bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4+ Self-Reactive T Cells
Authors: Terme Magali , Chaput Nathalie , Combadiere Behazine , Ma Averil , Ohteki Toshiaki , Zitvogel Laurence 
Published: April 2014

Abstract
The CD4+CD25+Foxp3+ regulatory T cells (Treg) play an important role in the control of peripheral tolerance by directly inhibiting conventional T cell proliferative and effector functions. However, the mechanisms by which Treg regulate the homeostasis of lymph nodes remain unclear. In this study, we show in a mouse model that Treg control two major checkpoints dictated by the interaction between self-reactive CD4+ T cells and resident dendritic cell (DC) in secondary lymphoid organs. First, Treg inhibit the production of CCR5 ligands, limiting the CCR5-dependent recruitment of DC in the lymph nodes. Second, Treg prevent the DC exposure of IL-15Rα, markedly interfering in the DC-mediated NK cell proliferation in vivo. Therefore, the DC/T cell autoreactivity leading to NK cell triggering could potentially be controlled by the coinhibition of both IL-15Rα and CCR5 in autoimmune disorders in which NK cells play a deleterious role.
Renal Cell Carcinoma Tumors Induce T Cell Apoptosis through Receptor-Dependent and Receptor-Independent Pathways
Authors: Das Tanya , Sa Gaurisankar , Paszkiewicz-Kozik Ewa , Hilston Cynthia , Molto Luis , Rayman Patricia , Kudo Daisuke , Biswas Kaushik , Bukowski Ronald M. , Finke James H. , Tannenbaum Charles S. 
Published: April 2014

AbstractTumors can promote their own progressive growth by inducing T cell apoptosis. Though previous studies suggested that tumor-mediated T cell killing is receptor dependent, we recently showed that tumor gangliosides also participate, a notion consistent with reports indicating that, in some cell types, gangliosides can activate the intrinsic apoptotic pathway by stimulating reactive oxygen species production, cytochrome c release, and caspase-9 activation. In this study, we used normal peripheral blood T cells, as well as caspase-8-, caspase-9-, and Fas-associated death domain protein-deficient Jurkat cells, to assess whether the death ligands and gangliosides overexpressed by the renal cell carcinoma (RCC) cell line SK-RC-45 can independently stimulate T cell apoptosis as a mechanism of immune escape. Anti-FasL Abs and the glycosylceramide synthase inhibitor 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP) each partially inhibited the ability of SK-RC-45 to kill cocultured activated T cells; together, as purified molecules, RCC gangliosides and rFasL induced a more extensive mitochondrial permeability transition and greater levels of apoptosis than either agent alone, equivalent to that induced by the FasL- and ganglioside-expressing RCC line itself. rFasL-mediated apoptosis was completely inhibited in caspase-8- and Fas-associated death domain protein-negative Jurkat cells, though apoptosis induced by purified gangliosides remained intact, findings that correlate with the observed partial inhibition of SK-RC-45-induced apoptosis in the Jurkat lines with defective death receptor signaling. Western blot analysis performed on lysates made from wild-type and mutant Jurkat cells cocultured with SK-RC-45 revealed caspase activation patterns and other biochemical correlates which additionally supported the concept that tumor-associated gangliosides and FasL independently activate the caspase cascade in T cells through the intrinsic and extrinsic pathways, respectively.
Hypoxia and Hypoxia-Inducible Factor-1α Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function
Authors: Jantsch Jonathan , Chakravortty Dipshikha , Turza Nadine , Prechtel Alexander T. , Buchholz Björn , Gerlach Roman G. , Volke Melanie , Gläsner Joachim , Warnecke Christina , Wiesener Michael S. , Eckardt Kai-Uwe , Steinkasserer Alexander , Hensel Michael , Willam Carsten 
Published: April 2014

Abstract
Dendritic cells (DC) play a key role in linking innate and adaptive immunity. In inflamed tissues, where DC become activated, oxygen tensions are usually low. Although hypoxia is increasingly recognized as an important determinant of cellular functions, the consequences of hypoxia and the role of one of the key players in hypoxic gene regulation, the transcription factor hypoxia inducible factor 1α (HIF-1α), are largely unknown. Thus, we investigated the effects of hypoxia and HIF-1α on murine DC activation and function in the presence or absence of an exogenous inflammatory stimulus. Hypoxia alone did not activate murine DC, but hypoxia combined with LPS led to marked increases in expression of costimulatory molecules, proinflammatory cytokine synthesis, and induction of allogeneic lymphocyte proliferation compared with LPS alone. This DC activation was accompanied by accumulation of HIF-1α protein levels, induction of glycolytic HIF target genes, and enhanced glycolytic activity. Using RNA interference techniques, knockdown of HIF-1α significantly reduced glucose use in DC, inhibited maturation, and led to an impaired capability to stimulate allogeneic T cells. Alltogether, our data indicate that HIF-1α and hypoxia play a crucial role for DC activation in inflammatory states, which is highly dependent on glycolysis even in the presence of oxygen.
Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions
Authors: Wang Liangchun , Bursch Laura S. , Kissenpfennig Adrien , Malissen Bernard , Jameson Stephen C. , Hogquist Kristin A. 
Published: April 2014

Abstract
There are conflicting data in the literature regarding the role of epidermal Langerhans cells (LC) in promoting skin immune responses. On one hand, LC can be extremely potent APCs in vitro, and are thought to be involved in contact hypersensitivity (CHS). On the other hand, it seems counterintuitive that a cell type continually exposed to pathogens at the organism’s barrier surfaces should readily trigger potent T cell responses. Indeed, LC depletion in one model led to enhanced contact hypersensitivity, suggesting they play a negative regulatory role. However, apparently similar LC depletion models did not show enhanced CHS, and in one case showed reduced CHS. In this study we found that acute depletion of mouse LC reduced CHS, but the timing of toxin administration was critical: toxin administration 3 days before priming did not impair CHS, whereas toxin administration 1 day before priming did. We also show that LC elimination reduced the T cell response to epicutaneous immunization with OVA protein Ag. However, this reduction was only observed when OVA was applied on the flank skin, and not on the ear. Additionally, peptide immunization was not blocked by depletion, regardless of the site. Finally we show that conditions which eliminate epidermal LC but spare other Langerin+ DC do not impair the epicutaneous immunization response to OVA. Overall, our results reconcile previous conflicting data in the literature, and suggest that Langerin+ cells do promote T cell responses to skin Ags, but only under defined conditions.
Homeostasis and Effector Function of Lymphopenia-Induced “Memory-Like” T Cells in Constitutively T Cell-Depleted Mice
Authors: Voehringer David , Liang Hong-Erh , Locksley Richard M. 
Published: April 2014

Abstract
Naive T lymphocytes acquire a phenotype similar to Ag-experienced memory T cells as a result of proliferation under lymphopenic conditions. Such “memory-like” T (TML) cells constitute a large fraction of the peripheral T cell pool in patients recovering from T cell ablative therapies, HIV patients under highly active antiretroviral therapy, and in the elderly population. To generate a model that allows characterization of TML cells without adoptive transfer, irradiation, or thymectomy, we developed genetically modified mice that express diphtheria toxin A under control of a loxP-flanked stop cassette (R-DTA mice). Crossing these mice to CD4Cre mice resulted in efficient ablation of CD4 single-positive thymocytes, whereas double-positive and CD8 single-positive thymocytes were only partially affected. In the periphery the pool of naive (CD44lowCD62Lhigh) T cells was depleted. However, some T cells were resistant to Cre activity, escaped deletion in the thymus, and underwent lymphopenia-induced proliferation resulting in a pool of TML cells that was similar in size and turnover to the pool of CD44highCD62Llow “memory phenotype” T cells in control mice. CD4Cre/R-DTA mice remained lymphopenic despite the large available immunological “space” and normal Ag-induced T cell proliferation. CD4Cre/R-DTA mice showed a biased TCR repertoire indicating oligoclonal T cell expansion. Infection with the helminth Nippostrongylus brasiliensis resulted in diminished effector cell recruitment and impaired worm expulsion, demonstrating that TML cells are not sufficient to mediate an effective immune response.
Doc2α and Munc13-4 Regulate Ca2+-Dependent Secretory Lysosome Exocytosis in Mast Cells
Authors: Higashio Hironori , Nishimura Noriyuki , Ishizaki Hiroyoshi , Miyoshi Jun , Orita Satoshi , Sakane Ayuko , Sasaki Takuya 
Published: April 2014

Abstract
The Doc2 family comprises the brain-specific Doc2α and the ubiquitous Doc2β and Doc2γ. With the exception of Doc2γ, these proteins exhibit Ca2+-dependent phospholipid-binding activity in their Ca2+-binding C2A domain and are thought to be important for Ca2+-dependent regulated exocytosis. In excitatory neurons, Doc2α interacts with Munc13-1, a member of the Munc13 family, through its N-terminal Munc13-1-interacting domain and the Doc2α-Munc13-1 system is implicated in Ca2+-dependent synaptic vesicle exocytosis. The Munc13 family comprises the brain-specific Munc13-1, Munc13-2, and Munc13-3, and the non-neuronal Munc13-4. We previously showed that Munc13-4 is involved in Ca2+-dependent secretory lysosome exocytosis in mast cells, but the involvement of Doc2 in this process is not determined. In the present study, we found that Doc2α but not Doc2β was endogenously expressed in the RBL-2H3 mast cell line. Doc2α colocalized with Munc13-4 on secretory lysosomes, and interacted with Munc13-4 through its two regions, the N terminus containing the Munc13-1-interacting domain and the C terminus containing the Ca2+-binding C2B domain. In RBL-2H3 cells, Ca2+-dependent secretory lysosome exocytosis was inhibited by expression of the Doc2α mutant lacking either of the Munc13-4-binding regions and the inhibition was suppressed by coexpression of Munc13-4. Knockdown of endogenous Doc2α also reduced Ca2+-dependent secretory lysosome exocytosis, which was rescued by re-expression of human Doc2α but not by its mutant that could not bind to Munc13-4. Moreover, Ca2+-dependent secretory lysosome exocytosis was severely reduced in bone marrow-derived mast cells from Doc2α knockout mice. These results suggest that the Doc2α-Μunc13-4 system regulates Ca2+-dependent secretory lysosome exocytosis in mast cells.
STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation
Authors: Diehl Sean A. , Schmidlin Heike , Nagasawa Maho , van Haren Simon D. , Kwakkenbos Mark J. , Yasuda Etsuko , Beaumont Tim , Scheeren Ferenc A. , Spits Hergen 
Published: April 2014

Abstract
STAT family members have been implicated in regulating the balance between B cell lymphoma (BCL)6 and B lymphocyte induced maturation protein (BLIMP)1 to control plasma cell differentiation. We previously showed that STAT5 induces BCL6 to block plasma cell differentiation and extend the life span of human B cells. The heterogeneity in STAT activation by cytokines and their effects on B cell differentiation prompted us to investigate the effect of STAT3 activation in plasma cell differentiation. First stimulation with IL-21, which promotes plasma cell differentiation, induced robust and prolonged STAT3 activation in primary human B cells. We then investigated effects of direct STAT3 activation on regulation of plasma cell genes, cellular phenotype, and Ig production. Activation of a tamoxifen-regulated STAT3-estrogen receptor fusion protein triggered BLIMP1 mRNA and protein up-regulation, plasma cell phenotypic features, and Ig secretion. When STAT3 was activated by IL-21 in B cells ectopically expressing BCL6, BLIMP1 was up-regulated, but only partial plasma cell differentiation was achieved. Lastly, through coexpression of BCL6 and STAT3-ER, we verified that STAT3 activation functionally mimicked IL-21 treatment and that STAT3-mediated BLIMP1 up-regulation occurred despite high BCL6 expression levels indicating that BCL6 is not the dominant repressor of BLIMP1. Thus, up-regulation of BLIMP1 alone is not sufficient for differentiation of primary human B cells into plasma cells; concomitant down-regulation of BCL6 is absolutely required for completion of the plasma cell differentiation program.
Nonhuman Primate IgA: Genetic Heterogeneity and Interactions with CD89
Authors: Rogers Kenneth A. , Jayashankar Lakshmi , Scinicariello Franco , Attanasio Roberta 
Published: April 2014

Abstract
Nonhuman primates are extremely valuable animal models for a variety of human diseases. However, it is now becoming evident that these models, although widely used, are still uncharacterized. The major role that nonhuman primate species play in AIDS research as well as in the testing of Ab-based therapeutics requires the full characterization of structure and function of their Ab molecules. IgA is the Ab class mostly involved in protection at mucosal surfaces. By binding to its specific Fc receptor CD89, IgA plays additional and poorly understood roles in immunity. Therefore, Ig heavy α (IGHA) constant (C) genes were cloned and sequenced in four different species (rhesus macaques, pig-tailed macaques, baboons, and sooty mangabeys). Sequence analysis confirmed the high degree of intraspecies polymorphism present in nonhuman primates. Individual animals were either homozygous or heterozygous for IGHA genes. Highly variable hinge regions were shared by animals of different geographic origins and were present in different combinations in heterozygous animals. Therefore, it appears that although highly heterogeneous, hinge sequences are present only in limited numbers in various nonhuman primate populations. A macaque recombinant IgA molecule was generated and used to assess its interaction with a recombinant macaque CD89. Macaque CD89 was able to bind its native ligand as well as human IgA1 and IgA2. Presence of Ag enhanced macaque IgA binding and blocking of macaque CD89 N-glycosylation reduced CD89 expression. Together, our results suggest that, despite the presence of IgA polymorphism, nonhuman primates appear suitable for studies that involve the IgA/CD89 system.
Dendritic Cell Programming by Cytomegalovirus Stunts Naive T Cell Responses via the PD-L1/PD-1 Pathway
Authors: Benedict Chris A. , Loewendorf Andrea , Garcia Zacarias , Blazar Bruce R. , Janssen Edith M. 
Published: April 2014

Abstract
Early during infection, CMV targets dendritic cells (DC) and alters their functions. Herein we show that CMV-infected DC maintain the ability to present both virus-derived and exogenous Ags, but that they actively induce tolerance or anergy in Ag-specific T cells. CMV accomplishes this by selectively maintaining high-level expression of the negative costimulatory molecule programmed death ligand-1 (PD-L1), while commensurately down-regulating positive costimulatory molecules and MHC on the DC surface. Consequently, CD4 and CD8 T cells activated by these infected DC have a stunted phenotype, characterized by poor proliferation, effector function. and recall responses. Blocking PD-L1, but not PD-L2, during direct priming of naive T cells by infected DC significantly restores Ag-specific T cell functions. Using systems where direct and cross-priming of T cells can be distinguished revealed that PD-L1/PD-1 signaling contributes only when naive T cells are primed directly by infected DC, and not upon cross-presentation of viral Ags by uninfected DC. These data suggest that murine CMV programs infected DC during acute infection to inhibit early host adaptive antiviral responses by tipping the balance between negative and positive cosignals.
Age-Related Dysregulation of CD8+ T Cell Memory Specific for a Persistent Virus Is Independent of Viral Replication
Authors: Lang Anna , Brien James D. , Messaoudi Ilhem , Nikolich-Žugich Janko 
Published: April 2014

Abstract
The immune system devotes substantial resources to the lifelong control of persistent pathogens, which were hypothesized to play an important role in immune aging. Specifically, the presence of latent herpesviruses has been correlated with immune exhaustion and shorter lifespan in octogenarians. But neither the causality nor the mechanistic link(s) were established, and the relative roles of persistent antigenic stimulation and of virus-independent homeostatic disturbances in T cell aging remain unresolved. We longitudinally analyzed expansion, contraction, and long-term maintenance of CD8+ T cells responding to localized infection with a latent virus, HSV-1. Young mice exhibited the expected expansion and contraction of HSV-1-specific cells and the stable maintenance of memory T cells into advanced adulthood. However, upon entry into senescence, many (&gt;40%) animals exhibited an accumulation in Ag-specific cells (memory inflation) which in some animals was comparable to that observed in acute infection. Inflation occurred to the same extent in control mice and mice continuously treated with the anti-HSV drug famciclovir, which inhibits viral replication and was able to reduce expression of the glycoprotein B. Age-related inflation was also found long after infection with an acute virus. The inflating cells largely maintained Ag-specific function, and exhibited typical central memory phenotype, with no signs of Ag-specific activation. They exhibited increased expression of CD122 and CD127, akin to the Ag-independent T cell clonal expansions found in old specific pathogen-free laboratory mice. This collectively suggests that, in this model, the inflating cells may be selected for high responsiveness to environmental cytokines largely in an Ag-independent manner.
Complement Factor H-Binding Protein, a Putative Virulence Determinant of Borrelia hermsii, Is an Antigenic Target for Protective B1b Lymphocytes
Authors: Colombo Matthew J. , Alugupalli Kishore R. 
Published: April 2014

Abstract
Vaccination is the most effective way to control infectious diseases. A variety of microbial pathogens use antigenic variation, an immune evasion strategy that poses a challenge for vaccine development. To understand protective immune responses against such pathogens, we have been studying Borrelia hermsii, a bacterium that causes recurrent bacteremia due to antigenic variation. An IgM response is necessary and sufficient to control B. hermsii infection. We have recently found a selective expansion of B1b cells concurrent with the resolution of B. hermsii bacteremia. B1b cells from convalescent but not naive mice confer long-lasting immunity, but the Ag(s) driving the protective IgM responses is unknown. Herein we demonstrate that convalescent B1b cell-derived IgM recognizes complement factor H-binding protein (FhbA), a B. hermsii outer-surface protein and putative virulence factor that does not undergo antigenic variation and is expressed by all clinical isolates. A progressive increase in the IgM response to FhbA correlated with the kinetics of B1b cell expansion, diminished the severity of bacteremic episodes, and led to the eventual resolution of the infection. These data indicate that FhbA is a specific target for protective B1b cell responses. Ags recognized by B1b cells may be considered as an important component in vaccination strategies.
Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase ofTrichinella spiralisInfection
Authors: Shin Kichul , Watts Gerald F. M. , Oettgen Hans C. , Friend Daniel S. , Pemberton Alan D. , Gurish Michael F. , Lee David M. 
Published: April 2014

AbstractAlthough the innate immune function of mast cells in the acute phase of parasitic and bacterial infections is well established, their participation in chronic immune responses to indolent infection remains incompletely understood. In parasitic infection with Trichinella spiralis, the immune response incorporates both lymphocyte and mast cell-dependent effector functions for pathogen eradication. Among the mechanistic insights still unresolved in the reaction to T. spiralis are the means by which mast cells respond to parasites and the mast cell effector functions that contribute to the immunologic response to this pathogen. We hypothesized that mast cell elaboration of tryptase may comprise an important effector component in this response. Indeed, we find that mice deficient in the tryptase mouse mast cell protease-6 (mMCP-6) display a significant difference in their response to T. spiralis larvae in chronically infected skeletal muscle tissue. Mechanistically, this is associated with a profound inability to recruit eosinophils to larvae in mMCP-6-deficient mice. Analysis of IgE-deficient mice demonstrates an identical defect in eosinophil recruitment. These findings establish that mast cell secretion of the tryptase mMCP-6, a function directed by the activity of the adaptive immune system, contributes to eosinophil recruitment to the site of larval infection, thereby comprising an integral link in the chronic immune response to parasitic infection.
Relative Levels of M-CSF and GM-CSF Influence the Specific Generation of Macrophage Populations during Infection withMycobacterium tuberculosis
Authors: Higgins David M. , Sanchez-Campillo Joaquin , Rosas-Taraco Adrian G. , Higgins Jonathan R. , Lee Eric J. , Orme Ian M. , Gonzalez-Juarrero Mercedes 
Published: April 2014

AbstractMembers of the CSF cytokine family play important roles in macrophage recruitment and activation. However, the role of M-CSF in pulmonary infection with Mycobacterium tuberculosis is not clear. In this study, we show the lungs of mice infected with M. tuberculosis displayed a progressive decrease in M-CSF in contrast to increasing levels of GM-CSF. Restoring pulmonary M-CSF levels during infection resulted in a significant decrease in the presence of foamy macrophages and increased expression of CCR7 and MHC class II, specifically on alveolar macrophages. In response to M-CSF, alveolar macrophages also increased their T cell-stimulating capacity and expression of DEC-205. These studies show that the levels of expression of M-CSF and GM-CSF participate in the progression of macrophages into foamy cells and that these cytokines are important factors in the differentiation and regulation of expression of dendritic cell-associated markers on alveolar macrophages. In addition, these studies demonstrate that M-CSF may have a role in the adaptive immune response to infection with M. tuberculosis.