bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravenous Infusion of Syngeneic Apoptotic Cells by Photopheresis Induces Antigen-Specific Regulatory T Cells
Authors: Maeda Akira , Schwarz Agatha , Kernebeck Kerstin , Gross Nicole , Aragane Yoshinori , Peritt David , Schwarz Thomas 
Published: April 2014

Abstract
The basis of extracorporeal photopheresis is the reinfusion of leukocytes previously exposed to 8-methoxypsoralen (8-MOP) and UVA radiation. It has been approved for the palliative treatment of cutaneous T cell lymphoma and has reported benefits in autoimmune diseases, transplant rejection, and graft-vs-host disease. However, the underlying mechanism of photopheresis remains unresolved. Because UVB radiation can cause immune tolerance via induction of regulatory T cells, we studied whether photopheresis exerts a similar effect extracorporeally. Therefore, we established a model of photopheresis using a murine model of contact hypersensitivity. Splenocytes and lymph node cells of mice that were sensitized with dinitrofluorobenzene were exposed to 8-MOP plus UVA in vitro. Intravenous injection of these cells into naive mice caused inhibition of a hapten immune response, which was lost upon depletion of CD11c+ cells but not T cells. Mice that received untreated cells or cells exposed to UVA or 8-MOP alone were not affected. Inhibition was cell-mediated and Ag-specific as demonstrated by transfer of tolerance from the primary recipients into naive animals, which could, however, properly respond to the unrelated hapten oxazolone. Transfer activity was lost when cells were depleted of CD4+ or CD25+ subpopulations. These data suggest that photopheresis exerts its immunomodulatory effects via the induction of Ag-specific regulatory T cells.
Identification of Grb2 As a Novel Binding Partner of the Signaling Lymphocytic Activation Molecule-Associated Protein Binding Receptor CD229
Authors: Martín Margarita , Del Valle Juana M. , Saborit Ifigènia , Engel Pablo 
Published: April 2014

AbstractAg recognition by the TCR determines the subsequent fate of the T cell and is regulated by the involvement of other cell surface molecules, termed coreceptors. CD229 is a lymphocyte cell surface molecule that belongs to the CD150 family of receptors. Upon tyrosine phosphorylation, CD229 recruits various signaling molecules to the membrane. One of these molecules is the signaling lymphocytic activation molecule-associated protein, of which a deficiency leads to the X-linked lymphoproliferative syndrome. We report that CD229 interacts in a phosphorylation-dependent manner with Grb2. We mapped this interaction showing that the Src homology 2 domain of Grb2 and the tyrosine residue Y606 in CD229 are required for CD229-Grb2 complex formation. The Grb2 motif in the cytoplasmic tail of CD229 is distinct and independent from the two tyrosines required for efficient signaling lymphocytic activation molecule-associated protein recruitment. CD229, but not other members of the CD150 family, directly bound Grb2. We also demonstrate that CD229 precipitates with Grb2 in T lymphocytes after pervanadate treatment, as well as CD229 or TCR ligation. Interestingly, the CD229 mutant lacking the Grb2 binding site is not internalized after CD229 engagement with specific Abs. Moreover, a dominant negative form of Grb2 (containing only Src homology 2 domain) impaired CD229 endocytosis. Unexpectedly, Erk phosphorylation was partially inhibited after activation of CD229 plus CD3. Consistent with this, CD229 ligation partially inhibited TCR signaling in peripheral blood cells and CD229-Jurkat cells transfected with the 3XNFAT-luciferase reporter construct. Altogether, the data suggest a model whereby CD229 ligation attenuates TCR signaling and Grb2 recruitment to CD229 controls its rate of internalization.
γδ T Cells Respond Directly to Pathogen-Associated Molecular Patterns
Authors: Hedges Jodi F. , Lubick Kirk J. , Jutila Mark A. 
Published: April 2014

Abstractγδ T cells recognize unprocessed or non-peptide Ags, respond rapidly to infection, and localize to mucosal surfaces. We have hypothesized that the innate functions of γδ T cells may be more similar to those of cells of the myeloid lineage than to other T cells. To begin to test this assumption, we have analyzed the direct response of cultured human and peripheral blood bovine γδ T cells to pathogen associated molecular patterns (PAMPs) in the absence of APCs using microarray, real-time RT-PCR, proteome array, and chemotaxis assays. Our results indicate that purified γδ T cells respond directly to PAMPs by increasing expression of chemokine and activation-related genes. The response was distinct from that to known γδ T cell Ags and different from the response of myeloid cells to PAMPs. In addition, we have analyzed the expression of a variety of PAMP receptors in γδ T cells. Freshly purified bovine γδ T cells responded more robustly to PAMPs than did cultured human cells and expressed measurable mRNA encoding a variety of PAMP receptors. Our results suggest that rapid response to PAMPs through the expression of PAMP receptors may be another innate role of γδ T cells.
Pertussis Toxin (PTX) B Subunit and the Nontoxic PTX Mutant PT9K/129G Inhibit Tat-Induced TGF-β Production by NK Cells and TGF-β-Mediated NK Cell Apoptosis
Authors: Zocchi M. Raffaella , Contini Paola , Alfano Massimo , Poggi Alessandro 
Published: April 2014

Abstract
We show that the pertussis toxin B oligomer (PTX-B), and the PTX mutant PT9K/129G, which is safely administered in vivo, inhibit both transcription and secretion of TGF-β elicited by HIV-1 Tat in NK cells. Tat-induced TGF-β mRNA synthesis is also blocked by the ERK1 inhibitor PD98059, suggesting that ERK1 is needed for TGF-β production. Moreover, Tat strongly activates the c-Jun component of the multimolecular complex AP-1, whereas TGF-β triggers c-Fos and c-Jun. Of note, treatment of NK cells with PTX-B or PT9K/129G inhibits Tat- and TGF-β-induced activation of AP-1. TGF-β enhances starvation-induced NK cell apoptosis, significantly reduces transcription of the antiapoptotic protein Bcl-2, and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-β-mediated effects are prevented by PTX-B or PT9K/129G through a PI3K-dependent mechanism, as demonstrated by use of the specific PI3K inhibitor, LY294002. Finally, PTX-B and PT9K/129G up-regulate Bcl-xL, the isoform of Bcl-x that protects cells from starvation-induced apoptosis. It is of note that in NK cells from patients with early HIV-1 infection, mRNA expression of Bcl-2 and Bcl-xL was consistently lower than that in healthy donors; interestingly, TGF-β and Tat were detected in the sera of these patients. Together, these data suggest that Tat-induced TGF-β production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.
B Cell Receptor (BCR) Cross-Talk: CD40 Engagement Creates an Alternate Pathway for BCR Signaling That Activates IκB Kinase/IκBα/NF-κB without the Need for PI3K and Phospholipase Cγ
Authors: Mizuno Takuya , Rothstein Thomas L. 
Published: April 2014

AbstractBCR signaling is propagated by a series of intermediaries and eventuates in NF-κB activation, among other outcomes. Interruption of several mediators that constitute the signalosome, such as PI3K and phospholipase Cγ2, completely blocks BCR signaling for NF-κB. We show here that this accepted, conventional paradigm is, in fact, limited to naive B cells. CD40L treatment reprograms normal B cells such that a novel, alternate pathway for BCR signaling is created. Through this alternate pathway BCR triggering induces nuclear NF-κB without the need for PI3K or for phospholipase Cγ2. Induction of NF-κB via the alternate pathway is accompanied by IκB kinase β (IKKβ) phosphorylation, IκBα phosphorylation, and IκBα degradation, and inhibition of IKKβ blocked IκBα degradation. Several key events in the conventional pathway, including early protein tyrosine phosphorylation, were unimpeded by generation of the alternate pathway which appears to operate in parallel, rather than in competition, with classical BCR signaling. These results demonstrate cross-talk between CD40 and BCR, such that the requirements for BCR signaling are altered by prior B cell exposure to CD40L. The alternate BCR signaling pathway bypasses multiple signalosome elements and terminates in IKKβ activation.
Expression of Killer Cell Lectin-Like Receptor G1 on Antigen-Specific Human CD8+ T Lymphocytes during Active, Latent, and Resolved Infection and its Relation with CD57
Authors: Ibegbu Chris C. , Xu Yong-Xian , Harris Wayne , Maggio David , Miller Joseph D. , Kourtis Athena P. 
Published: April 2014

Abstract
Killer cell lectin-like receptor G1 (KLRG1) is one of several inhibitory killer cell lectin-like receptors expressed by NK cells and T lymphocytes, mainly CD8+ effector/memory cells that can secrete cytokines but have poor proliferative capacity. Using multiparameter flow cytometry, we studied KLRG1 expression on CD8+ T cells specific for epitopes of CMV, EBV, influenza, and HIV. Over 92% of CD8+ cells specific for CMV or EBV expressed KLRG1 during the latent stage of these chronic infections. CD8+ T cell cells specific for HIV epitopes were mostly (72–89%) KLRG1+, even though not quite at the level of predominance noted with CMV or EBV. Lower frequency of KLRG1 expression was observed among CD8+ cells specific for influenza (40–73%), a resolved infection without a latent stage. We further observed that CD8+ cells expressing CD57, a marker of replicative senescence, also expressed KLRG1; however, a population of CD57−KLRG1+ cells was also identified. This population may represent a “memory” phenotype, because they also expressed CD27, CD28, CCR7, and CD127. In contrast, CD57+KLRG1+ cells did not express CD27, CD28, and CCR7, and expressed CD127 at a much lower frequency, indicating that they represent effector cells that are truly terminally differentiated. The combination of KLRG1 and CD57 expression might thus aid in refining functional characterization of CD8+ T cell subsets.
Tid1 Is Required for T Cell Transition from Double-Negative 3 to Double-Positive Stages
Authors: Lo Jeng-Fan , Zhou He , Fearns Colleen , Reisfeld Ralph A. , Yang Young , Lee Jiing-Dwan 
Published: April 2014

Abstract
Tid1, a DnaJ cochaperone protein, is the mammalian homologue of the Drosophila tumor suppressor Tid56 whose antitumor function is most likely mediated through its capacity to regulate cell differentiation in imaginal discs. We suspected that the mammalian counterpart, tid1, may also be involved in regulating cell differentiation. To investigate this, we exploited the system of T cell development to examine whether tid1 plays a role in this well-defined process. Mice with tid1 specifically deleted in T cells developed thymic atrophy, with dramatic reduction of double-positive and single-positive thymocytes in the tid1−/− thymus. Although the subpopulations of tid1−/− double-negative (DN) 1–3 thymocytes were normal, the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death. Immature tid1−/− thymocytes show normal VDJ β-chain rearrangement and pre-TCR and CD3 expression in both DN3 and DN4 thymocytes, but in DN4 thymocytes, there was significantly reduced expression of the antiapoptotic bcl-2 gene. Restoring the expression level of Bcl-2 protein in tid1−/− thymus by introduction of a transgenic human bcl-2 gene resulted in reversal of the developmental defects in tid1−/− thymus. Together, these results demonstrate that tid1 is critical in early thymocyte development, especially during transition from the DN3 to double-positive stages, possibly through its regulation of bcl-2 expression, which provides survival signals.
CpG-Independent Synergistic Induction of β-Chemokines and a Dendritic Cell Phenotype by Orthophosphorothioate Oligodeoxynucleotides and Granulocyte-Macrophage Colony-Stimulating Factor in Elutriated Human Primary Monocytes
Authors: Wang Jinhai , Alvarez Raymond , Roderiquez Gregory , Guan Ennan , Caldwell Quincy , Wang Jiun , Phelan Michael , Norcross Michael A. 
Published: April 2014

AbstractChemokines attract leukocytes bearing the relevant chemokine receptors and regulate innate immune responses. CpG oligodeoxynucleotides (ODN) and GM-CSF are potent vaccine adjuvants and in combination induce enhanced Th1 responses by mechanisms yet to be determined. We have examined combinations of CpG- or non-CpG-ODN and GM-CSF for effects on the production of chemokines and the differentiation of monocytes to dendritic cells. High levels of the Th1-attracting, HIV-1-inhibitory chemokines, CCL3/MIP-1α and CCL4/MIP-1β, were induced in human primary monocytes when CpG- or non-CpG-ODN was combined with GM-CSF, but not with IL-4 or IFN-γ. The synergistic induction of β-chemokines by non-CpG-ODN was phosphorothioate (PS) chemistry dependent and inhibited by blocking endosome maturation/acidification and ERK1/2 activation. Chemokine and TLR9 mRNAs were induced by PS-ODN. Cells treated with non-CpG PS-ODN and GM-CSF expressed dendritic cell marker CD83 and high levels of HLA-DR and costimulatory molecules, and were CD14− or CD14dim, consistent with monocyte differentiation into a dendritic cell phenotype. The induction of CD83 and β-chemokines was tyrosine phosphorylation dependent. Secreted CCL3 and CCL4 were detected as a heterodimer. Our results indicate the CpG-independent synergy between PS-ODN and GM-CSF mediated through chemokine and dendritic cell induction. In addition, our observations suggest that PS-ODN plus GM-CSF may be useful as potent ex vivo dendritic cell differentiation/maturation agents for dendritic cell therapy and as vaccine adjuvants for tumor and infectious microorganisms, including HIV-1.
Impaired TGF-β Responses in Peripheral T Cells of Gαi2−/− Mice
Authors: Wu Jim Y. , Jin YongZhu , Edwards Robert A. , Zhang Yujin , Finegold Milton J. , Wu Mei X. 
Published: April 2014

Abstract
Null mutation of heterotrimeric G protein α2 inhibitory subunit (Gαi2) induces Th1-skewed hyperimmune responses in the colon, leading to chronic colitis and the development of colonic adenocarcinoma. However, the underlying molecular mechanisms and cellular basis, in particular, for the role of Gαi2 in regulating immune responses, are poorly understood. We show here that peripheral T cells from Gαi2-deficient mice do not respond normally to the inhibitory effects of TGF-β on proliferation and cytokine production, revealing a previously unappreciated cross-talk between these two signaling pathways. Lack of Gαi2 resulted in decreased phosphorylation of Smad2 and Smad3 in T cells at the basal levels as well as at the late but not early phase of TGF-β stimulation, which appears to be ascribed to differential expression of neither cell surface TGF-β receptors nor Smad7. The altered phosphorylation of Smad proteins involves phospholipase C-mediated signaling, a downstream signaling molecule of Gαi2, because phospholipase C inhibitors could restore Smad2 and Smad3 phosphorylation in Gαi2−/− T cells at levels comparable to that in wild-type T cells. Moreover, adoptive transfer of Gαi2-deficient T cells into immunocompromised mice rendered an otherwise resistant mouse strain susceptible to trinitrobenzesulfonic acid-induced colitis, suggesting that an impaired response of Gαi2-deficient T cells to TGF-β may be one of the primary defects accounting for the observed colonic Th1-skewed hyperimmune responses. These findings shed new lights on the molecular and cellular basis of how Gαi2 down-regulates immune responses, contributing to the maintenance of mucosal tolerance.
Endosomal Translocation of Vertebrate DNA Activates Dendritic Cells via TLR9-Dependent and -Independent Pathways
Authors: Yasuda Kei , Yu Philipp , Kirschning Carsten J. , Schlatter Beatrix , Schmitz Frank , Heit Antje , Bauer Stefan , Hochrein Hubertus , Wagner Hermann 
Published: April 2014

AbstractTLRs discriminate foreign from self via their specificity for pathogen-derived invariant ligands, an example being TLR9 recognizing bacterial unmethylated CpG motifs. In this study we report that endosomal translocation of CpG DNA via the natural endocytotic pathway is inefficient and highly saturable, whereas endosomal translocation of DNA complexed to the cationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP) is not. Interestingly, DOTAP-mediated enhanced endosomal translocation of otherwise nonstimulatory vertebrate DNA or of certain noncanonical CpG motifs triggers robust dendritic cell activation in terms of both up-regulation of CD40/CD69 and cytokine production, such as type I IFN and IL-6. We report that the stimulatory activity of phosphorothioated noncanonical CpG oligodeoxynucleotides is TLR9 dependent, whereas phosphodiester DNA, such as vertebrate DNA, in addition trigger TLR9-independent pathways. We propose that the inefficiency of the natural route for DNA internalization hinders low affinity TLR9 ligands in endosomes to reach threshold concentrations required for TLR9 activation. Endosomal compartmentalization of TLR9 may thus reflect an evolutionary strategy to avoid TLR9 activation by self-DNA.
TGF-α Regulates TLR Expression and Function on Epidermal Keratinocytes
Authors: Miller Lloyd S. , Sørensen Ole E. , Liu Philip T. , Jalian H. Ray , Eshtiaghpour Deborah , Behmanesh Behnaz E. , Chung Woosin , Starner Timothy D. , Kim Jenny , Sieling Peter A. , Ganz Tomas , Modlin Robert L. 
Published: April 2014

Abstract
The expression of TLRs on epithelial cells provides a first line of defense against invading pathogens. We investigated the regulated expression and function of TLR5 and TLR9 on human keratinocytes, because we found by immunohistochemistry that these TLRs are expressed in distinct layers of the epidermis. We found that TGF-α, a growth and differentiation factor that is present during wound healing and in psoriasis, increased the expression of both TLR5 and TLR9 on keratinocytes. In addition, TGF-α regulated the function of TLR5 and TLR9, because activation with their respective ligands enhanced the production of IL-8 and human β-defensins. These findings provide evidence that TGF-α up-regulates TLR expression and function, augmenting host defense mechanisms at epithelial surfaces.
Transcriptional Profiling of γδ T Cells Identifies a Role for Vitamin D in the Immunoregulation of the Vγ9Vδ2 Response to Phosphate-Containing Ligands
Authors: Chen Lanfen , Cencioni Maria Teresa , Angelini Daniela F. , Borsellino Giovanna , Battistini Luca , Brosnan Celia F. 
Published: April 2014

AbstractVitamin D is a steroid hormone that, in addition to its well-characterized role in calcium/phosphate metabolism, has been found to have regulatory properties for immune system function. The nuclear vitamin D receptor is widely expressed in tissues, but has also been shown to be regulated by hormones, growth factors, and cytokines. In this study we show that activation of human Vδ2Vγ9 T cells by nonpeptidic monoalkyl phosphates such as isopentenyl pyrophosphate leads to the up-regulation of the vitamin D receptor via a pathway that involves the classical isoforms of protein kinase C. We further show that this receptor is active by demonstrating that the ligand 1α,25-dihydroxyvitamin D3 (vitD3) significantly inhibits in a dose-dependent fashion phospholigand-induced γδ T cell expansion, IFN-γ production, and CD25 expression. We also show that vitD3 negatively regulates signaling via Akt and ERK and, at high concentrations, potentiates Ag-induced cell death. As such, these data provide further support for the immunoregulatory properties of vitamin D, and suggest that the ability of vitD3 to negatively regulate the proinflammatory activity of γδ T cells may contribute to the protection this vitamin affords against inflammatory and autoimmune disorders dependent upon Th1-type responses.
An Ancient Role for a Prokineticin Domain in Invertebrate Hematopoiesis
Authors: Söderhäll Irene , Kim Young-A , Jiravanichpaisal Pikul , Lee So-Young , Söderhäll Kenneth 
Published: April 2014

Abstract
Hemopoietic development requires firm control of cell proliferation and differentiation. Although recent research has revealed conserved function of transcription factors and signaling pathways regulating lineage commitment in hemopoietic development in Drosophila melanogaster and vertebrates, little is known about hemopoietic cytokines among the invertebrate phyla. In the present study, we show that differentiation and growth of hemopoietic stem cells in vitro from an invertebrate, Pacifastacus leniusculus, require an endogenous cytokine-like factor, astakine, containing a prokineticin (PK) domain. Astakine induces a strong hematopoiesis response in live animals. An astakine homologue was also found in the shrimp, Penaeus monodon. So far, PK domains are only identified in vertebrates, in which they, for example, direct angiogenic growth. Our finding of the first PK-like cytokine characterized from any invertebrate provides novel information concerning the evolution of growth factors and blood cell development.
Testicular Immune Privilege Promotes Transplantation Tolerance by Altering the Balance between Memory and Regulatory T Cells
Authors: Nasr Isam W. , Wang Yinong , Gao Ge , Deng Songyan , Diggs Lonnette , Rothstein David M. , Tellides George , Lakkis Fadi G. , Dai Zhenhua 
Published: April 2014

AbstractImmune responses are suppressed in immunologically privileged sites, which may provide a unique opportunity to prolong allograft survival. However, it is unknown whether testicular immune privilege promotes transplantation tolerance. Mechanisms underlying immune privilege are also not well understood. Here we found that islet transplantation in the testis, an immunologically privileged site, generates much less memory CD8+ T cells but induces more Ag-specific CD4+CD25+ regulatory T cells than in a conventional site. These CD4+CD25+ cells exhibited the suppression of alloimmune responses in vivo and in vitro. Despite the immune regulation, intratesticular islet allografts all were rejected within 42 days after transplantation although they survived longer than renal subcapsular islet allografts. However, blocking CD40/CD40L costimulation induced the tolerance of intratesticular, but not renal subcapsular, islet allografts. Tolerance to intratesticular islet allografts spread to skin allografts in the non-privileged sites. Either transfer of memory CD8+ T cells or deletion of CD25+ T cells in vivo broke islet allograft tolerance. Thus, transplantation tolerance requires both costimulatory blockade, which suppresses acute allograft rejection, and a favorable balance between memory and regulatory T cells that could favorably prevent late allograft failure. These findings reveal novel mechanisms of immune privilege and provide direct evidence that testicular immune privilege fosters the induction of transplantation tolerance to allografts in both immunologically privileged and non-privileged sites.