bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Lipopolysaccharide Induces IL-10-Producing Regulatory CD4+ T Cells That Suppress the CD8+ T Cell Response
Authors: den Haan Joke M. M. , Kraal Georg , Bevan Michael J. 
Published: April 2014

Abstract
TLR ligands are potent activators of dendritic cells and therefore function as adjuvants for the induction of immune responses. We analyzed the capacity of TLR ligands to enhance CD8+ T cell responses toward soluble protein Ag. Immunization with OVA together with LPS or poly(I:C) elicited weak CD8+ T cell responses in wild-type C57BL/6 mice. Surprisingly, these responses were greatly increased in mice lacking CD4+ T cells indicating the induction of regulatory CD4+ T cells. In vivo, neutralization of IL-10 completely restored CD8+ T cell responses in wild-type mice and OVA-specific IL-10 producing CD4+ T cells were detected after immunization with OVA plus LPS. Our study shows that TLR ligands not only activate the immune system but simultaneously induce Ag specific, IL-10-producing regulatory Tr1 cells that strongly suppress CD8+ T cell responses. In this way, excessive activation of the immune system may be prevented.
Human CD4+ T Cells Displaying Viral Epitopes Elicit a Functional Virus-Specific Memory CD8+ T Cell Response
Authors: Adamopoulou Eleni , Diekmann Jan , Tolosa Eva , Kuntz Gaby , Einsele Hermann , Rammensee Hans-Georg , Topp Max S. 
Published: April 2014

Abstract
The Ag-specific cellular recall response to herpes virus infections is characterized by a swift recruitment of virus-specific memory T cells. Rapid activation is achieved through formation of the immunological synapse and supramolecular clustering of signal molecules at the site of contact. During the formation of the immunological synapse, epitope-loaded MHC molecules are transferred via trogocytosis from APCs to T cells, enabling the latter to function as Ag-presenting T cells (T-APCs). The contribution of viral epitope expressing T-APCs in the regulation of the herpes virus-specific CD8+ T cell memory response remains unclear. Comparison of CD4+ T-APCs with professional APCs such as Ag-presenting CD40L-activated B cells (CD40B-APCs) demonstrated reduced levels of costimulatory ligands. Despite the observed differences, CD4+ T-APCs are as potent as CD40B-APCs in stimulating herpes virus-specific CD8+ T cells resulting in a greater than 35-fold expansion of CD8+ T cells specific for dominant and subdominant viral epitopes. Virus-specific CD8+ T cells generated by CD4+ T-APCs or CD40B-APCs showed both comparable effector function such as specific lysis of targets and cytokine production and also did not differ in their phenotype after expansion. These results indicate that viral epitope presentation by Ag-specific CD4+ T cells may contribute to the rapid recruitment of virus-specific memory CD8+ T cells during a viral recall response.
Immune Modulation and Tolerance Induction by RelB-Silenced Dendritic Cells through RNA Interference
Authors: Li Mu , Zhang Xusheng , Zheng Xiufen , Lian Dameng , Zhang Zhu-Xu , Ge Weiwen , Yang Jinming , Vladau Costin , Suzuki Motohiko , Chen Dong , Zhong Robert , Garcia Bertha , Jevnikar Anthony M. , Min Wei-Ping 
Published: April 2014

Abstract
Dendritic cells (DC), the most potent APCs, can initiate the immune response or help induce immune tolerance, depending upon their level of maturation. DC maturation is associated with activation of the NF-κB pathway, and the primary NF-κB protein involved in DC maturation is RelB, which coordinates RelA/p50-mediated DC differentiation. In this study, we show that silencing RelB using small interfering RNA results in arrest of DC maturation with reduced expression of the MHC class II, CD80, and CD86. Functionally, RelB-silenced DC inhibited MLR, and inhibitory effects on alloreactive immune responses were in an Ag-specific fashion. RelB-silenced DC also displayed strong in vivo immune regulation. An inhibited Ag-specific response was seen after immunization with keyhole limpet hemocyanin-pulsed and RelB-silenced DC, due to the expansion of T regulatory cells. Administration of donor-derived RelB-silenced DC significantly prevented allograft rejection in murine heart transplantation. This study demonstrates for the first time that transplant tolerance can be induced by means of RNA interference using in vitro-generated tolerogenic DC.
Noncognate Interaction with MHC Class II Molecules Is Essential for Maintenance of T Cell Metabolism to Establish Optimal Memory CD4 T Cell Function
Authors: De Riva Alessandra , Bourgeois Christine , Kassiotis George , Stockinger Brigitta 
Published: April 2014

Abstract
CD4 memory T cells surviving in the absence of MHC class II contact lose their characteristic memory function. To investigate the mechanisms underlying the impaired function of memory T cells in the absence of MHC class II molecules, we analyzed gene expression profiles of resting memory T cells isolated from MHC class II-competent or -deficient hosts. The analysis focused on five transcripts related to T cell activation, metabolism, and survival that are underexpressed in resting memory T cells from MHC class II-deficient hosts compared with MHC class II-competent hosts. CD4 memory cells isolated from MHC class II-deficient hosts display alterations in their degree of differentiation as well as metabolic activity, and these changes are already manifest in the effector phase despite the presence of Ag-expressing dendritic cells. Our data suggest that the absence of interactions with noncognate MHC class II molecules compromises the progressive accumulation of signals that ensure optimal survival and fitness to sustain the metabolic activity of activated T cells and shape the functional capacity of the future memory compartment. Signals via AKT coordinate survival and metabolic pathways and may be one of the crucial events linking interaction with MHC class II molecules to the successful generation of a long-lived functional memory CD4 T cell population.
Characterizing T Cell Movement within Lymph Nodes in the Absence of Antigen
Authors: Beauchemin Catherine , Dixit Narendra M. , Perelson Alan S. 
Published: April 2014

Abstract
The recent application of two-photon microscopy to the visualization of T cell movement has presented trajectories of individual T cells within lymphoid organs both in the presence and in the absence of Ag-loaded dendritic cells. Remarkably, even though T cells largely move along conduits of the fibroblastic reticular cell network, they appear to execute random walks in lymphoid organs rather than chemotaxis. In this study, we analyze experimental trajectories of T cells using computer simulations of idealized random walks. Comparisons of simulations with experimental data provide estimates of key parameters that characterize T cell motion in vivo. For example, we find that the distance moved before turning is about twice the distance between intersections in the fibroblastic reticular cell network, suggesting that at an intersection a T cell will turn onto a new fiber ∼50% of the time. Although the calibrated model appears to offer an accurate representation of T cell movement, it has also uncovered inconsistencies across different experimental data sets.
CD56 Marks an Effector T Cell Subset in the Human Intestine
Authors: Cohavy Offer , Targan Stephan R. 
Published: April 2014

Abstract
T cells are key mediators of intestinal immunity, and specific T cell subsets can have differing immunoregulatory roles in animal models of mucosal inflammation. In this study, we describe human CD56+ T cells as a morphologically distinct population expressing a mature, nonproliferative phenotype that is frequent in the gut. Enhanced potential for IFN-γ and TNF synthesis suggested a proinflammatory function, and we directly demonstrate effector function mediated by direct T-T interaction with responder cells in vitro. CD56+ T cells from peripheral blood responded to the gut-related CD2 signal, and were necessary for effective CD2-mediated proliferation of peripheral blood CD56− T cells. Our findings associate CD56+ T cells with the intestinal immune compartment and suggest a putative effector function in human mucosal immunity.
Characterization of Human Lung Tumor-Associated Fibroblasts and Their Ability to Modulate the Activation of Tumor-Associated T Cells
Authors: Nazareth Michael R. , Broderick Lori , Simpson-Abelson Michelle R. , Kelleher Raymond J. , Yokota Sandra J. , Bankert Richard B. 
Published: April 2014

Abstract
The tumor microenvironment of human non-small cell lung cancer (NSCLC) is composed largely of stromal cells, including fibroblasts, yet these cells have been the focus of few studies. In this study, we established stromal cell cultures from primary NSCLC through isolation of adherent cells. Characterization of these cells by flow cytometry demonstrated a population which expressed a human fibroblast-specific 112-kDa surface molecule, Thy1, α-smooth muscle actin, and fibroblast activation protein, but failed to express CD45 and CD11b, a phenotype consistent with that of an activated myofibroblast. A subset of the tumor-associated fibroblasts (TAF) was found to express B7H1 (PD-L1) and B7DC (PD-L2) constitutively, and this expression was up-regulated by IFN-γ. Production of cytokines and chemokines, including IFN-γ, monokine induced by IFN-γ, IFN-γ-inducible protein-10, RANTES, and TGF-β1 was also demonstrated in these cells. Together, these characteristics provide multiple opportunities for the TAF to influence cellular interactions within the tumor microenvironment. To evaluate the ability of TAF to modulate tumor-associated T cell (TAT) activation, we conducted coculture experiments between autologous TAF and TAT. In five of eight tumors, TAF elicited a contact-dependent enhancement of TAT activation, even in the presence of a TGF-β1-mediated suppressive effect. In the three other tumors, TAF had a net suppressive effect upon TAT activation, and, in one of these cases, blockade of B7H1 or B7DC was able to completely abrogate the TAF-mediated suppression. We conclude that TAF in human NSCLC are functionally and phenotypically heterogeneous and provide multiple complex regulatory signals that have the potential to enhance or suppress TAT function in the tumor microenvironment.
Paradoxical Effect of Reduced Costimulation in T Cell-Mediated Colitis
Authors: Kim Gisen , Levin Matthew , Schoenberger Stephen P. , Sharpe Arlene , Kronenberg Mitchell 
Published: April 2014

AbstractB7-1 and B7-2 play different roles in the pathogenesis of autoimmunity, but this is controversial. We analyzed colitis induced by transfer of CD45RBhighCD4+ T cells to RAG−/− recipients lacking B7-1 and/or B7-2. Surprisingly, disease was greatly accelerated in RAG−/− recipients deficient for either B7-1 or B7-2, especially in the B7-2−/− recipients. This accelerated colitis induction correlated with increased T cell division in vivo and production of Th1 cytokines. Although colitis pathogenesis following T cell transfer was inhibited in the absence of CD40L expression, CD40-CD40L interactions were not required in the B7-2−/− RAG−/− recipients. In vitro priming by APCs lacking either B7-1 or B7-2 caused decreased IL-2 production, which led to decreased CTLA-4 expression, although T cells primed in this way could respond vigorously upon restimulation by producing increased IL-2 and proinflammatory cytokines. Consistent with this mechanism, we demonstrate that blocking IL-2 early after T cell transfer accelerated colitis. Our data therefore outline a mechanism whereby synergistic costimulation by B7-1 and B7-2 molecules during priming is required for optimal IL-2 production. The consequent inhibitory effect of full CTLA-4 expression, induced by IL-2, may slow colitis, even in the absence of regulatory T cells.
Skin-Infiltrating CD8+ T Cells Initiate Atopic Dermatitis Lesions
Authors: Hennino Ana , Vocanson Marc , Toussaint Yann , Rodet Karen , Benetière Josette , Schmitt Anne-Marie , Aries Marie-Françoise , Bérard Frédéric , Rozières Aurore , Nicolas Jean-François 
Published: April 2014

Abstract
Skin lesions in the allergic form of atopic dermatitis (AD) are induced by allergen-specific T cells that infiltrate the skin at the site of allergen exposure. Although Th2-type CD4+ T cells appear to be crucial in AD pathophysiology, little is known about the contribution of CD8+ T cells in the development of the allergic skin inflammation. In the present study, we have analyzed the respective role of CD8+ and CD4+ T cells in the development of AD skin lesions in a mouse model of allergen-induced AD. In sensitized mice, CD8+ T cells are rapidly and transiently recruited to the allergen-exposed site and initiate the inflammatory process leading to skin infiltration with eosinophils and Th1/Th2-producing cells. CD8+ T cell-depleted mice show no inflammation, demonstrating that these cells are mandatory for the development of AD. In contrast, CD4+ T cell-depleted mice develop a severe form of eczema. Furthermore, adoptive transfer of CD8+ T cells from sensitized mice into naive recipient mice leads to skin inflammation soon after allergen exposure. These data indicate that allergen-primed CD8+ T cells are required for the development of AD-like lesions in mice.
Autoimmune Uveitis Elicited with Antigen-Pulsed Dendritic Cells Has a Distinct Clinical Signature and Is Driven by Unique Effector Mechanisms: Initial Encounter with Autoantigen Defines Disease Phenotype
Authors: Tang Jun , Zhu Wei , Silver Phyllis B. , Su Shao-Bo , Chan Chi-Chao , Caspi Rachel R. 
Published: April 2014

AbstractHuman autoimmune uveitis is a heterogeneous group of potentially blinding ocular diseases in which most patients who exhibit immunity recognize the same retinal Ag. It is represented by the model of experimental autoimmune uveitis (EAU) induced in mice by immunization with retinal Ag in CFA. Murine EAU is characterized by a Th1/Th17 response pattern, which may not represent all types of human uveitis. We report in this study a new model of EAU induced by injection of matured dendritic cells loaded with a uveitogenic retinal peptide. Dendritic cell-induced EAU demonstrated unique characteristics compared with traditional EAU in terms of clinical manifestations, the nature of the inflammatory infiltrating cells, the cytokine response profile, and a strict requirement for IFN-γ, whereas IL-17 appeared to play a minor role. Disease was self-limiting, but could be reinduced with the same Ag in CFA, albeit with reduced severity, suggesting postrecovery resistance. Our study demonstrates in a disease setting that the context in which the same autoantigen is initially presented to the immune system precipitates distinct forms of pathology via a distinct pathogenic pathway on the same genetic background. These findings may shed new light on the complex biology and the heterogeneous nature of human uveitis, and provide an alternative model for uveitic diseases of immune origin.
Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer’s Patches
Authors: Taylor Rebekah T. , Patel Seema R. , Lin Eugene , Butler Betsy R. , Lake Jason G. , Newberry Rodney D. , Williams Ifor R. 
Published: April 2014

Abstract
Stromal cells play a crucial role in the organogenesis of lymphoid tissues. We previously identified VCAM-1+ stromal cells in cryptopatches (CP) and isolated lymphoid follicles (ILF) in the small intestine of C57BL/6 mice. Nonhemopoietic stromal cell networks in CP and ILF of adult mice also expressed FDC-M1, CD157 (BP-3), and TNF-related activation-induced cytokine (TRANCE). Individual stromal cells were heterogeneous in their expression of these markers, with not all stromal cells expressing the entire set of stromal cell markers. Expression of VCAM-1, FDC-M1, and CD157 on CP stromal cells was absent in alymphoplasia mice deficient in NF-κB-inducing kinase (NIK) and NIK knockout mice. Administration of lymphotoxin β receptor (LTβR)-Ig to wild-type mice on day 13 resulted in the absence of CP on day 20; delaying administration of LTβR-Ig until day 18 resulted in an 80% decrease in the number of CP on day 22 and diminished expression of VCAM-1, FDC-M1, and CD157 on the remaining CP. In sharp contrast, TRANCE expression by stromal cells was completely independent of NIK and LTβR. In addition, expression of TRANCE in ILF was concentrated just beneath the follicle-associated epithelium, a pattern of polarization that was also observed in Peyer’s patches. These findings suggest that TRANCE on stromal cells contributes to the differentiation and maintenance of organized lymphoid aggregates in the small intestine.
A Teleost Polymeric Ig Receptor Exhibiting Two Ig-Like Domains Transports Tetrameric IgM into the Skin
Authors: Hamuro Koji , Suetake Hiroaki , Saha Nil Ratan , Kikuchi Kiyoshi , Suzuki Yuzuru 
Published: April 2014

Abstract
The skin mucus IgM is an important molecule in the mucosal immune system of teleost skin. However, the transport mechanism associated with this molecule has yet to be clarified. In this study, we isolated a gene encoding a polymeric Ig receptor (pIgR) from a species of teleost fish, Takifugu rubripes (fugu). This gene is known to be an Ig transporter in the intestine of mammals. Our studies further demonstrated that fugu pIgR was expressed in the skin and that a fragment of pIgR bound to tetrameric IgM in the skin mucus. These results indicate that the skin pIgR transports tetrameric IgM into the skin mucus. The fugu pIgR exhibits a unique structure containing only two Ig-like domains corresponding to domain 1 and domain 4/5 of mammalian pIgR. This structure was sufficient for successful binding to tetrameric IgM. Teleost skin thus adopts the same Ig transport system as mammalian intestine via a unique pIgR.
TNF Trafficking to Human Mast Cell Granules: Mature Chain-Dependent Endocytosis
Authors: Olszewski Maciej B. , Groot Arjan J. , Dastych Jaroslaw , Knol Edward F. 
Published: April 2014

AbstractMast cells play a crucial role at the early stages of immune response against bacteria and parasites where their functionality is based on their capability of releasing highly bioactive compounds, among them TNF. Mast cells are considered the only cells storing preformed TNF, which allows for the immediate release of this cytokine upon contact with pathogens. We approached the question of mechanisms and amino acid motifs directing newly synthesized TNF for storage in cytoplasmic granules by analyzing the trafficking of a series of TNF-enhanced GFP fusion proteins in human mast cell lines HMC-1 and LAD2. Protein covering the full TNF sequence was successfully sorted into secretory granules in a process involving transient exposure on the outer membrane and re-endocytosis. In human cells, contrary to results previously obtained in a rodent model, TNF seems not to be glycosylated and, thus, trafficking is carbohydrate independent. In an effort to localize the amino acid motif responsible for granule targeting, we constructed additional fusion proteins and analyzed their trafficking, concluding that granule-targeting sequences are localized in the mature chain of TNF and that the cytoplasmic tail is expendable for endocytotic sorting of this cytokine, thus excluding direct interactions with intracellular adaptor proteins.
Identification of the Site of Human Mannan-Binding Lectin Involved in the Interaction with Its Partner Serine Proteases: The Essential Role of Lys55
Authors: Teillet Florence , Lacroix Monique , Thiel Steffen , Weilguny Dietmar , Agger Teit , Arlaud Gérard J. , Thielens Nicole M. 
Published: April 2014

Abstract
Mannan-binding lectin (MBL) is an oligomeric lectin that binds neutral carbohydrates on pathogens, forms complexes with MBL-associated serine proteases (MASP)-1, -2, and -3 and 19-kDa MBL-associated protein (MAp19), and triggers the complement lectin pathway through activation of MASP-2. To identify the MASP binding site(s) of human MBL, point mutants targeting residues C-terminal to the hinge region were produced and tested for their interaction with the MASPs and MAp19 using surface plasmon resonance and functional assays. Mutation Lys55Ala abolished interaction with the MASPs and MAp19 and prevented formation of functional MBL-MASP-2 complexes. Mutations Lys55Gln and Lys55Glu abolished binding to MASP-1 and -3 and strongly inhibited interaction with MAp19. Conversely, mutation Lys55Arg abolished interaction with MASP-2 and MAp19, but only weakened interaction with MASP-1 and -3. Mutation Arg47Glu inhibited interaction with MAp19 and decreased the ability of MBL to trigger the lectin pathway. Mutant Arg47Lys showed no interaction with the MASPs or MAp19, likely resulting from a defect in oligomerization. In contrast, mutation Arg47Ala had no impact on the interaction with the MASPs and MAp19, nor on the ability of MBL to trigger the lectin pathway. Mutation Pro53Ala only had a slight effect on the interaction with MASP-1 and -3, whereas mutations at residues Leu49 and Leu56 were ineffective. In conclusion, the MASP binding site of MBL involves a sequence stretch centered on residue Lys55, which may form an ionic bond representing the major component of the MBL-MASP interaction. The binding sites for MASP-2/MAp19 and MASP-1/3 have common features but are not strictly identical.
E2A and HEB Are Required to Block Thymocyte Proliferation Prior to Pre-TCR Expression
Authors: Wojciechowski Jason , Lai Anne , Kondo Motonari , Zhuang Yuan 
Published: April 2014

Abstract
Thymocytes undergoing TCRβ gene rearrangements are maintained in a low or nonproliferating state during early T cell development. This block in cell cycle progression is not released until the expression of a functional pre-TCR, which is composed of a successfully rearranged TCRβ-chain and the Pre-Tα-chain. The regulatory molecules responsible for the coordination of these differentiation and proliferation events are currently unknown. E2A and HEB are structurally and functionally related basic helix-loop-helix transcription factors involved in T cell development. To reveal the function of E2A and HEB through the stage of pre-TCR expression and alleviate functional compensation between E2A and HEB, we use a double-conditional knockout model. The simultaneous deletion of E2A and HEB in developing thymocytes leads to a severe developmental block before pre-TCR expression and a dramatic reduction of Pre-Tα expression. These developmentally arrested thymocytes exhibit increased proliferation in vivo and dramatic expansion ex vivo in response to IL-7 signaling. These results suggest that E2A and HEB are not only critical for T cell differentiation but also necessary to retain developing thymocytes in cell cycle arrest before pre-TCR expression.