DC activators, thereby potentiating the ability of DCs to generate Th1 cells. The DNA-mediated promotion of Ag uptake would be advantageous for evoking host immune responses against invading microorganisms.
Constitutive Expression of MHC Class II Genes in Melanoma Cell Lines Results from the Transcription of Class II Transactivator Abnormally Initiated from Its B Cell-Specific Promoter
Authors: Deffrennes Virginie , Vedrenne Jocelyn , Stolzenberg Marie-Claude , Piskurich Janet , Barbieri Giovanna , Ting Jenny P. , Charron Dominique , Alcaïde-Loridan Catherine 
Published: April 2014

AbstractIn melanoma cell lines, two different patterns of MHC class II expression have been described, either an IFN γ-inducible expression of HLA-DR and HLA-DP, with a faint or null expression of HLA-DQ, resembling that described for melanocytes, or a constitutive expression, i.e., IFN-γ independent, of all three HLA-D isotypes. As this latter phenotype has been associated with a more rapid progression of melanoma tumors, we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression. In agreement with the evidence of a coordinate transcription of the HLA-D genes in these cell lines, we have shown the constitutive expression of CIITA (class II transactivator) transcripts, CIITA being known as the master switch of MHC class II expression. Unexpectedly, these transcripts initiate from promoter III of the CIITA gene, a promoter that is mainly used constitutively in B lymphocytes. This expression was further shown to occur through factor(s) acting on the enhancer located upstream of CIITA promoter III, which was previously described in epithelioid cells as an IFN-γ-response sequence. The hypothesis of a general abnormality of the IFN-γ transduction pathway was dismissed. Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines, we propose the hypothesis that this phenomenon might not be a random event, but could be linked to the neoplasic state of the melanoma cells.
Cutting Edge: Recipient MHC Class II Expression Is Required to Achieve Long-Term Survival of Murine Cardiac Allografts After Costimulatory Blockade
Authors: Yamada Akira , Chandraker Anil , Laufer Terri M. , Gerth Andrea J. , Sayegh Mohamed H. , Auchincloss Hugh 
Published: April 2014

AbstractTo study the role of the direct and indirect pathways in achieving tolerance, we used genetically altered mouse strains in two ways: 1) MHC class II-deficient mice were used as donors of skin and cardiac grafts to eliminate the direct CD4+ T cell response, and 2) B6 II−4+ mice, which are MHC class II-deficient mice expressing an MHC class II transgene only on thymic epithelium, were used as recipients of normal grafts. These mice cannot mount an indirect response. Eliminating the indirect pathway actually made it more difficult to achieve prolonged allograft survival when we used costimulatory blockade than when both pathways were available. Costimulatory blockade was ineffective even when CD4+ T cells from normal animals were transferred into recipients that lacked MHC class II molecules. These results suggest that an active CD4+ response through the indirect pathway is necessary for costimulatory blockade to be effective in prolonging allograft survival.
Cutting Edge: NKG2D Receptors Induced by IL-15 Costimulate CD28-Negative Effector CTL in the Tissue Microenvironment
Authors: Roberts Arthur I. , Lee Leanne , Schwarz Eliezer , Groh Veronika , Spies Thomas , Ebert Ellen C. , Jabri Bana 
Published: April 2014

AbstractUnlike primary T cells in lymph nodes, effector CD8+ CTL in tissues do not express the costimulatory receptor CD28. We report that NKG2D, the receptor for stress-induced MICA and MICB molecules expressed in the intestine, serves as a potent costimulatory receptor for CTL freshly isolated from the human intestinal epithelium. Expression and function of NKG2D are selectively up-regulated by the cytokine IL-15, which is released by the inflamed intestinal epithelium. These findings identify a novel CTL costimulatory pathway regulated by IL-15 and suggest that tissues can fine-tune the activation of effector T cells based on the presence or absence of stress and inflammation. Uncontrolled secretion of IL-15 could lead to excessive induction of NKG2D and thus contribute to the development of autoimmune disease by facilitating the activation of autoreactive T cells.
Cutting Edge: A Major Fraction of Human Bone Marrow Lymphocytes Are Th2-Like CD1d-Reactive T Cells That Can Suppress Mixed Lymphocyte Responses
Authors: Exley Mark A. , Tahir Syed Muhammad Ali , Cheng Olivia , Shaulov Angela , Joyce Robin , Avigan David , Sackstein Robert , Balk Steven P. 
Published: April 2014

AbstractMurine bone marrow (BM) NK T cells can suppress graft-vs-host disease, transplant rejection, and MLRs. Human BM contains T cells with similar potential. Human BM was enriched for NK T cells, ∼50% of which recognized the nonpolymorphic CD1d molecule. In contrast to the well-characterized blood-derived CD1d-reactive invariant NK T cells, the majority of human BM CD1d-reactive T cells used diverse TCR. Healthy donor invariant NK T cells rapidly produce large amounts of IL-4 and IFN-γ and can influence Th1/Th2 decision-making. Healthy donor BM CD1d-reactive T cells were Th2-biased and suppressed MLR and, unlike the former, responded preferentially to CD1d+ lymphoid cells. These results identify a novel population of human T cells which may contribute to B cell development and/or maintain Th2 bias against autoimmune T cell responses against new B cell Ag receptors. Distinct CD1d-reactive T cell populations have the potential to suppress graft-vs-host disease and stimulate antitumor responses.
Cutting Edge: B Cell Specificity Contributes to the Outcome of Diabetes in Nonobese Diabetic Mice
Authors: Hulbert Chrys , Riseili Brent , Rojas Mauricio , Thomas James W. 
Published: April 2014

AbstractType I diabetes mellitus (TIDM) is an autoimmune disorder characterized by T cell-mediated destruction of insulin-producing β cells in the pancreas. In the nonobese diabetic (NOD) model of TIDM, insulitis and diabetes are dependent on the presence of B lymphocytes; however, the requirement for specificity within the B cell repertoire is not known. To determine the role of Ag-specific B cells in TIDM, VH genes with different potential for insulin binding were introduced into NOD as H chain transgenes. VH125 H chain combines with endogenous L chains to produce a repertoire in which 1–3% of mature B cells are insulin specific, and these mice develop accelerated diabetes. In contrast, NOD mice harboring a similar transgene, VH281, with limited insulin binding develop insulitis but are protected from TIDM. The data indicate that Ag-specific components in the B cell repertoire may alter the course of TIDM.
Cross-Priming as a Predominant Mechanism for Inducing CD8+ T Cell Responses in Gene Gun DNA Immunization
Authors: Cho Jae Ho , Youn Jin Won , Sung Young Chul 
Published: April 2014

AbstractDNA immunization induces CD8+ CTL responses by bone marrow-derived APCs, which are directly transfected with a plasmid DNA and/or acquire Ags from DNA-transfected non-APCs. To investigate the relative contribution of DNA-transfected APCs vs non-APCs to the initiation of CD8+ T cell responses, we used tissue-specific promoter-directed gene expression and adoptive transfer systems in gene gun DNA immunization. In this study, we demonstrated that non-APC-specific gene expressions induced significant CD8+ CTL and IFN-γ-producing cells and Ab responses, whereas APC-specific gene expressions led to moderate CTL and IFN-γ-producers, but no Ab responses. Interestingly, mice immunized with a non-APC-specific plasmid induced more rapid, vigorous, and prolonged proliferation of adoptively transferred Ag-specific CD8+ T cells than APC-specific plasmid-immunized mice. In addition, the in vivo proliferative responses elicited by a non-APC-specific plasmid administration were dependent on TAP, but were independent of CD4+ T cell help. Collectively, our results suggest that cross-priming, in which Ags expressed in non-APCs are taken up, processed, and presented by APCs, plays an important role in the initiation, magnitude, and maintenance of CD8+ T cell responses in gene gun DNA immunization.
FcγRIIB in IgG-Mediated Suppression of Antibody Responses: Different Impact In Vivo and In Vitro
Authors: Karlsson Mikael C. I. , Getahun Andrew , Heyman Birgitta 
Published: April 2014

AbstractThe suppressive effect of IgG on Ab responses to particulate Ags such as erythrocytes is well documented. IgG-mediated suppression is used clinically in rhesus prophylaxis to prevent RhD-negative mothers from becoming immunized against their Rh D-positive fetuses. We have recently shown that IgG anti-SRBC, passively administered together with SRBC, can induce efficient suppression of primary Ab responses to SRBC in mice lacking the known FcRs for IgG (FcγRI, FcγIII, and FcγRIIB or the neonatal FcR). The lack of a demonstrable effect of the inhibitory FcγRIIB was particularly surprising, and, in this study, the involvement of this receptor is further investigated during broader experimental conditions. The data show that SRBC-specific IgG administered up to 5 days after SRBC can induce suppression both in wild-type and FcγRIIB-deficient mice. Suppression of secondary Ab responses to SRBC in vivo was similar in the two strains. In contrast, IgG-mediated suppression of Ab responses in vitro was impaired in cultures with primed FcγRIIB-deficient spleen cells. In conclusion, inhibition of in vivo Ab responses to SRBC by passively administered IgG can take place via an FcγRIIB-independent pathway. This pathway causes &gt;99% suppression and operates during all experimental conditions studied so far. The nature of the mechanism can at present only be hypothesized. Masking of epitopes and/or rapid elimination of IgG-Ag complexes would both be compatible with the observations.
IL-10 Induces CCR6 Expression During Langerhans Cell Development While IL-4 and IFN-γ Suppress It
Authors: Dieu-Nosjean Marie-Caroline , Massacrier Catherine , Vanbervliet Béatrice , Fridman Wolf-Herman , Caux Christophe 
Published: April 2014

AbstractImmune responses are initiated by dendritic cells (DC) that form a network comprising different populations. In particular, Langerhans cells (LC) appear as a unique population of cells colonizing epithelial surfaces. We have recently shown that macrophage-inflammatory protein-3α/CCL20, a chemokine secreted by epithelial cells, induces the selective migration of LC among DC populations. In this study, we investigated the effects of cytokines on the expression of the CCL20 receptor, CCR6, during differentiation of LC. We found that both IL-4 and IFN-γ blocked the expression of CCR6 and CCL20 responsiveness at different stages of LC development. The effect of IL-4 was reversible and most likely due to the transient blockade of LC differentiation. In contrast, IFN-γ-induced CCR6 loss was irreversible and was concomitant to the induction of DC maturation. When other cytokines involved in DC and T cell differentiation were tested, we found that IL-10, unlike IL-4 and IFN-γ, maintained CCR6 expression. The effect of IL-10 was reversible and upon IL-10 withdrawn, CCR6 was lost concomitantly to final LC differentiation. In addition, IL-10 induced the expression of CCR6 and responsiveness to CCL20 in differentiated monocytes that preserve their ability to differentiate into mature DC. Finally, TGF-β, which induces LC differentiation, did not alter early CCR6 expression, but triggered its irreversible down-regulation, in parallel to terminal LC differentiation. Taken together, these results suggest that the recruitment of LC at epithelial surface might be suppressed during Th1 and Th2 immune responses, and amplified during regulatory immune responses involving IL-10 and TGF-β.
CD4 Ligation Promotes the IL-4-Independent Development of IL-4-Producing Clones from Naive CD4+ T Cells
Authors: Campbell Scott B. , Komata Tadashi , Kelso Anne 
Published: April 2014

AbstractThe signals that trigger IL-4-independent IL-4 synthesis by conventional CD4+ T cells are not yet defined. In this study, we show that coactivation with anti-CD4 mAb can stimulate single naive CD4+ T cells to form IL-4-producing clones in the absence of APC and exogenous IL-4, independently of effects on proliferation. When single CD4+ lymph node cells from C57BL/6 mice were cultured with immobilized anti-CD3ε mAb and IL-2, 65–85% formed clones over 12–14 days. Coimmobilization of mAb to CD4, CD11a, and/or CD28 increased the size of these clones but each exerted different effects on their cytokine profiles. Most clones produced IFN-γ and/or IL-3 regardless of the coactivating mAb. However, whereas 0–6% of clones obtained with mAb to CD11a or CD28 produced IL-4, 10–40% of those coactivated with anti-CD4 mAb were IL-4 producers. A similar response was observed among CD4+ cells from BALB/c mice. Most IL-4-producing clones were derived from CD4+ cells of naive (CD44low or CD62Lhigh) phenotype and the great majority coproduced IFN-γ and IL-3. The effect of anti-CD4 mAb on IL-4 synthesis could be dissociated from effects on clone size since anti-CD4 and anti-CD11a mAb stimulated formation of clones of similar size which differed markedly in IL-4 production. Engagement of CD3 and CD4 in the presence of IL-2 is therefore sufficient to induce a substantial proportion of naive CD4+ T cells to form IL-4-producing clones in the absence of other exogenous signals, including IL-4 itself.
Deletional Analysis of the Murine IL-12 p35 Promoter Comparing IFN-γ and Lipopolysaccharide Stimulation
Authors: Kollet Jutta , Witek Christian , Gentry John D. , Liu Xiaojuan , Schwartzbach Steven D. , Petro Thomas M. 
Published: April 2014

AbstractIL-12, pivotal to the development of Th1 cells and formed by association of p35 and p40 subunits, is made by macrophages and the macrophage cell line RAW264.7. In this study, the promoter for p35 was cloned and analyzed. The murine IL-12 p35 gene has promoters upstream from each of the first two exons. The exon 1 and exon 2 promoters, cloned into a reporter vector, were responsive to LPS or IFN-γ/CD40 ligation in transfected RAW264.7 cells. The exon 2 promoter containing bp −809 to +1 has significant homology to the human p35 promoter. Thus, deletion analysis was performed to determine the regions required for responsiveness to LPS, CD40, and/or IFN-γ. Base pairs −809 to −740 influenced responsiveness to LPS. In contrast, bp −740to −444 and bp −122 to −100 were required for responses to IFN-γ, IFN-γ/LPS, or IFN-γ/CD40 ligation. Removal of bp −444 to −392 increased the response of the exon 2 promoter to each stimulant. IFN regulatory factor (IRF)-1 is involved in the activity of this promoter at bp −108 to −103 because levels of nuclear IRF-1 correlated with exon 2 promoter activity in response to IFN-γ and IRF-1 overexpression stimulated and enhanced exon 2 promoter activity. Also, site or deletion mutation of the IRF-1 element at bp −108 to −103 reduced the responsiveness of the promoter and IRF-1 bound to an oligonucleotide containing bp −108 to −103. The data suggest that the response of the p35 promoter to IFN-γ requires a distinct IRF-1 positive regulatory element at bp −108 to −103.
Homeostatic Expansion Occurs Independently of Costimulatory Signals
Authors: Prlic Martin , Blazar Bruce R. , Khoruts Alexander , Zell Traci , Jameson Stephen C. 
Published: April 2014

AbstractNaive T cells undergo homeostatic proliferation in lymphopenic mice, a process that involves TCR recognition of specific self peptide/MHC complexes. Since costimulation signals regulate the T cell response to foreign Ags, we asked whether they also regulate homeostatic expansion. We report in this study that homeostatic expansion of CD4 and CD8 T cells occurs independently of costimulation signals mediated through CD28/B7, CD40L/CD40, or 4-1BB/4-1BBL interactions. Using DO11.10 TCR transgenic T cells, we confirmed that CD28 expression was dispensable for homeostatic expansion, and showed that the presence of endogenous CD4+CD25+ regulatory cells did not detectably influence homeostatic expansion. The implications of these findings with respect to regulation of T cell homeostasis and autoimmunity are discussed.
CD45 Modulates Galectin-1-Induced T Cell Death: Regulation by Expression of Core 2O-Glycans
Authors: Nguyen Julie T. , Evans Douglas P. , Galvan Marisa , Pace Karen E. , Leitenberg David , Bui Thanhmy N. , Baum Linda G. 
Published: April 2014

AbstractGalectin-1 induces death of immature thymocytes and activated T cells. Galectin-1 binds to T cell-surface glycoproteins CD45, CD43, and CD7, although the precise roles of each receptor in cell death are unknown. We have determined that CD45 can positively and negatively regulate galectin-1-induced T cell death, depending on the glycosylation status of the cells. CD45+ BW5147 T cells lacking the core 2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) were resistant to galectin-1 death. The inhibitory effect of CD45 in C2GnT− cells appeared to require the CD45 cytoplasmic domain, because Rev1.1 cells expressing only CD45 transmembrane and extracellular domains were susceptible to galectin-1 death. Moreover, treatment with the phosphotyrosine-phosphatase inhibitor potassium bisperoxo(1,10-phenanthroline)oxovanadate(V) enhanced galectin-1 susceptibility of CD45+ T cell lines, but had no effect on the death of CD45− T cells, indicating that the CD45 inhibitory effect involved the phosphatase domain. Expression of the C2GnT in CD45+ T cell lines rendered the cells susceptible to galectin-1, while expression of the C2GnT in CD45− cells had no effect on galectin-1 susceptibility. When CD45+ T cells bound to galectin-1 on murine thymic stromal cells, only C2GnT+ T cells underwent death. On C2GnT+ cells, CD45 and galectin-1 co-localized in patches on membrane blebs while no segregation of CD45 was seen on C2GnT− T cells, suggesting that oligosaccharide-mediated clustering of CD45 facilitated galectin-1-induced cell death.
Opposing Effects of Anti-Activation-Inducible Lymphocyte- Immunomodulatory Molecule/Inducible Costimulator Antibody on the Development of Acute Versus Chronic Graft-Versus-Host Disease
Authors: Ogawa Shu-hei , Nagamatsu Go , Watanabe Masashi , Watanabe Shiho , Hayashi Tomohito , Horita Shigeru , Nitta Kosaku , Nihei Hiroshi , Tezuka Katsunari , Abe Ryo 
Published: April 2014

AbstractThe functional role of inducible costimulator (ICOS)-mediated costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F1 model of acute or chronic graft-vs-host disease (GVHD), respectively. When the Ab specific for mouse ICOS was injected into chronic GVHD-induced mice, activation of B cells, production of autoantibody, and development of glomerulonephritis were strongly suppressed. In contrast, the same treatment enhanced donor T cell chimerism and host B cell depletion in acute GVHD induced host mice. Blocking of B7-CD28 interaction by injection of anti-B7-1 and anti-B7-2 Abs inhibited both acute and chronic GVHD. These observations clearly indicate that the costimulatory signal mediated by CD28 caused the initial allorecognition resulting in the clonal expansion of alloreactive T cells, whereas the costimulatory signal mediated by ICOS played a critical role in the functional differentiation and manifestation of alloreactive T cells. Furthermore, treatment with anti-ICOS Ab selectively suppresses Th2-dominant autoimmune disease.
Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes
Authors: Kawai Taro , Takeuchi Osamu , Fujita Takashi , Inoue Jun-ichiro , Mühlradt Peter F. , Sato Shintaro , Hoshino Katsuaki , Akira Shizuo 
Published: April 2014

AbstractBacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates in pathogen recognition. TLRs recruit a cytoplasmic protein, MyD88, upon pathogen recognition, mediating its function for immune responses. Two major pathways for LPS have been suggested in recent studies, which are referred to as MyD88-dependent and -independent pathways. We report in this study the characterization of the MyD88-independent pathway via TLR4. MyD88-deficient cells failed to produce inflammatory cytokines in response to LPS, whereas they responded to LPS by activating IFN-regulatory factor 3 as well as inducing the genes containing IFN-stimulated regulatory elements such as IP-10. In contrast, a lipopeptide that activates TLR2 had no ability to activate IFN-regulatory factor 3. The MyD88-independent pathway was also activated in cells lacking both MyD88 and TNFR-associated factor 6. Thus, TLR4 signaling is composed of at least two distinct pathways, a MyD88-dependent pathway that is critical to the induction of inflammatory cytokines and a MyD88/TNFR-associated factor 6-independent pathway that regulates induction of IP-10.