bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal Expansions and Loss of Receptor Diversity in the Naive CD8 T Cell Repertoire of Aged Mice
Authors: Ahmed Mushtaq , Lanzer Kathleen G. , Yager Eric J. , Adams Pamela S. , Johnson Lawrence L. , Blackman Marcia A. 
Published: April 2014

AbstractThere are well-characterized age-related changes in the peripheral repertoire of CD8 T cells characterized by reductions in the ratio of naive:memory T cells and the development of large clonal expansions in the memory pool. In addition, the TCR repertoire of naive T cells is reduced with aging. Because a diverse repertoire of naive T cells is essential for a vigorous response to new infections and vaccinations, there is much interest in understanding the mechanisms responsible for declining repertoire diversity. It has been proposed that one reason for declining repertoire diversity in the naive T cell pool is an increasing dependence on homeostatic proliferation in the absence of new thymic emigrants for maintenance of the naive peripheral pool. In this study, we have analyzed the naive CD8 T cell repertoire in young and aged mice by DNA spectratype and sequence analysis. Our data show that naive T cells from aged mice have perturbed spectratype profiles compared with the normally Gaussian spectratype profiles characteristic of naive CD8 T cells from young mice. In addition, DNA sequence analysis formally demonstrated a loss of diversity associated with skewed spectratype profiles. Unexpectedly, we found multiple repeats of the same sequence in naive T cells from aged but not young mice, consistent with clonal expansions previously described only in the memory T cell pool. Clonal expansions among naive T cells suggests dysregulation in the normal homeostatic proliferative mechanisms that operate in young mice to maintain diversity in the naive T cell repertoire.
Tuberculosis-Induced Variant IL-4 mRNA Encodes a Cytokine Functioning As Growth Factor for (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Specific Vγ2Vδ2 T Cells
Authors: Yuan ZhuQing , Wang Richard , Lee Yuyang , Chen Crystal Y. , Yu XingBing , Wu ZhongDao , Huang Dan , Shen Ling , Chen Zheng W. 
Published: April 2014

Abstract
The possibility that mycobacterial infections induce variant cytokine mRNA encoding a functionally distinct protein for immune regulation has not been addressed. In this study, we reported that Mycobacterium tuberculosis and bacillus Calmette-Guérin infections of macaques induced expression of variant IL-4 (VIL-4) mRNA encoding a protein comprised of N-terminal 97 aa identical with IL-4, and unique C-terminal 96 aa including a signaling-related proline-rich motif. While VIL-4 could be stably produced as intact protein, the purified VIL-4 induced apparent expansion of phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)-specific Vγ2Vδ2 T cells in dose- and time-dependent manners. The unique C-terminal 96 aa bearing the proline-rich motif (PPPCPP) of VIL-4 appeared to confer the ability to expand Vγ2Vδ2 T cells, since simultaneously produced IL-4 had only a subtle effect on these γδ T cells. Moreover, VIL-4 seemed to use IL-4R α for signaling and activation, as the VIL-4-induced expansion of Vγ2Vδ2 T cells was blocked by anti-IL-4R α mAb but not anti-IL-4 mAb. Surprisingly, VIL-4-expanded Vγ2Vδ2 T cells after HMBPP stimulation appeared to be heterologous effector cells capable of producing IL-4, IFN-γ, and TNF-α. Thus, mycobacterial infections of macaques induced variant mRNA encoding VIL-4 that functions as growth factor promoting expansion of HMBPP-specific Vγ2Vδ2 T effector cells.
Plasmacytoid Dendritic Cells Are Dispensable during Primary Influenza Virus Infection
Authors: Wolf Amaya I. , Buehler Darya , Hensley Scott E. , Cavanagh Lois L. , Wherry E. John , Kastner Philippe , Chan Susan , Weninger Wolfgang 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (pDC) are thought to be pivotal in the first line of defense against viral infections. Although previous studies have suggested that pDC regulate the immune response against respiratory syncytial virus, their role in pulmonary infection with influenza virus has remained unclear. Using mice with GFP-tagged pDC, we observed a marked increase in pDC numbers in the lung airways 3 days after intranasal infection with influenza virus A/PR/8/34. To further investigate their potential involvement in the disease, we made use of pDC-deficient IkarosL/L mice. In the absence of pDC, the recruitment of T cells to the bronchoalveolar space was delayed, which could be reversed by the adoptive transfer of pDC before infection. Surprisingly, however, when compared with wild-type animals, IkarosL/L mice revealed a similar course of disease, as determined by weight loss, viral titers, levels of neutralizing Ab, and lung pathology. Moreover, the activation and differentiation of influenza-specific CD8+ effector T cells was unaltered in the absence of pDC, as was the generation of CD8+ memory T cells. Taken together, our study suggests that pDC regulate the accumulation of T cells in the bronchoalveolar space during early influenza virus infection, but are dispensable for the control of this disease.
Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7
Authors: Vultaggio Alessandra , Nencini Francesca , Fitch Paul M. , Filì Lucia , Maggi Laura , Fanti Paola , deVries Annick , Beccastrini Enrico , Palandri Francesca , Manuelli Cinzia , Bani Daniele , Giudizi Maria Grazia , Guarna Antonio , Annunziato Francesco , Romagnani Sergio , Maggi Enrico , Howie Sarah E. M. , Parronchi Paola 
Published: April 2014

Abstract
Substitute adenine (SA)-2, a synthetic heterocycle chemically related to adenine with substitutions in positions 9-, 2-, and 8- (i.e., 9-benzyl-2-butoxy-8-hydroxyadenine), induces in vitro immunodeviation of Th2 cells to a Th0/Th1 phenotype. In this article, we evaluate the in vivo ability of SA-2 to affect Th2-mediated lung inflammation and its safety. TLR triggering and NF-κB activation by SA-2 were analyzed on TLR-transfected HEK293 cells and on purified bone marrow dendritic cells. The in vivo effect of SA-2 on experimental airway inflammation was evaluated in both prepriming and prechallenge protocols by analyzing lung inflammation, including tissue eosinophilia and goblet cell hyperplasia, bronchoalveolar lavage fluid cell types, and the functional profile of Ag-specific T cells from draining lymph nodes and spleens. SA-2 induced mRNA expression and production of proinflammatory (IL-6, IL-12, and IL-27) and regulatory (IL-10) cytokines and chemokines (CXCL10) in dendritic cells but down-regulated TGF-β. Prepriming administration of SA-2 inhibited OVA-specific Abs and Th2-driven lung inflammation, including tissue eosinophilia and goblet cells, with a prevalent Foxp3-independent regulatory mechanism. Prechallenge treatment with SA-2 reduced the lung inflammation through the induction of a prevalent Th1-related mechanism. In this model the activity of SA-2 was route-independent, but adjuvant- and Ag dose-dependent. SA-2-treated mice did not develop any increase of serum antinuclear autoantibodies. In conclusion, critical substitutions in the adenine backbone creates a novel synthetic TLR7 ligand that shows the ability to ameliorate Th2-mediated airway inflammation by a complex mechanism, involving Th1 redirection and cytokine-mediated regulation, which prevents autoreactivity.
Differential Capability of Human Cutaneous Dendritic Cell Subsets to Initiate Th17 Responses
Authors: Mathers Alicia R. , Janelsins Brian M. , Rubin Joseph P. , Tkacheva Olga A. , Shufesky William J. , Watkins Simon C. , Morelli Adrian E. , Larregina Adriana T. 
Published: April 2014

Abstract
Human skin-migratory dendritic cells (DCs) have the ability to prime and bias Th1 and Th2 CD4+ T lymphocytes. However, whether human cutaneous DCs are capable of initiating proinflammatory Th17 responses remains undetermined. We report that skin-migratory DCs stimulate allogeneic naive CD4+ T cells that differentiate simultaneously into two distinct effector Th17 and Th1 populations capable of homing to the skin, where they induce severe cutaneous damage. Skin-migratory Langerhans cells (smiLCs) were the main cutaneous DC subset capable of inducing Th17 responses dependent on the combined effects of IL-15 and stabilized IL-6, which resulted in IL-6 trans-signaling of naive CD4+ T cells. Different from smiLCs, purified skin-migratory dermal DCs did not synthesize IL-15 and were unable to bias Th17 responses. Nevertheless, these dermal DCs were capable of differentiating Th17 cells in mixed leukocyte cultures supplemented with IL-15 and stabilized IL-6. Overall, our data demonstrate that human epidermal smiLCs induce Th17 responses by mechanisms different from those previously described and highlight the need to target clinical treatments based on these variations.
Cutting Edge: An IL-17F-CreEYFP Reporter Mouse Allows Fate Mapping of Th17 Cells
Authors: Croxford Andrew L. , Kurschus Florian C. , Waisman Ari 
Published: April 2014

Abstract
The need for reporter lines able to faithfully track Th17 cells in vivo has become an issue of exceptional importance. To address this, we generated a mouse strain in which Cre recombinase is expressed from the IL-17F promoter. Crossing the IL-17F-Cre allele to a conditional enhanced yellow fluorescent protein (EYFP) reporter mouse yielded the IL-17F-CreEYFP strain, in which IL-17F expression is twinned with EYFP in live IL-17F-expressing cells. Although we demonstrate that IL-17F expression is restricted to CD4+ T cells during experimental autoimmune encephalomyelitis, IL-17F-CreEYFP CD8 T cells robustly expressed IL-17F in response to TGF-β, IL-6, and IL-23. Fate mapping of IL-17F-expressing reporter T cells revealed a significant down-regulation of Th17 cytokines after homeostatic expansion in RAG1-deficient animals. Despite this loss of effector phenotype, committed Th17 cells were resistant to Foxp3 expression in vitro or in vivo. Thus, the IL-17F-Cre strain furthers our understanding of Th17 biology.
Cutting Edge: Permissive MHC Class II Allele Changes the Pattern of Antitumor Immune Response Resulting in Failure of Tumor Rejection
Authors: Klyushnenkova Elena N. , Kouiavskaia Diana V. , Berard Carla A. , Alexander Richard B. 
Published: April 2014

Abstract
We studied the growth of transgenic adenocarcinoma of mouse prostate (TRAMP)-C1 tumor cells expressing human prostate-specific Ag (PSA) in HLA-DRB1*1501 (DR2b) transgenic mice. TRAMP-PSA tumors were frequently rejected by HLA-DR2b− mice but had increased incidence in HLA-DR2b+ littermates. The levels of PSA-specific CD8 T cell responses were significantly higher in the HLA-DR2b− mice that rejected TRAMP-PSA tumors compared with HLA-DR2b+ tumor-bearing littermates. In contrast, Ab responses to PSA were strong in HLA-DR2b+ mice bearing TRAMP-PSA tumors and were virtually undetectable in HLA-DR2b− littermates. The analysis of CD4 T cell responses to PSA revealed the presence of several CD4 T cell epitopes in HLA-DR2b+ mice but failed to identify strong I-Ab-restricted epitopes in HLA-DR2b− mice. Our data demonstrate that the expression of a permissive HLA class II allele can change the pattern of the immune response to a tumor Ag, resulting in the failure of tumor rejection.
ISCOMATRIX Adjuvant Induces Efficient Cross-Presentation of Tumor Antigen by Dendritic Cells via Rapid Cytosolic Antigen Delivery and Processing via Tripeptidyl Peptidase II
Authors: Schnurr Max , Orban Martin , Robson Neil C. , Shin Amanda , Braley Hal , Airey Denise , Cebon Jonathan , Maraskovsky Eugene , Endres Stefan 
Published: April 2014

Abstract
Cancer vaccines aim to induce antitumor CTL responses, which require cross-presentation of tumor Ag to CTLs by dendritic cells (DCs). Adjuvants that facilitate cross-presentation of vaccine Ag are therefore key for inducing antitumor immunity. We previously reported that human DCs could not efficiently cross-present the full-length cancer/testis Ag NY-ESO-1 to CTL unless formulated as either an immune complex (NY-ESO-1/IC) or with ISCOMATRIX adjuvant. We now demonstrate that NY-ESO-1/ICs induce cross-presentation of HLA-A2- and HLA-Cw3-restricted epitopes via a proteasome-dependent pathway. In contrast, cross-presentation of NY-ESO-1/ISCOMATRIX vaccine was proteasome independent and required the cytosolic protease tripeptidyl peptidase II. Trafficking studies revealed that uptake of ICs and ISCOMATRIX vaccine by DCs occurred via endocytosis with delivery to lysosomes. Interestingly, ICs were retained in lysosomes, whereas ISCOMATRIX adjuvant induced rapid Ag translocation into the cytosol. Ag translocation was dependent on endosomal acidification and IL-4-driven differentiation of monocytes into DCs. This study demonstrates that Ag formulation determines Ag processing and supports a role for tripeptidyl peptidase II in cross-presentation of CTL epitopes restricted to diverse HLA alleles.
A New Triggering Receptor Expressed on Myeloid Cells (Trem) Family Member, Trem-Like 4, Binds to Dead Cells and Is a DNAX Activation Protein 12-Linked Marker for Subsets of Mouse Macrophages and Dendritic Cells
Authors: Hemmi Hiroaki , Idoyaga Juliana , Suda Koji , Suda Nao , Kennedy Kathleen , Noda Masaki , Aderem Alan , Steinman Ralph M. 
Published: April 2014

Abstract
Dendritic cells (DCs) are professional APCs that can control immune responses against self and altered self, typically foreign, determinants. DCs can be divided into several subsets, including CD8α+ and CD8α− DCs. These subsets possess specific functions. For example, mouse splenic CD8α+, but not CD8α− DCs selectively take up dying cells and cross-present cell-associated Ags to naive T cells. In this study, we identified genes that were more expressed in CD8α+ than CD8α− DCs by microarray analysis. Only one of these genes, when the extracellular domains were linked to human IgG Fc domain, could bind to late apoptotic or necrotic cells. This gene was a new member of the triggering receptor expressed on myeloid cells (Trem) family, Trem-like 4 (Treml4). Treml4 mRNA and protein, the latter detected with a new mAb, were predominantly expressed in spleen. Treml4, like other Trem family members, could associate with the adaptor molecule DNAX activation protein 12 kDa, but neither DNAX activation protein 10 kDa nor FcRγ. Consistent with the microarray data, we confirmed that Treml4 protein was more expressed on CD8α+ than CD8α− DCs, and we also found that Treml4 was expressed at high levels on splenic macrophages in spleen, particularly red pulp and marginal metallophilic macrophages. In addition, Treml4 expression on DCs was not changed after maturation induced by TLR ligands. Thus, Treml4 is a new Trem family molecule that is abundantly expressed on CD8α+ DCs and subsets of splenic resident macrophages, and can recognize dead cells by different types of phagocytes in spleen.
CXC Chemokine Ligand 12 Promotes CCR7-Dependent Naive T Cell Trafficking to Lymph Nodes and Peyer’s Patches
Authors: Bai Zhongbin , Hayasaka Haruko , Kobayashi Masayoshi , Li Wenzhe , Guo Zijin , Jang Myoung Ho , Kondo Akihiro , Choi Byung-il , Iwakura Yoichiro , Miyasaka Masayuki 
Published: April 2014

Abstract
A number of chemokines, including CCL21, CCL19, CXCL12, and CXCL13, are coexpressed on the lumen or basal lamina of high endothelial venules (HEVs) in lymph nodes (LNs) and Peyer’s patches (PPs), consistent with the idea that they might cooperate to regulate lymphocyte trafficking into these lymphoid tissues. In this study we report that CXCL12, acting through its receptor, CXCR4, cooperates with CCR7 ligands to promote T cell trafficking across HEVs. CXCL12 enhanced the CCR7-induced chemotaxis of wild-type but not CXCR4-deficient T cells in vitro at suboptimal concentrations of a CCR7 ligand, but without affecting the expression level or ligand-binding ability of CCR7. Real-time chemotaxis analysis showed that CXCL12 substantially shortened the lag time before cell migration began in vitro, but not the migration speed of T cells responding to suboptimal CCR7 ligand concentrations. In addition, CXCL12 augmented the CCR7 ligand-driven ERK phosphorylation and actin polymerization in T cells under the same conditions. In adoptive transfer experiments, CXCL12 promoted naive T cell trafficking to LNs and PPs in wild-type but not CCR7 ligand-deficient plt/plt recipient mice; this increased T cell trafficking was associated with enhanced binding of the T cells to HEVs and their subsequent migration into the LN parenchyma. Thus, CXCL12 synergizes with CCR7 ligands to promote T cell migration by sensitizing T cells through CXCR4, thus enabling them to respond to lower concentrations of CCR7 ligands. Such concerted action of chemokines provides an additional, previously unknown mechanism for efficient lymphocyte trafficking across HEVs into LNs and PPs.
MicroRNA-513 Regulates B7-H1 Translation and Is Involved in IFN-γ-Induced B7-H1 Expression in Cholangiocytes
Authors: Gong Ai-Yu , Zhou Rui , Hu Guoku , Li Xiaoqing , Splinter Patrick L. , O'Hara Steven P. , LaRusso Nicholas F. , Soukup Garrett A. , Dong Haidong , Chen Xian-Ming 
Published: April 2014

Abstract
Biliary epithelial cells (cholangiocytes) respond to proinflammatory cytokines such as IFN-γ and actively participate in the regulation of biliary inflammatory response in the liver. B7-H1 (also known as CD274 or PD-L1) is a member of the B7 costimulatory molecules and plays a critical immunoregulatory role in cell-mediated immune responses. In this study, we show that resting human cholangiocytes in culture express B7-H1 mRNA, but not B7-H1 protein. IFN-γ induces B7-H1 protein expression and alters the microRNA (miRNA) expression profile in cholangiocytes. Of those IFN-γ-down-regulated miRNAs, we identified microRNA-513 (miR-513) with complementarity to the 3′-untranslated region of B7-H1 mRNA. Targeting of the B7-H1 3′-untranslated region by miR-513 results in translational repression. Transfection of cholangiocytes with an antisense oligonucleotide to miR-513 induces B7-H1 protein expression. Additionally, transfection of miR-513 precursor decreases IFN-γ-induced B7-H1 protein expression and consequently influences B7-H1-associated apoptotic cell death in cocultured Jurkat cells. Thus, miR-513 regulates B7-H1 translation and is involved in IFN-γ-induced B7-H1 expression in human cholangiocytes, suggesting a role for miRNA-mediated gene silencing in the regulation of cholangiocyte response to IFN-γ.
Protein Tyrosine Phosphatases Regulate Asthma Development in a Murine Asthma Model
Authors: Pouliot Philippe , Camateros Pierre , Radzioch Danuta , Lambrecht Bart N. , Olivier Martin 
Published: April 2014

Abstract
Allergic asthma is a chronic inflammatory disease characterized by Th2-type inflammation. Although the cellular interactions are now well studied, the intracellular signaling involved in asthma development is still a developing field. Protein tyrosine kinases are one focus of such research and their inhibition shows improvement of asthmatic features. Interestingly, very little attention was given to protein tyrosine phosphatases (PTPs), the counterparts to protein tyrosine kinases, in the development of asthma. Previous studies from our laboratory showed that pharmacological inhibition of PTPs induced a transient Th1 response in the spleen. Therefore, we hypothesized that modulation of PTPs could influence asthma development. To assess PTP functions, we used the PTP inhibitor bis-peroxovanadium bpV(phen) in a murine model of asthma during either allergen sensitization or challenge. Inhibition of PTPs during allergen sensitization resulted in the reduction of key features of allergic asthma: serum IgE levels, lung tissue inflammation, eosinophilia, and airway hyperresponsiveness. Of utmost interest, PTP inhibition at allergen challenge resulted in a very similar improvement of asthmatic features. Of further importance, we observed that bpV(phen) treatment modulated cytokine expression in the spleen and, more specifically, favored Th1 cytokines while inhibiting Th2 cytokines. Collectively, we show for the first time that intact activity of PTPs is required for a complete induction of asthma in a mouse model. This clearly suggests that PTPs have a pivotal regulatory role in the development of asthmatic diseases, which opens the possibility of new therapeutic avenues.
Affinity-Based Selection of Regulatory T Cells Occurs Independent of Agonist-Mediated Induction of Foxp3 Expression
Authors: Relland Lance M. , Mishra Manoj K. , Haribhai Dipica , Edwards Brandon , Ziegelbauer Jennifer , Williams Calvin B. 
Published: April 2014

Abstract
Natural regulatory T (nTreg) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in the thymus is incomplete. We use altered peptide ligands in transgenic mice and in organ culture to create thymic environments spanning a broad range of ligand affinity. We demonstrate that the nTreg TCR repertoire is shaped by affinity-based selection, similar to conventional T cells. The effect of each ligand on the two populations is distinct, consistent with early nTreg cell lineage specification. Foxp3 expression is an independent process that does not rely on “high affinity” binding per se, but requires a high-potency agonistic interaction for its induction. The timing of ligand exposure, TGFβ signaling, and the organization of the thymic architecture are also important. The development of nTreg cells is therefore a multistep process in which ligand affinity, potency, and timing of presentation all play a role in determining cell fate.
Placental Cytokine Expression Covaries with Maternal Asthma Severity and Fetal Sex
Authors: Scott Naomi M. , Hodyl Nicolette A. , Murphy Vanessa E. , Osei-Kumah Annette , Wyper Hayley , Hodgson Deborah M. , Smith Roger , Clifton Vicki L. 
Published: April 2014

Abstract
In the presence of maternal asthma, we have previously reported reduced placental blood flow, decreased cortisol metabolism, and reductions in fetal growth in response to maternal asthma and asthma exacerbations. We have proposed that these changes in placental function and fetal development may be related to activation of proinflammatory pathways in the placenta in response to maternal asthma. In the present study, we examined the influence of maternal asthma severity, inhaled glucocorticoid treatment, maternal cigarette use, placental macrophage numbers, and fetal sex on placental cytokine mRNA expression from a prospective cohort study of pregnant women with and without asthma. Placental expression of TNF-α, IL-1β, IL-6, IL-8, and IL-5 mRNA were all increased significantly in placentae of female fetuses whose mothers had mild asthma, but no changes were observed in placentae of male fetuses. The proinflammatory cytokines TNF-α, IL-1β, and IL-6 were negatively correlated with female cord blood cortisol, but there were no such correlations in placentae from males. Multivariate analysis indicated the strongest predictor of both cytokine mRNA expression in the placenta and birth weight was fetal cortisol but only in females. Placental cytokine mRNA levels were not significantly altered by inhaled glucocorticoid use, placental macrophage numbers, cigarette use, moderate-severe asthma, or male sex. These data suggest that placental basal cytokine mRNA expression is sex specifically regulated in pregnancies complicated by asthma, and interestingly these changes are more prevalent in mild rather than severe asthma.