European Journal of Immunology (Eur J Immunol)

Publications in this journal

• Article: High sequence diversity and structural conservation in the human T-cell receptor β junctional region during thymic development.

  Anni Tuulasvaara, Julie Baussand, Pia Laine, Lars Paulin, Jukka Salminen, Petri Auvinen, Guy Gorochov, T Petteri Arstila
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  ABSTRACT: The T-cell repertoire depends on intrathymic genetic rearrangement events in the T-cell receptor (TCR) locus, followed by positive and negative selection. The repertoire thus generated is highly diverse, but recent data indicate that the recombination of gene segments is less stochastic than previously suggested. Very little is known of the junctional complementarity determining region 3 (CDR3), which is to a large degree not germline-encoded. We have analyzed the development of the human TCR β CDR3 repertoire, from the nonselected CD4(+) CD8(+) CD3(-) cells up to the fully selected CD4(+) CD8(-) thymocytes. In addition to spectratyping, a fraction of the CDR3 repertoire was sequenced and a structural in silico analysis of the CDR3 loop characteristics performed. Our data show that the thymic TCR repertoire is extremely diverse, and the effect of the selection events can be detected as a measurable loss of polyclonality in the CDR3 loop. However, the main physico-chemical features of the CDR3 loop were found already at the nonselected repertoire and showed no progressive changes during the selection. Thus the main structural characteristics of the CDR3 loop were already determined by the recombination process and not significantly affected by the extensive thymocyte death associated with selection in the thymus. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells.

  Reva S Thakur, Sultan Tousif, Vikky Awasthi, Anirban Sanyal, P K Atul, Parveen Punia, Jyoti Das
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  ABSTRACT: Plasmodium spp. parasites, the causative agents of malaria, survive and replicate in human hosts by modulating host protective immune responses. In a rodent model, malaria manifests as a severe splenomegaly, with infiltration of cells and lymphoproliferation as major contributing factors of the immunopathology. However, the cellular contents and the functions of these cells have not been well studied. Here, we report that Plasmodium berghei infection of mice leads to massive recruitment of mesenchymal stem cells (MSCs) in secondary lymphoid organs. Infusion of these cells into naïve mice was able to confer host resistance against malaria. Furthermore, MSCs augmented interleukin (IL)-12 production but suppressed IL-10 production in recipient animals. In addition, we observed dramatic reductions of regulatory T cells in animals that received MSCs. Taken together, our findings have identified recruitment of MSCs as a novel host protective mechanism adopted by the host to combat malaria by modulating regulatory T cell responses. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: p300, but not PCAF, collaborates with IRF-1 in stimulating TRIM22 expression independently of its histone acetyltransferase activity.

  Bo Gao, Wei Xu, Linmao Zhong, Qilin Zhang, Ya Su, Sidong Xiong
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  ABSTRACT: Tripartite motif (TRIM) 22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IRF-1 was crucial for constitutive and IFN-induced TRIM22 expression via binding to a special cis-element named 5' extended IFN-stimulating response element (5'eISRE). Here, we further investigate the molecular mechanisms of TRIM22 with a focus on the co-activators of IRF-1. Using an in vitro DNA affinity binding assay and an in vivo chromatin immunoprecipitation assay, we found that IFN-γ stimulation significantly enhanced the binding of p300 and PCAF, but not other co-activators such as GCN-5, SRC-1 and ACTR, to the 5'eISRE-containing TRIM22 promoter region together with IRF-1. Overexpression and knockdown analysis demonstrated that it was p300, but not PCAF, that functioned as a transcriptional co-activator of IRF-1 in IFN-γ induction of TRIM22. We further show that p300 contributed to both IFN-γ- and IRF-1-mediated TRIM22 transcription independent of its histone acetyltransferase activity, however, it was required for the recruitment of RNA polymerase II to TRIM22 promoter region. These data indicate that p300 plays a critical role in IFN-γ-induced TRIM22 expression via recruiting RNA polymerase II to the TRIM22 promoter, and might serve as a bridge between IRF-1 and the basal transcriptional apparatus in TRIM22 induction. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Chemotaxis of bone marrow-derived eosinophils in vivo: A novel method to explore receptor-dependent trafficking in the mouse.

  Eva M Sturm, Kimberly D Dyer, Caroline M Percopo, Akos Heinemann, Helene F Rosenberg
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  ABSTRACT: Here we describe a novel method via which ex vivo cultured mouse bone marrow-derived eosinophils (bmEos) can be adoptively transferred into recipient mice in order to study receptor-dependent recruitment to lung tissue in vivo. Intratracheal instillation of hCCL24 prior to introduction of bmEos via tail vein injection resulted in a ∼fourfold increase in Siglec F positive/CD11c negative eosinophils in the lungs of eosinophil-deficient ΔdblGATA recipient mice compared with controls. As anticipated, bmEos generated from CCR3-gene-deleted mice did not migrate to the lung in response to hCCL24 in this model, indicating specific receptor dependence. BmEos generated from GFP positive BALB/c mice responded similarly hCCL24 in vitro and were detected in lung tissue of BALB/c wild-type as well as BALB/c ΔdblGATA eosinophil-deficient recipient mice, at ∼fourfold (at 5 h post-injection) and ∼threefold (at 24 h post-injection) over baseline respectively. Comparable results were obtained with GFP positive C57BL/6 bmEos responding to intratracheal hCCL24 in C57BL/6 ΔdblGATA recipient mice. The use of ex vivo cultured bmEos via one or more of these methods offers the possibility of manipulating bmEos prior to transfer into a wild-type or gene-deleted recipient host. Thus, this chemotaxis model represents a novel and robust tool for pharmacological studies in vivo. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Migration and tolerance: On the road to tolerance - Generation and migration of gut regulatory T cells.

  Oliver Pabst, Günter Bernhardt
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  ABSTRACT: The intestinal immune system potently supports the generation of induced Treg (iTreg) cells. Within intestinal lymphoid compartments iTreg cells receive homing cues, which direct these cells to the gut lamina propria where they expand and locally suppress immune responses. Yet iTreg cells are but one side of a coin, the other side of which comprises natural Treg (nTreg) cells generated in the thymus. nTreg cells, which act in concert with iTreg cells, also acquire a diversified pattern of homing receptors. Thus iTreg and nTreg cells can enter the gut, and draining lymph nodes to cooperatively ensure intestinal homeostasis.
  European Journal of Immunology 05/2013;
• Article: Multiple sclerosis lymphocytes upregulate A2A adenosine receptors which are anti-inflammatory when stimulated.

  Fabrizio Vincenzi, Carmen Corciulo, Martina Targa, Stefania Merighi, Stefania Gessi, Ilaria Casetta, Mauro Gentile, Enrico Granieri, Pier Andrea Borea, Katia Varani
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  ABSTRACT: Multiple sclerosis (MS) is an autoimmune-mediated inflammatory disease characterized by multifocal areas of demyelination. Experimental evidence indicates that A2A adenosine receptors (ARs) play a pivotal role in the inhibition of inflammatory processes. The aim of this study was to investigate the contribution of A2A ARs in the inhibition of key pro-inflammatory mediators for the pathogenesis of MS. In lymphocytes from MS patients, A1 , A2A , A2B and A3 ARs were analyzed by using RT-PCR, western blotting, immunofluorescence and binding assays. Moreover the effect of A2A AR stimulation on pro-inflammatory cytokine release such as tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), interleukin (IL)-6, IL-1β, IL-17 and on lymphocyte proliferation was evaluated. The capability of an A2A AR agonist on the modulation of very late antigen-4 (VLA-4) expression and nuclear factor κB (NF-κB) was also explored. A2A AR upregulation was observed in lymphocytes from MS patients in comparison with healthy subjects. The stimulation of these receptors mediated a significant inhibition of TNF-α, IFN-γ, IL-6, IL-1β, IL-17 and cell proliferation as well as VLA-4 expression and NF-κB activation. This new evidence highlights that A2A AR agonists could represent a novel therapeutic tool for MS treatment as suggested by the anti-inflammatory role of A2A ARs in lymphocytes from MS patients. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Detection of a TLR2 agonist by hematopoietic stem and progenitor cells (HSPCs) impacts the function of the macrophages they produce.

  Alberto Yáñez, Nargess Hassanzadeh-Kiabi, Madelena Y Ng, Javier Megías, Aparna Subramanian, George Y Liu, David M Underhill, María Luisa Gil, Helen S Goodridge
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  ABSTRACT: Several groups have shown that detection of microbial components by Toll-like receptors (TLRs) on hematopoietic stem and progenitor cells (HSPCs) instructs myeloid cell generation, raising interest in the possibility of targeting TLRs on HSPCs to boost myelopoiesis. However, although "TLR-derived" cells exhibit myeloid cell characteristics (phagocytosis, cytokine production, antigen presentation), it isn't clear whether they are functionally equivalent to macrophages derived in the absence of TLR activation. Our in vitro and in vivo studies show that macrophages derived from mouse and human HSPC subsets (including stem cells) exposed to a TLR2 agonist prior to or during macrophage differentiation produce lower levels of inflammatory cytokines (TNF-a, IL-6 and IL-1b) and reactive oxygen species (ROS). This is in contrast to prior exposure of differentiated macrophages to the TLR2 agonist ("tolerance"), which suppresses inflammatory cytokine production, but elevates ROS. Soluble factors produced following exposure of HSPCs to a TLR2 agonist can also act in a paracrine manner to influence the function of macrophages derived from unexposed HSPCs. Our data demonstrate that macrophage function can be influenced by TLR signaling in the HSPCs from which they are derived, and that this may impact the clinical utility of targeting TLRs on HSPCs to boost myelopoiesis. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Invariant natural killer T (iNKT) cell exhaustion in sarcoidosis.

  Jennifer E Snyder-Cappione, Douglas F Nixon, Joyce C Chi, Michelle-Linh T Nguyen, Christopher K Kirby, Jeffrey M Milush, Laura L Koth
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  ABSTRACT: Invariant natural killer T (iNKT) cells are integral components of immune responses during many chronic diseases, yet their surface phenotypes, subset distribution, and polyfunctional capacity in this environment are largely unknown. Therefore, using flow cytometry, we determined iNKT-cell phenotypic and functional characteristics in subjects with the chronic inflammatory disease sarcoidosis and matched controls. We found that sarcoidosis subjects displayed lower iNKT-cell frequencies, which correlated with lung fibrosis, C-reactive protein levels, and other measures of clinical disease. The CD4(-) CD8(-) (DN) iNKT-cell population was selectively lower in diseased individuals and the remaining DN iNKT cells exhibited higher frequencies of the activation markers CD69 and CD56. Functionally, both total IFN-γ(+) and the dual-functional IFN-γ(+) TNF-α(+) iNKT cells were decreased in sarcoidosis subjects and these functional defects correlated with total iNKT-cell circulating frequencies. As the loss of polyfunctionality can reflect functional exhaustion, we measured the surface antigens PD-1 and CD57 and found that levels inversely correlated with dual-functional iNKT-cell percentages. These findings reveal that, similar to traditional T cells, iNKT cells may also undergo functional exhaustion, and that circulating iNKT-cell frequencies reflect these defects. PD-1 antagonists may therefore be attractive therapeutic candidates for sarcoidosis and other iNKT-cell-mediated chronic diseases.
  European Journal of Immunology 05/2013;
• Article: With(out) a little help from my friends: an IL-12/CD40L-mediated feed-forward loop between CD8(+) T cells and DCs.

  Martijn A Nolte, Rene A W van Lier
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  ABSTRACT: CD40-CD40L interactions are important for both antigen-dependent B-cell differentiation and effector and memory T-cell formation. The prevailing view is that CD40L is expressed on activated CD4(+) T cells, which enables them to provide help to high-affinity B cells in germinal centers and to license DCs for efficient induction of CD8(+) T-cell responses. Interestingly, CD8(+) T cells themselves can also express CD40L and, in this issue of the European Journal of Immunology, Thiel and colleagues [Eur. J. Immunol. 2013. 43: XXXX-XXXX] show that CD40L expression on these cells can be part of a self-sustaining feed-forward loop, in which expression of CD40L is induced by IL-12 and TCR signaling. This provides a paradigm shift in our thinking about the requirements of effector CD8(+) T-cell development and the role herein of CD4(+) T cells to provide help in this process. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Vitamin A notches up CD11b(hi) dendritic cell development.

  Angus T Stock, Sammy Bedoui
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  ABSTRACT: Vitamin A and its metabolite retinoic acid influence various aspects of immunity. Although the capacity of vitamin A to condition intestinal CD103(+) dendritic cells (DCs) to imprint tissue-specific homing programs onto activated lymphocytes is well documented, it is unclear whether vitamin A also regulates DC populations in other tissues. A study published in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43: XXXX-XXXX] now demonstrates that vitamin A exerts profound effects on the subset composition of splenic DCs. By resolving that splenic ESAM(hi) CD11b(hi) DCs are preferentially responsive to regulation by vitamin A, these novel insights not only further support the notion that ESAM expression marks two distinct lineages of splenic CD11b(hi) DCs, but also provide an important extension to our understanding of how vitamin A influences the immune system. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Direct interaction between cholera toxin and dendritic cells is required for oral adjuvant activity.

  Tobias Gustafsson, Yeu-Jiann Hua, Madelene Dahlgren, Megan Livingston, Bengt Johansson-Lindbom, Ulf Yrlid
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  ABSTRACT: Cholera toxin (CT) binds to GM1-ganglioside receptors present on all nucleated cells. Despite this it is a very potent mucosal adjuvant that has a dramatic impact on immune cells as well as nerve and epithelial cells, causing diarrhea. This fact has hampered our understanding of whether the adjuvanticity of CT is direct or indirect, as cells that bind CT may or may not be involved in its adjuvant function. The mucosal barrier is maintained by tight junctions between epithelial cells but dendritic cells (DCs) can protrude luminal dendrites. Here we investigated which cells are involved in the immune augmenting effect of CT. We explored oral immunizations with ovalbumin (OVA) and CT in bone marrow chimeric mice deficient in GM1-ganglioside in defined cellular subsets. We found that chimeric mice lacking GM1 in non-hematopoietic cells, including epithelial cells, mounted an unaltered intestinal IgA response. In contrast, chimeric mice lacking GM1-expressing hematopoietic cells in general but specifically GM1-expressing DCs largely failed to elicit anti-OVA adaptive immune responses. Therefore, the adjuvanticity of CT does not require epithelial activation, but is directly dependent on binding of CT via GM1-ganglioside to gut DCs. These results could have important implications for the generation of novel oral adjuvants. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: The interaction between CD300a and phosphatidylserine inhibits tumor cell killing by NK cells.

  Dikla Lankry, Tihana L Rovis, Stipan Jonjic, Ofer Mandelboim
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  ABSTRACT: The activity of NK cells is controlled by inhibitory and activating receptors. The inhibitory receptors interact mostly with MHC class I proteins, however, inhibitory receptors such as CD300a, which bind to non-MHC class I ligands, also exist. Recently it was discovered that phosphatidylserine (PS) is a ligand for CD300a and that the interaction between PS expressed on apoptotic cells and CD300a inhibits the uptake of apoptotic cells by phagocytic cells. Whether PS can inhibit NK-cell activity through CD300a is unknown. Here we have generated specific antibodies directed against CD300a and we used these mAbs to demonstrate that various NK-cell clones express different levels of CD300a. We further demonstrated that both CD300a and its highly homologous molecule CD300c bind to the tumor cells equally well and that they recognize PS and additional unknown ligand/s expressed by tumor cells. Finally we showed that blocking the PS-CD300a interaction resulted in increased NK-cell killing of tumor cells. Collectively, we demonstrate a new tumor immune evasion mechanism that is mediated through the interaction between PS and CD300a and we suggest that CD300c, similarly to CD300a, also interacts with PS. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: 4-1BB signal stimulates the activation, expansion, and effector functions of γδ T cells in mice and humans.

  Seung J Lee, Young H Kim, Sun H Hwang, Yu I Kim, In S Han, Dass S Vinay, Byoung S Kwon
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  ABSTRACT: We show here that expression of 4-1BB is rapidly induced in γδ T cells following antigenic stimulation in both mice and humans, and ligation of the newly acquired 4-1BB with an agonistic anti-4-1BB augments cell division and cytokine production. We further demonstrate that γδ rather than αβ T cells protect mice from Listeria monocytogenes (LM) infection and 4-1BB stimulation enhances the γδ T-cell activities in the acute phase of LM infection. IFN-γ produced from γδ T cells was the major soluble factor regulating LM infection. Vγ1(+) T cells were expanded in LM-infected mice and 4-1BB signal triggered an exclusive expansion of Vγ1(+) T cells and induced IFN-γ in these Vγ1(+) T cells. Similarly, 4-1BB was induced on human γδ T cells and shown to be fully functional. Combination treatment with human γδ T cells and anti-hu4-1BB effectively protected against LM infection in human γδ T cell-transferred NOD-SCID mice. Taken together, these data provide evidence that the 4-1BB signal is an important regulator of γδ T cells and induces robust host defense against LM infection. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis.

  Laura Piccio, Claudia Cantoni, Jacob G Henderson, Daniel Hawiger, Michael Ramsbottom, Robert Mikesell, Jiyoon Ryu, Chyi-Song Hsieh, Viviana Cremasco, Wesley Haynes, Lily Q Dong, Lawrence Chan, Daniela Galimberti, Anne H Cross
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  ABSTRACT: Multiple Sclerosis (MS) is a presumed autoimmune disease directed against central nervous system (CNS) myelin, in which diet and obesity are implicated as risk factors. Immune responses can be influenced by molecules produced by fat cells, called adipokines. Adiponectin is an adipokine with anti-inflammatory effects. We tested the hypothesis that adiponectin has a protective role in the experimental autoimmune encephalomyelitis (EAE) model for MS, that can be induced by immunization with myelin antigens or transfer of myelin-specific T lymphocytes. Adiponectin deficient (ADPKO) mice developed worse EAE with greater CNS inflammation, demyelination and axon injury. Lymphocytes from myelin-immunized ADP KO mice proliferated more, produced higher amounts of IFN-γ, IL-17, TNF-α, IL-6 and transferred more severe EAE than wild type (WT) lymphocytes. At EAE peak, the spleen and CNS of ADPKO had fewer regulatory T (Treg) cells Treg cellsthan WT mice and during EAE recovery, Foxp3, IL-10 and TGF-β expression levels in the CNS were reduced in ADPKO compared with WT mice. Treatment with globular adiponectin (gADP) in vivo ameliorated EAE, and was associated with an increase in Treg cells. These data indicate that adiponectin is an important regulator of T-cell functions during EAE, suggesting a new avenue of investigation for MS treatment. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: IFN-β therapy modulates B-cell and monocyte crosstalk via TLR7 in multiple sclerosis patients.

  Elena Giacomini, Martina Severa, Fabiana Rizzo, Rosella Mechelli, Viviana Annibali, Giovanni Ristori, Valeria Riccieri, Marco Salvetti, Eliana Marina Coccia
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  ABSTRACT: The implication of B lymphocytes in the immunopathology of multiple sclerosis (MS) is increasingly recognized. Here we investigated the response of B cells to IFN-β, a first-line therapy for relapsing-remitting MS patients, upon stimulation with TLR. IFN-β restored the frequency of TLR7-induced IgM and IgG-secreting cells in MS patients to the levels found in healthy donors (HDs), showing a specific deficiency in TLR7 pathway. However, no difference was observed in the TLR9 response. Furthermore, in MS-derived PBMCs, TLR7-mediated production of IL-6 and the ex vivo expression of B-cell-activating factor of the TNF family (BAFF), two crucial cytokines for B-cell differentiation and survival, were induced by IFN-β. Depletion of monocytes, which are key producers of both IL-6 and BAFF, showed that TLR7-mediated B-cell differentiation into Ig-secreting cells is strongly dependent on the cross-talk between B cells and monocytes. Accordingly, impaired expression of TLR7 mRNA was observed in PBMCs and monocytes isolated from MS-affected individuals as compared with those from HDs, which was rescued by IFN-β therapy. Collectively, our data unveil a novel TLR7-regulated mechanism in in vivo IFN-β-stimulated whole leukocytes that could be exploited to define new TLR7-based strategies for the treatment of MS. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Positive selection of self antigen-specific CD8(+) T cells by hematopoietic cells.

  Hisakata Yamada, Kensuke Shibata, Koji Sakuraba, Kenjiro Fujimura, Yasunobu Yoshikai
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  ABSTRACT: In contrast to thymic epithelial cells, which induce the positive selection of conventional CD8(+) T cells, hematopoietic cells (HCs) select innate CD8(+) T cells whose antigen specificity is not fully understood. Here we show that CD8(+) T cells expressing an H-Y antigen-specific transgenic (Tg) TCR were able to develop in mice in which only HCs expressed MHC class I, when HCs also expressed the H-Y antigen. These HC-selected self-specific CD8(+) T cells resemble innate CD8(+) T cells in wild-type mice in terms of the expression of memory markers and effector functions, but are phenotypically distinct from the thymus-independent CD8(+) T-cell population.. The peripheral maintenance of H-Y-specific CD8(+) T cells required presentation of the self antigen and IL-15 on HCs. HC-selected CD8(+) T cells in mice lacking the Tg TCR also showed these features. Furthermore, by using MHC class I tetramers with a male antigen peptide, we found that self antigen-specific CD8(+) T cells in TCR non-Tg mice could develop via HC-induced positive selection, supporting results obtained from H-Y TCR Tg mice. These findings indicate the presence of self-specific CD8(+) T cells that are positively selected by HCs in the peripheral T-cell repertoire. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Direct effect of dsRNA mimetics on cancer cells induces endogenous IFN-β production capable of improving dendritic cell function.

  Gerardo Gatti, Nicolás Gonzalo Nuñez, David Andrés Nocera, Lien Dejager, Claude Libert, Constancio Giraudo, Mariana Maccioni
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  ABSTRACT: Viral double-stranded RNA (dsRNA) mimetics have been explored in cancer immunotherapy to promote antitumoral immune response. Polyinosine-polycytidylic acid (poly I:C) and Polyadenylic-polyuridylic acid (poly A:U) are synthetic analogs of viral dsRNA and strong inducers of type I Interferon (IFN). We describe here a novel effect of dsRNA analogs on cancer cells: besides their potential to induce cancer cell apoptosis through an IFN-β autocrine loop, dsRNA-elicited IFN-β production improves dendritic cell functionality. Human A549 lung and DU145 prostate carcinoma cells significantly responded to poly I:C stimulation, producing IFN-β at levels that were capable of activating STAT1 and enhancing CXCL10, CD40 and CD86 expression on human monocyte-derived dendritic cells (MoDCs). IFN-β produced by poly I:C-activated human cancer cells increased the capacity of MoDCs to stimulate IFN-γ production in an allogeneic stimulatory culture in vitro. When melanoma murine B16 cells were stimulated in vitro with poly A:U and then inoculated into TLR3(-/-) mice, smaller tumors were elicited. This tumor growth inhibition was abrogated in IFNAR1(-/-) mice. Thus, dsRNA compounds are effective adjuvants not only because they activate DCs and promote strong adaptive immunity, but also because they can directly act on cancer cells to induce endogenous IFN-β production and contribute to the antitumoral response. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Developmental maturation of innate immune cell function correlates with susceptibility to central nervous system autoimmunity.

  Deetje Hertzenberg, Klaus Lehmann-Horn, Silke Kinzel, Veronika Husterer, Petra D Cravens, Bernd C Kieseier, Bernhard Hemmer, Wolfgang Brück, Scott S Zamvil, Olaf Stüve, Martin S Weber
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  ABSTRACT: Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder which typically occurs in early adulthood and rarely in children. Here we tested whether functional maturation of innate immune cells may determine susceptibility to CNS autoimmune disease in experimental autoimmune encephalomyelitis (EAE). Two week-old mice were resistant to active EAE, which causes fulminant paralysis in adult mice; this resistance was associated with an impaired development of Th1 and Th17 cells. Resistant, young mice had higher frequencies of myeloid derived suppressor cells and plasmacytoid dendritic cells. Furthermore, myeloid antigen-presenting cells (APCs) and B cells from young mice expressed lower levels of MHC class II and CD40, produced decreased amounts of pro-inflammatory cytokines, and released enhanced levels of anti-inflammatory IL-10. When used as APCs, splenocytes from two week-old mice failed to differentiate naïve T cells into Th1 and Th17 cells irrespective of the T-cell donor's age, and promoted development of regulatory T cells and Th2 cells instead. Adoptive transfer of adult APCs restored the ability of two week-old mice to generate encephalitogenic T cells and develop EAE. Collectively, these findings indicate that the innate immune compartment functionally matures during development which may be a prerequisite for development of T-cell-mediated CNS autoimmune disease. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 05/2013;
• Article: Traumatic brain injury induces macrophage subsets in the brain.

  Christine L Hsieh, Charles C Kim, Bryan E Ryba, Erene C Niemi, Jennifer K Bando, Richard M Locksley, Jialing Liu, Mary C Nakamura, William E Seaman
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  ABSTRACT: Traumatic brain injury (TBI) elicits innate inflammatory responses that can lead to secondary brain injury. To better understand the mechanisms involved in TBI-induced inflammation, we examined the nature of macrophages responding to TBI in mice. In this model, brain macrophages were increased >20-fold the day after injury and >77-fold four days after injury in the ipsilateral hemisphere compared with sham controls. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an IRES inserted at the 3' end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21±1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by YFP, and this subpopulation declined thereafter. Arg1(+) cells localized with macrophages near the TBI lesion. Gene expression analysis of sorted Arg1(+) and Arg1(-) brain macrophages revealed that both populations had profiles that included features of conventional M2 macrophages and classically activated (M1) macrophages. The Arg1(+) cells differed from Arg1(-) cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI initially involves heterogeneous polarization towards at least two major subsets. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 04/2013;
• Article: Defects of leukocyte migration in primary immunodeficiencies.

  Raffaele Badolato
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  ABSTRACT: This Viewpoint gives an overview of the inherited disorders that are characterized by defects of leukocyte trafficking. Three paradigmatic diseases have been selected: WHIM, Wiskott-Aldrich and LAD syndromes. These conditions encompass defects in the steps that are required for leukocyte motility: from the response to chemokines, which is altered in WHIM syndrome, to the impairment of leukocyte adhesion and migration found in LAD syndrome, and finally to abnormal actin filament formation, which is affected in leukocytes of Wiskott-Aldrich syndrome patients. This article is protected by copyright. All rights reserved.
  European Journal of Immunology 04/2013;