bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific and Redundant Roles for NFAT Transcription Factors in the Expression of Mast Cell-Derived Cytokines
Authors: Klein Matthias , Klein-Hessling Stefan , Palmetshofer Alois , Serfling Edgar , Tertilt Christine , Bopp Tobias , Heib Valeska , Becker Marc , Taube Christian , Schild Hansjörg , Schmitt Edgar , Stassen Michael 
Published: April 2014

Abstract
By virtue of their ability to express a plethora of biologically highly active mediators, mast cells (MC) are involved in both adaptive and innate immune responses. MC-derived Th2-type cytokines are thought to act as local amplifiers of Th2 reactions, including chronic inflammatory disorders such as allergic asthma, whereas MC-derived TNF-α is a critical initiator of antimicrobial defense. In this study, we demonstrate that the transcription factors NFATc1 and NFATc2 are part of a MC-specific signaling network that regulates the expression of TNF-α and IL-13, whereas NFATc3 is dispensable. Primary murine bone marrow-derived MC from NFATc2−/− mice, activated by either ionomycin or IgE/Ag cross-link, display a strong reduction in the production of these cytokines, compared with bone marrow-derived MC from wild-type mice. Detailed analyses of TNF-α and IL-13 expression using small interfering RNA-mediated knockdown reveals that both NFATc2 and NFATc1 are able to drive the expression of these cytokines, whereas neither degranulation nor the expression of IL-6 depends on NFAT activity. These results support the view that high NFAT activity is necessary for TNF-α and IL-13 promoter induction in MC, irrespective of whether NFATc2 or NFATc1 or a combination of both is present.
Partial versus Full Allogeneic Hemopoietic Chimerization Is a Preferential Means to Inhibit Type 1 Diabetes as the Latter Induces Generalized Immunosuppression
Authors: Serreze David V. , Osborne Melissa A. , Chen Yi-Guang , Chapman Harold D. , Pearson Todd , Brehm Michael A. , Greiner Dale L. 
Published: April 2014

Abstract
In both humans and NOD mice, particular combinations of MHC genes provide the primary risk factor for development of the autoreactive T cell responses causing type 1 diabetes (T1D). Conversely, other MHC variants can confer dominant T1D resistance, and previous studies in NOD mice have shown their expression on hemopoietically derived APC is sufficient to induce disease protection. Although allogeneic hemopoietic chimerization can clearly provide a means for blocking T1D development, its clinical use for this purpose has been obviated by a requirement to precondition the host with what would be a lethal irradiation dose if bone marrow engraftment is not successful. There have been reports in which T1D-protective allogeneic hemopoietic chimerization was established in NOD mice that were preconditioned by protocols not including a lethal dose of irradiation. In most of these studies, virtually all the hemopoietic cells in the NOD recipients eventually converted to donor type. We now report that a concern about such full allogeneic chimeras is that they are severely immunocompromised potentially because their T cells are positively selected in the thymus by MHC molecules differing from those expressed by the APC available in the periphery to activate T cell effector functions. However, this undesirable side effect of generalized immunosuppression is obviated by a new protocol that establishes without a lethal preconditioning component, a stable state of mixed allogeneic hemopoietic chimerism sufficient to inhibit T1D development and also induce donor-specific tolerance in NOD recipients.
Quantification of Repertoire Diversity of Influenza-Specific Epitopes with Predominant Public or Private TCR Usage
Authors: Kedzierska Katherine , Day E. Bridie , Pi Jing , Heard Stephen B. , Doherty Peter C. , Turner Stephen J. , Perlman Stanley 
Published: April 2014

Abstract
The H-2Db-restricted CD8 T cell immune response to influenza A is directed at two well-described epitopes, nucleoprotein 366 (NP366) and acid polymerase 224 (PA224). The responses to the two epitopes are very different. The epitope NP366-specific response is dominated by TCR clonotypes that are public (shared by most mice), whereas the epitope PA224-specific response is private (unique within each infected animal). In addition to being public, the NP366-specific response is dominated by a few clonotypes, when T cell clonotypes expressing the Vβ8.3 element are analyzed. Herein, we show that this response is similarly public when the NP366+Vβ4+ CD8 T cell response is analyzed. Furthermore, to determine whether these features resulted in differences in total TCR diversity in the NP366+ and PA224+ responses, we quantified the number of different CD8 T clonotypes responding to each epitope. We calculated that 50–550 clonotypes recognized each epitope in individual mice. Thus, although the character of the response to the two epitopes appeared to be different (private and diverse vs public and dominated by a few clonotypes), similar numbers of precursor cells responded to both epitopes and this number was of similar magnitude to that previously reported for other viral CD8 T cell epitopes. Therefore, even in CD8 T cell responses that appear to be oligoclonotypic, the total response is highly diverse.
CD4+ T Cells in the Absence of the CD8+ Cytotoxic T Cells Are Critical and Sufficient for NKT Cell-Dependent Tumor Rejection
Authors: Hong Changwan , Lee Hyunji , Oh Mihwa , Kang Chang-Yuil , Hong Seokmann , Park Se-Ho 
Published: April 2014

Abstract
NKT cells perform crucial roles in tumor surveillance, functioning as regulators of early host response. In this study, we have assessed the effects of NKT activation at the time of tumor Ag immunization, and have evaluated the contributions of CD4+ and CD8+ T cells in tumor rejection during adaptive immune response against live tumor cells. Our data indicate that CD4+ T cells play critical roles, not only in assisting CTL, but also in the orchestration of host response against the tumor. The CD4+ T cells were found to reject the transplanted tumor cells very efficiently under conditions in which the CTLs were removed either genetically, or via the action of anti-CD8 Ab in mice that had been immunized with tumor extracts and α-galactosylceramide. Immunization resulted in an NKT cell-dependent antitumor adaptive immune response, which was associated with both CD4+ T cells and cytokine IFN-γ.
Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection
Authors: Dolganiuc Angela , Chang Serena , Kodys Karen , Mandrekar Pranoti , Bakis Gennadiy , Cormier Maureen , Szabo Gyongyi 
Published: April 2014

Abstract
IFN-α production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-α-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-α production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-α production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-α and increased TNF-α and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-α and IL-10 induced apoptosis and inhibited IFN-α production in PDCs. Neutralization of TNF-α and/or IL-10 prevented HCV core-induced inhibition of IFN-α production. We identified CD14+ monocytes as the source of TNF-α and IL-10 in the HCV core-induced inhibition of PDC IFN-α production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-α production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-α production. These mechanisms are likely to contribute to HCV viral escape from immune responses.
The Wild-Type Sequence (wt) p5325–35 Peptide Induces HLA-DR7 and HLA-DR11-Restricted CD4+ Th Cells Capable of Enhancing the Ex Vivo Expansion and Function of Anti-wt p53264–272 Peptide CD8+ T Cells
Authors: Ito Daisuke , Albers Andreas , Zhao Yong Xiang , Visus Carmen , Appella Ettore , Whiteside Theresa L. , DeLeo Albert B. 
Published: April 2014

Abstract
Tumor peptide-based vaccines are more effective when they include tumor-specific Th cell-defined as well as CTL-defined peptides. Presently, two overlapping wild-type sequences (wt) p53 helper peptides, p53108–122 and p53110–124, have been identified as HLA-DR1- and/or HLA-DR4-restricted epitopes. These HLA-DR alleles are expressed by ∼35% of subjects with cancer. To identify Th cell-defined wt p53 peptides suitable for use on the remaining subject population, a dendritic cell (DC)-based coculture system was developed. CD4+ T cells isolated from PBMC obtained from HLA-DR4− normal donors were stimulated ex vivo with autologous DC transfected with wt p53 or mutant p53 cDNA. Reactivity of T cells was tested in ELISPOT IFN-γ assays against DC pulsed individually with a panel of algorithm-predicted, multiple HLA-DR-binding wt p53 peptides. The wt p5325–35 peptide was identified as capable of inducing and being recognized by CD4+ T cells in association, at a minimum, with HLA-DR7 and -DR11 molecules, each of which is expressed by ∼15% of the population. In addition, the presence of anti-p5325–35 CD4+ Th cells was shown to enhance the in vitro generation/expansion of HLA-A2-restricted, anti-wt p53264–272 CD8+ T cells, which from one donor were initially “nonresponsive” to the wt p53264–272 peptide. The wt p5325–35 peptide has attributes of a naturally presented Th cell-defined peptide, which could be incorporated into antitumor vaccines applicable to a broader population of subjects for whom a wt p53 helper peptide is presently unavailable, as well as used for monitoring anti-p53 Th cell activity in cancer subjects receiving p53-based immunotherapy.
Fc Receptor Homolog 3 Is a Novel Immunoregulatory Marker of Marginal Zone and B1 B Cells
Authors: Won Woong-Jai , Foote Jeremy B. , Odom Mary R. , Pan Jicun , Kearney John F. , Davis Randall S. 
Published: April 2014

Abstract
Two members of the recently identified FcR homolog (FcRH) family in mice demonstrate preferential B cell expression. One of these, FcRH3, encodes a type I transmembrane protein with five extracellular Ig domains and a cytoplasmic tail with a consensus ITIM and a noncanonical ITAM. Analysis of full-length cDNAs from five different mouse strains defines two FcRH3 alleles. A panel of FcRH3-specific mAbs was generated to define its expression pattern and functional potential on B lineage cells. Although poorly detected on the majority of bone marrow or peripheral blood cells, FcRH3 was readily identified on splenic marginal zone (MZ) and MZ precursor B cells, but not on the bulk of newly formed B cells, follicular B cells, germinal center B cells, and plasma cells. In the peritoneal cavity, FcRH3 was found on B1 cells, and not on the majority of B2 cells. Consistent with its possession of an ITIM and ITAM-like sequence, FcRH3 was tyrosine phosphorylated following pervanadate treatment, and its coligation with the BCR inhibited calcium mobilization. These results suggest FcRH3 is a novel immunoregulatory marker of MZ and B1 B lineage cells.
Adaptation of Solitary Intestinal Lymphoid Tissue in Response to Microbiota and Chemokine Receptor CCR7 Signaling
Authors: Pabst Oliver , Herbrand Heike , Friedrichsen Michaela , Velaga Sarvari , Dorsch Martina , Berhardt Günter , Worbs Tim , Macpherson Andrew J. , Förster Reinhold 
Published: April 2014

Abstract
Besides Peyer’s patches, solitary intestinal lymphoid tissue (SILT) provides a structural platform to efficiently initiate immune responses in the murine small intestine. SILT consists of dynamic lymphoid aggregates that are heterogeneous in size and composition, ranging from small clusters of mostly lineage-negative cells known as cryptopatches to larger isolated lymphoid follicles rich in B cells. In this study, we report that in chemokine receptor CCR7-deficient mice SILT is enlarged, although unchanged in frequency and cellular composition compared with wild-type mice. This phenotype is conferred by bone marrow-derived cells and is independent of the presence of intestinal bacteria. Remarkably, particularly small-sized SILT predominates in germfree wild-type mice. Colonization of wild-type mice with commensal bacteria provokes an adjustment of the spectrum of SILT to that observed under specific pathogen-free conditions by the conversion of pre-existing lymphoid structures into larger-sized SILT. In conclusion, our findings establish that intestinal microbes influence the manifestation of gut-associated lymphoid tissues and identify CCR7 signaling as an endogeneous factor that controls this process.
A Novel Model of Demyelinating Encephalomyelitis Induced by Monocytes and Dendritic Cells
Authors: Furtado Glaucia C. , Piña Beatrice , Tacke Frank , Gaupp Stefanie , van Rooijen Nico , Moran Thomas M. , Randolph Gwendalyn J. , Ransohoff Richard M. , Chensue Stephen W. , Raine Cedric S. , Lira Sergio A. 
Published: April 2014

Abstract
Local inflammation may be a precipitating event in autoimmune processes. In this study, we demonstrate that regulated influx of monocytes and dendritic cells (DC) into the CNS causes an acute neurological syndrome that results in a demyelinating encephalomyelitis. Expansion of monocytes and DC by conditional expression of Flt3 ligand in animals expressing CCL2 in the CNS promoted parenchymal cell infiltration and ascending paralysis in 100% of the mice within 9 days of Flt3 ligand induction. Depletion of circulating monocytes and DC reduced disease incidence and severity. Unlike the classical models of experimental autoimmune encephalomyelitis, depletion of CD4+ and CD8+ T cells did not affect disease induction. T cells and demyelinating lesions were observed in the CNS at a later stage as a result of organ-specific inflammation. We propose that alterations in the numbers or function of monocytes and DC coupled to dysregulated expression of chemokines in the neural tissues, favors development of CNS autoimmune disease.
Functional Interaction of Common γ-Chain and Growth Hormone Receptor Signaling Apparatus
Authors: Adriani Marsilio , Garbi Corrado , Amodio Giada , Russo Ilaria , Giovannini Marica , Amorosi Stefania , Matrecano Eliana , Cosentini Elena , Candotti Fabio , Pignata Claudio 
Published: April 2014

Abstract
We previously reported on an X-linked SCID (X-SCID) patient, who also had peripheral growth hormone (GH) hyporesponsiveness and abnormalities of the protein phosphorylation events following GH receptor (GHR) stimulation. In the present study, we examined a potential role of common cytokine receptor γ-chain (γc) in GHR signaling using EBV-transformed lymphocytes from healthy subjects and γc-negative X-SCID patients. We demonstrated that the proliferative response to GH stimulation of the B cell lines of γc-negative patients was impaired despite a comparable cellular expression of GHR molecules to controls. In patients, after GH stimulation, no phosphorylation of STAT5 was observed. In addition, the molecule localization through confocal microscopy revealed that in B cell lines of patients no nuclear translocation of STAT5b following GH stimulation occurred differently from controls. Biochemical analysis of the nuclear extracts of γc-negative cell lines provided further evidence that the amount of STAT5b and its phosphorylated form did not increase following GH stimulation. In patients, cells reconstituted with wild-type γc abnormal biochemical and functional events were restored resulting in nuclear translocation of STAT5. Confocal experiments revealed that GHR and γc were colocalized on the cell membrane. Our study demonstrates the existence of a previously unappreciated relationship between GHR-signaling pathway and γc, which is required for the activation of STAT5b in B cell lines. These data also confirm that growth failure in X-SCID is primarily related to the genetic alteration of the IL2RG gene.
Segregation of HLA-C from ICAM-1 at NK Cell Immune Synapses Is Controlled by Its Cell Surface Density
Authors: Almeida Catarina R. , Davis Daniel M. 
Published: April 2014

Abstract
NK cell activity is controlled by the integration of signals from numerous activating and inhibitory receptors at the immunological synapse (IS). However, the importance of segregation and patterning of proteins at the NK cell IS is unknown. In this study, we report that the level of expression of HLA-C on target cells determined its supramolecular organization and segregation from ICAM-1 at the NK cell IS, as well as its capacity to inhibit NK cell cytotoxicity. At YTS NK cell synapses formed with target cells expressing low levels of HLA-C (i.e., 104/cell surface), a multifocal patterning of MHC class I protein predominated, whereas for higher levels of expression (105/cell surface), clusters of HLA-C were more commonly homogeneous, ring-shaped, or containing multiple exclusions. This correlation of protein density with its patterning at the IS was independent of ATP- or actin-driven processes. Importantly, ICAM-1 and HLA-C segregated only at synapses involving target cells expressing high levels of MHC protein. For peripheral blood NK clones, there were specific thresholds in the level of target cell HLA-C needed to inhibit cytotoxicity and to cause segregation of HLA-C from ICAM-1 at the synapse. Thus, the synapse organization of HLA-C, determined by its level of expression, could directly influence NK cell inhibition, e.g., by regulating the proximity of activating and inhibitory receptors. For the first time, this suggests an important function for the assembly of an inhibitory NK cell IS. More broadly, segregation of proteins at intercellular contacts could transmit information about protein expression levels between cells.
CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes
Authors: Soler Dulce , Chapman Tobias R. , Poisson Louis R. , Wang Lin , Cote-Sierra Javier , Ryan Mark , McDonald Alice , Badola Sunita , Fedyk Eric , Coyle Anthony J. , Hodge Martin R. , Kolbeck Roland 
Published: April 2014

Abstract
CD4+ Th2 cells are important regulators of allergic inflammation. CCR8 is thought to play a role in Th2-mediated responses, however, expression of CCR8 in peripheral blood has not been fully characterized. Using a fluorescent form of the ligand selective for CCR8 (F-CCL1), we identified the leukocytes expressing CCR8 in human, monkey, and mouse peripheral blood. CCR8 expression is primarily restricted to a subset of human CD4 memory T lymphocytes (15%). Approximately 40% of CCR8+CD4+ T cells express Th2 cytokines IL-4 or IL-13 while 13% express the Th1 cytokine IFN-γ. In fact, 50% of all Th2, but only 5% of Th1, cells express CCR8. Upon anti-CD3/anti-CD28 mAb-mediated activation, CCR8+CD4+ T cells secrete 3- to 7-fold higher levels of IL-4, IL-5, IL-9, and IL-13 and 10- to 20-fold lower levels of IFN-γ or IL-17, compared with CCR8−CD4+ memory T cells. Two-thirds of CCR8+CD4 T cells express cutaneous lymphocyte-associated Ag while the majority lack gut-homing receptors. CCR8+CD4+ cells express CCR7 and CD62L and are present in spleen and lymph nodes of mice. Approximately 25% of CCR8+CD4 T cells express CD25high while 20% of CCR8+CD4+ express the T regulatory cell transcription factor FOXP3 accounting for 60% of all FOXP3-expressing CD4+ T cells. In conclusion, CCR8 marks a diverse subset of CD4 memory T cells enriched for T regulatory and Th2 cells which have the potential for recruitment into sites of allergic inflammation where they could participate in the induction and regulation of the allergic response.
Distinct Molecular Program Imposed on CD4+ T Cell Targets by CD4+CD25+ Regulatory T Cells
Authors: Sukiennicki Teresa L. , Fowell Deborah J. 
Published: April 2014

Abstract
CD4+CD25+ regulatory T cells (Tregs) are key modulators of immunity, but their mechanism of action is unclear. To elucidate the molecular consequences of Treg encounter, we analyzed changes in gene expression in CD4+ T cell targets activated in the presence or absence of CD4+CD25+ Tregs. Tregs did not alter the early activation program of CD4+ T cells, but had reversed many of the activation-induced changes by 36 h. It is not known whether Tregs simply induce a set of transcriptional changes common to other nonproliferative states or whether instead Tregs mediate a distinct biological activity. Therefore, we compared the gene profile of T cells following Treg encounter with that of T cells made anergic, TGF-β-treated, or IL-2-deprived; all possible modes of Treg action. Strikingly, all genes down-regulated in suppressed cells were indeed common to these nonproliferative states. In contrast, Treg encounter led to elevated expression of a unique set of genes in the target T cells. Although different from the nonproliferative states tested, the Treg-imposed gene program is exemplified by expression of many genes associated with growth arrest or inhibition of proliferation. We suggest that Tregs function by the induction of a distinct set of negative regulatory factors that initiate or maintain target T cells in a nonproliferative state.
Oligomerization of CXCL10 Is Necessary for Endothelial Cell Presentation and In Vivo Activity
Authors: Campanella Gabriele S. V. , Grimm Jan , Manice Lindsay A. , Colvin Richard A. , Medoff Benjamin D. , Wojtkiewicz Gregory R. , Weissleder Ralph , Luster Andrew D. 
Published: April 2014

Abstract
The chemokine IFN-γ-inducible protein of 10 kDa (IP-10; CXCL10) plays an important role in the recruitment of activated T lymphocytes into sites of inflammation by interacting with the G protein-coupled receptor CXCR3. IP-10, like other chemokines, forms oligomers, the role of which has not yet been explored. In this study, we used a monomeric IP-10 mutant to elucidate the functional significance of oligomerization. Although monomeric IP-10 had reduced binding affinity for CXCR3 and heparin, it was able to induce in vitro chemotaxis of activated T cells with the same efficacy as wild-type IP-10. However, monomeric IP-10 was unable to induce recruitment of activated CD8+ T cells into the airways of mice after intratracheal instillation. Use of a different IP-10 mutant demonstrated that this inability was due to lack of oligomerization rather than reduced CXCR3 or heparin binding. Molecular imaging demonstrated that both wild-type and monomeric IP-10 were retained in the lung after intratracheal instillation. However, in vitro binding assays indicated that wild-type, but not monomeric, IP-10 was retained on endothelial cells and could induce transendothelial chemotaxis of activated T cells. We therefore propose that oligomerization of IP-10 is required for presentation on endothelial cells and subsequent transendothelial migration, an essential step for lymphocyte recruitment in vivo.