Editor's choice: featured articles (free access)
Articles published from 2008 onwards
To view Editor's Choice articles published between 2002-2007, click here.
APCs use CCR8 to remain in the skin and suppress allergic contact dermatitis
By Rikio Yabe, Kenji Shimizu, Soichiro Shimizu, Satoe Azechi, Byung-Il Choi, Katsuko Sudo, Sachiko Kubo, Susumu Nakae, Harumichi Ishigame, Shigeru Kakuta and Yoichiro Iwakura
Contact hypersensitivity (CHS) is induced using the hapten 2,4-dinitrofluorobenzene in a model of allergic contact dermatitis—a common form of delayed-type hypersensitivity in humans. In CHS, hapten activates dendritic cells (DCs), which migrate to draining lymph nodes (LNs) using CCR7–CCL19/CCL21, where they sensitize T cells; upon re-exposure, the hapten activates memory and effector T cells to elicit inflammation. Here, Yabe et al. (p. 169) report upregulated Langerhans cell (LC) CCR8 and keratinocyte CCL8 in CHS. Ccr8–/– mice are more susceptible than wild-type (WT) mice to CHS, with expanded Th1/Th17/Tc1 LN populations; and T cells from hapten-sensitized Ccr8–/– mice show enhanced hapten-induced proliferation. In WT mice, T cells transferred from draining LNs of Ccr8–/– mice elicit enhanced CHS responses. In Ccr8–/– mice, LCs, dermal DCs and inflammatory DCs migrate to, and accumulate in, draining LNs after sensitization. The authors conclude that CCR8 retains antigen-presenting cells (APCs) in the skin, reducing migration to LNs and decreasing CHS.
IRF-1 suppresses Th2 responses in Listeria infection in vivo
By Saho Maruyama, Makoto Kanoh, Akira Matsumoto, Makoto Kuwahara, Masakatsu Yamashita and Yoshihiro Asano
A paradigm of Th1 responses is protection against intracellular bacteria such as Listeria monocytogenes, which survives and multiplies in antigen-presenting cells (APCs). The transcription factor interferon regulatory factor-1 (IRF-1) is involved in Th1 cell induction via transcription of the IL-12p40 gene in APCs. Using mice with disrupted genes for IRF-1 or IL-12p40, Maruyama et al. (p. 143) show that, although IRF-1 is not essential for Th1-associated T-cell IFN-γ production following in vivo Listeria infection, IL-12p40 is required; whereas inhibition of Th2-associated IL-4 production requires IRF-1 but not IL-12p40. IL-4, but not IFN-γ, production can be inhibited by supernatant from Listeria-infected APCs during culture of spleen cells in vitro. This activity is due to IL-1α and IL-1β, via the T-cell IL-1R. IL-1R stabilizes IRF-1 and increases its nuclear translocation, where it binds the 3′untranslated region of Il4 and decreases transcription. The authors conclude that IRF-1 not only induces Th1 responses but also suppresses Th2 responses.
A new anti-LAP antibody that enhances inflammation in vivo
By Andre P. da Cunha, Henry Y. Wu, Rafael M. Rezende, Tyler Vandeventer and Howard L. Weiner
Cell surface transforming growth factor-β (TGF-β) is crucial for Treg cell-mediated immunosuppression. Latency-associated peptide (LAP) forms a complex with TGF-β, and LAP+ Treg cells are induced in anti-CD3-stimulated oral tolerance to MOG peptides that otherwise induce experimental autoimmune encephalomyelitis (EAE) (a model of multiple sclerosis). Here, da Cunha et al.(p. 73) report the effects of their mAb against mouse LAP in vivo. In naive mice, anti-LAP decreases the percentage of LAP+ cells among CD4+ T cells and among Foxp3+ Treg cells in spleen and lymph nodes without affecting the percentage of CD4+Foxp3+ Treg cells. Treg cell suppressive activity is unaffected but anti-LAP-treated CD4+ T cells are pro-inflammatory (increased proliferation IL-2, IL-17 and IFN-γ) in vitro. In vivo, anti-LAP abrogates the protective effect of anti-CD3 on MOG-induced EAE; if MOG is given without pertussis toxin (or anti-CD3), anti-LAP worsens EAE, with increased Th1 and Th17 cell infiltration. The new reagent therefore reveals roles for CD4+LAP+ T cells in immunosuppression, inflammation and autoimmunity.
Introduction: Antibody-Targeted Therapy Special Issue
By: Tadamitsu Kishimoto
Lymphocytes are the crucial orchestrators of the adaptive immune system because the enormous flexibility of antibody or TCR gene expression and modification in B or T lymphocyte populations allows adaptive selection of individual lymphocytes that express antibodies or TCRs that can recognize and tag almost any candidate molecule and potentially trigger a range of effector functions. In this Special Issue of review articles, our authors detail many of the current and future uses of antibodies in human diseases.
UDP is a danger signal from necrotic cells that induces MCP-3 in macrophages
By Toshifumi Kimura, Shuhei Kobayashi, Fumito Hanihara-Tatsuzawa, Aoi Sayama, Takashi MaruYama and Tatsushi Muta
Induction of necrosis (in contrast to apoptosis) is perceived by immune cells as dangerous and triggers macrophages and neutrophils to infiltrate and repair any damage. Necrotic cells release various‘danger signals’and UTP and UDP, which signal via P2X and P2Y purinergic receptors, were recently identified as danger signals that induce chemokines such as monocyte chemotactic protein 1 (MCP-1) in glial cells. In this article, Kimura et al. (p.697) show that necrotic A20 (B lymphoma) cells induce peritoneal infiltration by macrophages and granulocytes. MCP-3 is induced in macrophages by necrotic cells but this is abolished by apyrase, which removes phosphates from nucleotide diphosphates (and triphosphates). UDP is found to stimulate MCP-3 and knockdown of P2Y6 (the UDP receptor) reduces the response; whereas ectopic expression of P2Y6 confers responsiveness. P2Y6 signals via the MEK1/2–ERK signaling pathway. Necrotic cells therefore release UDP as an important danger signal and its receptor is required for the induction of MCP-3 in macrophages.
A novel and effective vaccine-delivery system that targets PP M-cells
By Hideaki Shima, Takashi Watanabe, Shinji Fukuda, Shin-Ichi Fukuoka, Osamu Ohara and Hiroshi Ohno
Mucosal vaccines can not only prevent local pathogen invasion and neutralize toxins but also induce systemic protection. IgA is the most abundant isotype in the body, playing a crucial role in many host–microbe interactions at mucosal surfaces and thereby regulating many immune responses; induction of secretory IgA (sIgA) is a major aim of mucosal vaccines. M-cells specifically express GP2 (glycoprotein 2) and sample antigen from the gut lumen into Peyer’s patches (PPs). Streptavidin (SA) is a bacterial product that strongly binds biotin. In this paper, Shima et al. (p. 619) describe a novel delivery system—the FAb region of a mAb against GP2, fused with SA (anti-GP2-SA). This binds M-cells specifically. Oral administration of anti-GP2-SA conjugated to biotinylated ovalbumin induces antigen-specific sIgA. Similar conjugation to biotinylated Salmonella Typhimurium lysate and oral delivery induces strong protection from subsequent oral infection. Targeting M-cells with this oral vaccine-delivery system is therefore an effective, adjuvant-free strategy.
PEI induces robust adjuvant effects when delivered systemically
By Neil C. Sheppard, Sarah A. Brinckmann, Kate H. Gartlan, Manoj Puthia, Catharina Svanborg, George Krashias, Stephanie C. Eisenbarth, Richard A. Flavell, Quentin J. Sattentau and Frank Wegmann
Polyethyleneimine (PEI) is a synthetic polymer of variable size and complexity. In this paper, Sheppard et al. (p. 531) examine the adjuvant activity of PEI when mixed with a ‘model’ antigen (HIV-1 gp140; the figure shows an electron micrograph of PEI–gp140). In mice, subcutaneous administration of all forms of PEI enhances antigen-specific IgG production and modifies the Th-cell bias; adjuvant activity is lower than Freund’s adjuvants but higher than alum. In rabbits, subcutaneous PEI triggers neutralizing antibodies against the vaccine antigen, in particular against native conformations thereof. In mice, intraperitoneal administration of PEI recruits neutrophils, then monocytes, and enhances antigen uptake. Although PEI acts via the Nlrp3 inflammasome to modify Th-cell responses, Nlrp3 is not required for adjuvanticity. PEI also synergizes with CpG oligodeoxynucleotides to trigger Th1-biased responses. PEI formulations therefore trigger potent antibody responses, especially to native antigen structures, and the authors discuss its use as a systemic adjuvant.
Introduction: Mucosal Immunology Special Issue
By Kiiyoshi Takeda
Mucosal tissues that are covered by an epithelial cell layer are exposed to the external environment and are vulnerable to invasion by pathogenic micro-organisms. These mucosal tissues are equipped with a specialized immune system—the mucosal immune system—to combat pathogenic micro-organisms. This Special Issue of review articles focusses on intestinal mucosal immunology to survey our present knowledge of the interplay between the intestinal environmental factors and the mucosal immune system.
The association of CD20 with CD40 enhances rituximab-mediated B-cell apoptosis
By Loubna Al-Zoobi, Suzanne Salti, Anna Colavecchio, Malek Jundi, Amal Nadiri1, Ghada S. Hassan, Hani El-Gabalawy and Walid Mourad
Rituximab is a chimeric (human-mouse) monoclonal anti-CD20 antibody tahat depletes B cells by antibody- and complement-medicated cytotoxicity; it also induces B-cell apoptosis although the mechanisms remain unclear, especially since CD20 lacks a death domain. Rituximab is successfully being used to treat people with B-cell malignancies and rheumatoid arthritis. In this report, Al-Zoobi et al. (p.451) show that the maturation state of B cells affects susceptibility to apoptosis, as does the level of CD20; however, apoptosis is independent of Fc-medicated interactions. The physical association of CD40 with CD20, and the presence of disulfide-linked CD40 homodimers, also enhances rituximab-induced apoptosis. Similarly, the association of CD20 with CD40 enhances anti-CD40-triggered apoptosis. Combining anti-CD20 and anti-CD40 has an additive effect compared with either antibody used separately. These results increase our knowledge of the interactions between CD20 and CD40 during rituximab-induced apoptosis and might identify potential improvements to the therapeutic efficacy of rituximab.
IDO2 and IDO1 cooperate in some inflammatory responses but IDO2 also has unique roles
Indoleamine 2,3-dioxygenase (IDO) enzymes are crucial for catabolism of tryptophan to kynurenine and can thus inhibit immune responses. In humans and mice, the genes for IDO1 and IDO2 are present tandemly in a tail-tohead arrangement. The functions of IDO1 are better characterized so, for this study, Metz et al. (p. 357) generate Ido2−/− mice. No abnormalities are apparent in blood kynurenine levels, embryo development or immune cell populations in lymphoid organs. Ido2−/− mice share some of the defects seen in Ido1−/− mice and some, but not all, Ido1-mediated functions are affected, for example, Treg cell generation. Ido2−/− mice also have some nonredundant features, for example, they have attenuated production of various immunoregulatory cytokines during contact hypersensitivity and their development of inflammatory skin papilloma is unaffected. The authors conclude from their initial characterization that IDO2 interacts with IDO1 but also has nonredundant and unique activities in the immune system.
Lymphocyte migration does not depend on endothelial heparan sulfate
By Liat Stoler-Barak, Sagi Barzilai, Ayelet Zauberman, and Ronen Alon
Both neutrophils and lymphocytes must detect chemoattractants during transendothelial migration (TEM). Whereas lipid chemoattractants can be adsorbed on the endothelial cell (EC) membrane, it was thought that chemokines require surface heparan sulfate (HS)-mediated ‘presentation’ to leukocytes. Using HUVECs (human umbilical vein ECs; a model of nonlymph-node vessels), Stoler-Barak et al. (p. 315) report that HS is mainly expressed on basolateral, rather than apical, surfaces in resting and inflamed ECs. Silencing the enzyme exostoses 1 (Ext1) ablates HS biosynthesis but does not affect the expression or distribution of adhesion molecules or chemokine vesicles (chemokines are green in the permeabilized IL-1β-stimulated HUVECs in the figure). Ext1 silencing reduces the arrest and impairs the TEM of human neutrophils; however, adhesion and TEM of effector T cells are unaffected. The authors suggest that neutrophils rely on chemokines being presented by HS on the surface of inflamed ECs; but T cells can respond to chemokines stored in ECs independently of extracellular deposition on HS scaffolds.
Loss of MHC class II ubiquitination in DCs downregulates integrin β2 and inhibits T-cell activation
By Rikiya Ishikawa, Mizuho Kajikawa, and Satoshi Ishido
Ubiquitination is a post-translational modification that affects protein degradation, stability, function and location. Ubiquitin is added after activation, ligation and conjugation steps, and the ligases include the MARCH family. MARCH-I-mediated ubiquitation participates in the degradation of peptide–MHC class II (pMHCII) complexes, and downregulation of this process is a characteristic of conventional dendritic cells (cDCs), in which it stabilizes surface expression of pMHCII. This stabilization might be expected to enhance stimulation of T cells. Here, Ishikawa et al. (p. 283) show that loss of pMHCII ubiquitination in cDCs actually inhibits the activation and Th1/Th17 differentiation of CD4+ T cells. The cDCs have decreased IL-12 production and integrin β2 expression; in contrast, similar stabilization of CD86 does not impair T-cell activation. Loss of pMHCII ubiquitination and consequent downregulation of integrin β2 and IL-12 in cDCs is therefore actually a mechanism for negative regulation of CD4+ T cell responses.
Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production
By Akihiro Kimura, Hiromi Abe, Sanae Tsuruta, Sayuri Chiba, Yoshiaki Fujii-Kuriyama, Takashi Sekiya, Rimpei Morita, Akihiko Yoshimura
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with an increasing array of known environmental and endogenous ligands. The known roles of the AhR are similarly expanding, including effects on many immune cells types; for example, LPS-induced inflammatory responses in macrophages. Listeria monocytogenes is a bacterium that can survive and replicate within macrophages and can cause severe illness (e.g. sepsis) and even death in humans. In this paper, Kimura et al. (p. 209) show that the AhR is induced in mice after infection with L. monocytogenes. AhR deficiency increases growth of L. monocytogenes and increases the mortality of the mice, despite enhanced production of pro-inflammatory cytokines. In wild-type mice, AhR ligands reduce mortality, enhance macrophage survival via AIM (apoptosis inhibitor of macrophages) and increase the production of macrophage reactive oxygen species (ROS). AhR is therefore crucial for containment and clearance of L. monocytogenes and therapeutic AhR ligands might protect against listeriosis.
The AhR protects the liver during ConA-induced hepatitis by altering the balance of IFN-γ and IL-22
By Hiromi Abe, Akihiro Kimura, Sanae Tsuruta, Tomohiro Fukaya, Ryota Sakaguchi, Rimpei Morita, Takashi Sekiya, Takashi Shichita, Kazuaki Chayama, Yoshiaki Fujii-Kuriyama and Akihiko Yoshimura
The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed transcription factor that is known to participate in multiple regulatory mechanisms and thereby regulates a range of immune responses. Using wild-type (WT) or AhR-knockout (Ahr–/–) mice, Abe et al. (p.129) examine the role of AhR in acute liver injury. In WT mice, expression of AhR increases during ConA-induced hepatitis; all of the WT mice survive whereas none of the Ahr–/– mice do. Serum levels of IFN-γ are higher, and levels of IL-22 are lower, in the Ahr–/– mice; hematopoietic cells are responsible for this effect. Ahr suppresses production of IFN-γ by NKT cells, whereas it promotes IL-22 production from RORγt+ (retinoic acid-related orphan receptor γt+) innate-lymphoid 22 (ILC22) cells. ILC22 is a recently identified cell type that protects epithelial cells from various injuries. AhR is therefore important in protecting the liver during inflammation both by inducing IL-22 and by repressing IFN-γ production.
Inflammatory DCs are crucial for the development of airway hyper-reactivity
By Arifumi Iwata, Saki Kawashima, Midori Kobayashi, Ayako Okubo, Hirotoshi Kawashima, Akira Suto, Koichi Hirose, Toshinori Nakayama and Hiroshi Nakajima
During inflammation, monocytes can be recruited to tissues and develop into ‘inflammatory’ dendritic cells (iDCs). In a mouse model of asthma, Iwata et al. (p. 103) examine the roles of iDCs at the site of ovalbumin-induced allergic airway inflammation, in comparison with various other myeloid populations. The lung iDCs are derived from monocytes via CCR2 and capable of inducing proliferation of naive CD4+ T cells. In a Th2 environment, induced by transferring Th2 cells to the lung, iDCs produce arginase 1 and resistin-like molecule α and thus partly resemble ‘alternatively activated’ macrophages (i.e. those found in Th2 conditions); iDCs require Stat6 for this. In a Th1 environment, iDCs produce TNF and inducible NO synthase and thus become TNF/iNOS-producing (TIP)-DCs. In a Th2 environment, iDCs are not required to induce allergic inflammation but they are indispensable for airway hyper-reactivity (see figure). The function of iDCs therefore depends on the T-cell-orchestrated environment and they may represent a therapeutic target in asthma.
Chemical modifications on siRNAs avoid Toll-like-receptor-mediated activation of the hepatic immune system in vivo and in vitro
By Broering et al.
RNA interference is a powerful mechanism to control gene expression but the resemblance of small interfering RNAs (siRNAs) to viral products can trigger innate immune responses. Synthetic siRNAs are being assessed in clinical trials and formulations with lipid nanoparticles (LNPs) accumulate in the liver, which is thus a good therapeutic tool. Broering et al. (p. 35) administer various siRNAs to mice in vivo (with LNPs) or to isolated mouse or human liver cells in vitro. In vivo, an unmodified siRNA for apolipoprotein B1 suppresses the mRNA by 80%. Unmodified galactosidase siRNA (GAL), but not a modified (2′O-methylated) luciferase siRNA (LUC 2′O-Me), induces inflammatory cytokines although this is not seen in Myd88-deficient mice. Neither signs of necrosis nor infiltration of immune cells are induced (as illustrated below). In vitro results support these findings—unmodified, but not modified, siRNAs induce immune genes. There are variations in immune activation between the different siRNA sequences and between different cell types. The authors conclude that siRNA can knock down hepatic target genes in vivo and that methylation avoids TLR-mediated immune activation.
Human skin-derived keratinocytes and fibroblasts co-cultured on 3D poly ε-caprolactone scaffold support in vitro HSC differentiation into T-lineage committed cells
By Palamaro et al.
While developing in the thymus from hematopoietic stem cells (HSCs), T cells interact with thymic epithelial cells (TECs) on a 3-dimensional scaffold of thymic stromal cells (TSCs). Because TECs and TSCs share many features with skin-derived keratinocytes and fibroblasts, Palamaro et al. (p. 703) examine whether these skin cells, on an artificial 3-dimensional scaffold of poly-ε-caprolactone, can support T-cell differentiation from human HSCs. Fibroblasts and keratinocytes adhere to the scaffold and interact with each other. When HSCs are added with IL-7, IL-15 and Flt3-ligand, a pattern of surface markers (CD7, CD1a and CD4 up-regulated) and genes (TAL1 down-regulated; SPIB, PTCRA and RAG2 up-regulated) that is associated with T-cell lineage commitment and TCR repertoire generation is seen. Even without thymic components, this multicellular biocomposite, which is based on easily accessible cells, therefore recapitulates key aspects of the thymus and may be useful in generating T cells for immunotherapy.
Cigarette smoke impairs phagocytosis of apoptotic neutrophils by alveolar macrophages via inhibition of the histone deacetylase/Rac/CD9 pathways
By Naotaka Noda, Koichiro Matsumoto, Satoru Fukuyama, Yukari Asai, Hiroko Kitajima, Nanae Seki, Yuko Matsunaga, Keiko Kan-o, Atsushi Moriwaki, Konosuke Morimoto, Hiromasa Inoue, and Yoichi Nakanishi
Efferocytosis is the uptake of apoptotic or necrotic cells by professional or non-professional phagocytes and is important in limiting local tissue damage. Chronic obstructive pulmonary disease (COPD) is associated with cigarette smoke and features lung inflammation dominated by neutrophils as well as reduced histone deacetylase (HDAC) activity in alvelolar macrophages (AMs). Here, Noda et al. (p. 643) examine the role of HDAC in efferocytosis of neutrophils by mouse AMs. In AMs, cigarette smoke extract (CSE) reduces the activity of HDAC and of the GTPase, Rac. Treatment with CSE or an HDAC inhibitor decreases the efferocytosis of neutrophils by AMs. The HDAC inhibitor down-regulates CD9, and CD9 downregulation reduces binding of apoptotic neutrophils to AMs. Cigarette smoke thus appears to affect efferocytosis by inhibiting HDAC, Rac and CD9. An HDAC activator (aminophylline) reverses the inhibition of efferocytosis and the authors suggest this as a potential therapeutic strategy in COPD.
Mast cells enhance a range of effector functions in neutrophils
By Fatma Doener, Anastasija Michel, Sebastian Reuter, Pamela Friedrich, Livia Böhm, Manfred Relle, Laura Codarri, Stefan Tenzer, Matthias Klein, Tobias Bopp, Edgar Schmitt, Hansjörg Schild, Markus Philipp Radsak, Christian Taube, Michael Stassen and Marc Becker
Mast cells were first described over 100 years ago but only recently has research established a role for them in recruiting neutrophils at the initiation of inflammatory sites. Doener et al. (p. 553) show that mast cells downregulate neutrophil CD62L but upregulate CD11b, phagocytosis and generation of reactive oxygen species. TNF and especially GM-CSF (but not histamine) from mast cells are crucial mediators of these enhancements. Mast-cell GM-CSF also decreases neutrophil apoptosis and thereby increases survival. In vivo, mast cells boost neutrophil hagocytosis in acute lung inflammation. In addition to their many well-established roles in immunity, mast cells—which are located at the interface between the host and its environment— are therefore important regulators of several pro-inflammatory neutrophil functions.
Interferons and estrogen up-regulate expression of the SLE-associated ER protein Unc93b1
By Ravichandran Panchanathan, Hongzhu Liu, and Divaker Choubey
Systemic lupus erythematosus (SLE), an autoimmune disease, predominantly develops in females. Moreover, SLE patients exhibit increased serum levels of IFN-α and increased levels of Unc93b1, the endoplasmic reticulum (ER) transmembrane protein that is essential for trafficking of endosomal TLRs from the ER to endosomes. Because dysregulation of TLR signaling is associated with increased levels of IFN-α, Panchanathan et al. (p. 521) investigate whether interferons and the female sex hormone estrogen (E2) could regulate expression of Unc93b1. They report higher levels of Unc93b1 protein in immune cells from female B6 mice as compared with males. Unc93b1 protein levels are increased by estrogen or interferon (α, β or γ) treatment of immune cells. This increase depends on the lupus-associated p202 protein that is upregulated by activation of estrogen or interferon signaling. Reduced p202 expression in cells also affects the TLR9-mediated activation of interferon signaling. The authors suggest a role for increased levels of the Unc93b1 protein in the sex bias and the increased levels of IFN-α in SLE.
IL-7 is expressed by lymphatic endothelial cells and its production increases during lymphopenia
By Corey N. Miller, Dennis J. Hartigan-O’Connor, Myeong Sup Lee, Grace Laidlaw, Ivo P. Cornelissen, Mehrdad Matloubian, Shaun R. Coughlin, Donald M. McDonald, and Joseph M. McCune
Although IL-7 is known to be a non-redundant regulator of T-cell development and homeostasis, the identity and location of the crucial source cells have proved elusive. Using GFP-transgenic mice that report IL-7 expression, Miller et al. (p.471) show that IL-7 is produced by lymphatic endothelial cells (LECs) throughout the body; fibroblastic reticular cells are another dominant source in resting lymph nodes, but hematopoietic cells are minor contributors. Exposure to IL-7 appears to be higher when lymphocytes are in lymph nodes or efferent lymph than in blood. In lymph nodes depleted of lymphocytes, IL-7 transcription increases in the stromal cells, but not myeloid cells. The authors conclude that there is a dynamic interplay between immune cells and adherent/structural cells, with LECs as a source of IL-7 that bathes T cells (and perhaps other cells) as they traffic through the lymphatic network.
The N-terminal part of TLR7 remains disulfide-linked to the C-terminal part to sense microbial RNA
By Atsuo Kanno, Chikako Yamamoto, Masahiro Onji, Ryutaro Fukui, Shin-ichiroh Saitoh, Yuji Motoi, Takuma Shibata, Fumi Matsumoto, Tatsushi Muta and Kensuke Miyake
Although cell-surface and intracellularly expressed TLRs are extremely important in detecting pathogens, the intracellular TLR7 can also recognize self-RNA and is implicated in triggering autoimmunity. One potential mechanism to prevent this would be if ligand sensing only occurs after the N-terminal part of TLR7 (TLR7N) is cleaved off to leave a truncated C-terminal part (TLR7C) that senses microbial RNA in endolysosomes. Here, Kanno et al. (p. 413) show that TLR7N remains associated, via a disulfide bond, with TLR7C. In TLR9, another intracellular TLR, there is no such bond between TLR9N and TLR9C. The cysteines required for TLR7N–TLR7C association are required for RNA-sensing; proteolytic cleavage of TLR7 is also required but TLR7C alone does not sense ligand. Thus, sensing microbial RNA does not require that TLR7N is cleaved and separated from TLR7C.
Fas-expressing natural helper (F-NH) cells plus IL-4 and anti-CD40 enhance B-cell IgE secretion
By Ayumi Fukuoka, Shizue Futatsugi-Yumikura, Suzuka Takahashi, Hirotaka Kazama, Tomonori Iyoda, Tomohiro Yoshimoto, Kayo Inaba, Kenji Nakanishi, and Shin Yonehara
Previously, Fukuoka et al. (p. 373) reported that Fas-knockout Balb/c mice develop allergic inflammation with hyper-IgE production. Here, they identify a novel splenocyte type that, with IL-4 and anti-CD40, enhances B-cell IgE production, both in Fas-knockout and wild-type Balb/c mice. These Lin– Thy-1+Sca-1+ ‘F-NH’ (Fas-expressing natural helper) cells express IL-18R and secrete Th2 cytokines in co-culture with B cells.
An IL-6-triggered NF-κB loop: the ‘IL-6 amplifier’ occurs in epithelia of a transplanted human lung
By Jihye Lee, Tomoyuki Nakagiri, Daisuke Kamimura, Masaya Harada, Takahiro Oto, Yoshiyuki Susaki, Yasushi Shintani, Masayoshi Inoue, Shinichiro Miyoshi, Eiichi Morii, Toshio Hirano, Masaaki Murakami, and Meinoshin Okumura
IL-6 signalling is amplified via NF-κB and STAT3 to induce chemokines and increase inflammation. Lee et al. (p. 319) examine bronchial epithelium in a human lung allograft. NF-κB and STAT3 are phosphorylated and CCL2, CD4+ cells and macrophages are increased. The authors conclude that the ‘IL-6 amplifier’, previously identified in a mouse model of chronic rejection, operates in human transplantation.
Transport of misfolded endoplasmic reticulum proteins to the cell surface by MHC class II molecules
By Yan Jiang, Noriko Arase, Masako Kohyama, Kouyuki Hirayasu, Tadahiro Suenaga, Hui Jin, Maki Matsumoto, Kyoko Shida, Lewis L. Lanier, Takashi Saito, and Hisashi Arase
Most misfolded endoplasmic-reticulum(ER) proteins are degraded. Jiang et al. (p.) show that MHC class II binds some misfolded ER proteins in the peptidebinding groove, where they compete with the invariant chain. These proteins are cell-surface-expressed without further processing and efficiently stimulate antigen-specific B cells. class II thus presents intact proteins as well as peptides.
In human neonates, IL-21 induces IL-10-producing Th1 cells, but inhibits Th2 and Th17 cells
By Aysefa Doganci, Julia Birkholz, Stephan Gehring, Alexander G. Puhl, Fred Zepp and Claudius U. Meyer
Here, Doganci et al. (p. 157) show that IL-21 polarizes umbilical-cord naive CD4+ T cells into Th1 cells that produce IL-10. IL-21 also increases IFN-γ production and inhibits Th2- and Th17-cell development. The authors contrast these findings with a lack of equivalent effects of IL-21 on adult T cells and discuss the implications for neonatal immune responses.
Agonistic anti-TLR4 can boost or inhibit B-cell responses depending on when it is given
By Nurlaely Mida Rachmawati, Kenji Fukudome, Naoko Tsuneyoshi, Uleng Bahrun, Hiroki Tsukamoto, Tsutomu Yanagibashi, Yoshinori Nagai, Kiyoshi Takatsu, Shoichiro Ohta and Masao Kimoto
In this paper, Rachmawati et al. (p. 117) report that an anti-TLR4 agonist antibody boosts antigen-specific antibody production if given with antigen. In contrast, anti-TLR4-mediated ‘pre-stimulation’ inhibits subsequent specific-antibody production. Prestimulation affects B cells, not T-helper cells, and affects primary, not recall, responses. The authors discuss anti-TLR4 as an adjuvant or in preventing lethal effects of LPS.
Disease-associated TLR4 polymorphisms affect ligand-induced dimerization
By Natsuko Yamakawa, Umeharu Ohto, Sachiko Akashi-Takamura, Koichiro Takahashi, Shin-Ichiroh Saitoh, Natsuko Tanimura, Takayoshi Suganami, Yoshihiro Ogawa, Takuma Shibata, Toshiyuki Shimizu and Kensuke Miyake
The cell-surface TLR4–MD-2 complex recognises LPS; two complexes then dimerise to trigger signalling. Yamakawa et al. (p. 45) use a new antibody recognising TLR4 with polymorphisms (D229G and T339I) that are found in humans. MD-2 or LPS binding is not affected, but a conformational change interferes with ligand-induced dimerization of polymorphic TLR4, which may explain the associated diseases.
Macaque mast-cell chymase is an ideal experimental model
By Michael Thorpe, Jing Yu, Vamsi Boinapally, Parvin Ahooghalandari, Jukka Kervinen, Lawrence de Garavilla and Lars Hellman
In this paper, Thorpe et al. (p. 771) compare the sequence and extended specificity of mast-cell chymases from macaques with those from humans and dogs. The macaque and human chymases are almost identical but both differ from dog chymase. The authors suggest using macaque chymase rather than, for example, rodent chymases when modelling therapeutic chymase inhibition.
Moesin regulates lymphocyte homeostasis
By Takako Hirata, Akira Nomachi, Kazuo Tohya, Masayuki Miyasaka, Sachiko Tsukita, Takeshi Watanabe and Shuh Narumiya
Lymphocytes express moesin and ezrin, two members of a cytoskeletalprotein family that show considerable functional redundancy. Hirata et al. (p. 705) demonstrate that moesin-deficient mice have blood lymphopaenia. B- and T-cell numbers and egress are also decreased in lymphoid organs. Moesin is the major family member regulated during cell-shape changes. Moesin therefore has several unique roles in lymphocytes.
PRAT4A dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells
By Takuma Shibata, Naoki Takemura, Yuji Motoi, Yoshiyuki Goto, Thangaraj Karuppuchamy, Kumi Izawa, Xiaobing Li, Sachiko Akashi-Takamura, Natsuko Tanimura, Jun Kunisawa, Hiroshi Kiyono, Shizuo Akira, Toshio Kitamura, Jiro Kitaura, Satoshi Uematsu, and Kensuke Miyake
Here, Miyake and colleagues (p. 613) use a new monoclonal antibody to reveal cell-surface expression of TLR5 on neutrophils, Ly6Chi, not Ly6Clo, monocytes and some, not all, dendriticcell subsets. Expression depends on the chaperone PRAT4A (protein associated with TLR4A). The monocytes, but not neutrophils, produce cytokines in response to flagellin. The authors thus verify cell-surface TLR5 expression.
Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity
By Masanori Miyanishi, Katsumori Segawa and Shigekazu Nagata
Macrophage MFG-E8 (milk fat globule EGF factor VIII) and Tim4 (T-cell immunoglobulin- and mucin-domain-containing 4) bind phosphatidylserine on apoptotic cells and enhance their engulfment. Nagata and colleagues (p.551) report that double (but not single) deficiency of MFG-E8/Tim4 in female B6 mice causes age-dependent increases in autoantibodies. The authors also demonstrate reciprocal roles for TNF and IFN-α in this process.
Multiple potential regulatory sites of TLR4 activation induced by LPS as revealed by novel inhibitory human TLR4 mAbs
By Hiroki Tsukamoto, Kenji Fukudome, Shoko Takao, Naoko Tsuneyoshi, Hideyuki Ihara, Yoshitaka Ikeda and Masao Kimoto
In this paper, Tsukamoto et al. (p. 495) describe two novel monoclonal anti-TLR4 antibodies that inhibit a range of features of LPS-stimulated TLR4 activation. The antibodies bind different parts of TLR4 but do not block LPS binding. The authors suggest that such antibodies, or drugs derived by them, might help prevent situations such as septic shock and autoimmunity.
Residual methylprednisolone suppresses human T-cell responses to spleen, but not islet, extracts from deceased organ donors
By Max Joffe, Andra S. Necula, Rochna Chand, Brett C. McWhinney, Balasubramanian Krishnamurthy, Tom Loudovaris, David Goodman3, Helen E. Thomas, Thomas W. H. Kay and Stuart I. Mannering
Here, Mannering and colleagues (p. 447) report that extracts from spleens of human pancreatic-islet donors inhibit T-cell proliferation in vitro. Methylprednisolone is presentat doses that suppress T-cells, and suppression is reversed by mifepristone (a glucocorticoid receptor antagonist). Spleen (but probably not islet) extracts from deceased donors may therefore have enough residual methylprednisolone to suppress immune responses.
The RP105/MD-1 complex is indispensable for TLR4/MD-2-dependent proliferation and IgM-secreting plasma cell differentiation of marginal zone B cells
By Yoshinori Nagai, Tsutomu Yanagibashi, Yasuharu Watanabe, Masashi Ikutani, Ai Kariyone, Shoichiro Ohta, Yoshikatsu Hirai, Masao Kimoto, Kensuke Miyake, and Kiyoshi Takatsu
RP105 (radioprotective 105) is a TLR4 homologue expressed on marginal-zone (MZ) B cells, and Nagai et al. (p. 389) define its roles. Simultaneous crosslinking of RP105 and TLR4 enhances survival, differentiation to plasma cells and IgM production. RP105-deficient MZ B cells do not produce such IgM. The authors conclude that RP105 interacts extensively with TLR4 in splenic B cells.
CD4+ T-cell dysfunctions through the impaired lipid rafts ameliorate concanavalin A-induced hepatitis in sphingomyelin synthase 1-knockout mice
By Lingli Dong, Ken Watanabe, Mari Itoh, Cheng-Ri Huan, Xiao-Peng Tong, Takuji Nakamura, Miyuki Miki, Haruka Iwao, Akio Nakajima, Tomoyuki Sakai, Takafumi Kawanami, Toshioki Sawaki, Yasufumi Masaki, Toshihiro Fukushima, Yoshimasa Fujita, Masao Tanaka, Masato Yano, Toshiro Okazaki and Hisanori Umehara
Dong et al. (p. 327) examine mice lacking sphingomyelin synthase 1 (SMS1). CD4+ T cells from SMS1/ mice show reduced proliferation, cytokine production, LAT phosphorylation and TCR clustering/localisation in lipid rafts. After injection of Con A, sphingomyelin deficiency causes lower IL-6 levels and less-severe hepatitis. The authors conclude that impaired lipidraft formation reduces Con-A-induced liver injury.
Smad2 and Smad3 are redundantly essential for the suppression of iNOS synthesis in macrophages by regulating IRF3 and STAT1 pathways
By Yuki Sugiyama, Kyosuke Kakoi, Akihiro Kimura, Ichiro Takada, Ikko Kashiwagi, Yu Wakabayashi, Rimpei Morita, Masatoshi Nomura and Akihiko Yoshimura
Yoshimura and colleagues (p.253) show that mice with double knockouts for Smad2 and Smad3 have higher levels of inducible NO synthase in LPS-stimulated macrophages than either individual knockout and that TGF-b1- ediated suppression is impaired. IL-6 and TNF levels are augmented. TLR3- or TLR4-mediated IRF3 activation, IFN-b production and STAT1 phosphorylation are also increased. Smad2 and Smad3 therefore suppress multiple pathways.
IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1β by keratinocytes via the ROS-NLRP3-caspase-1 pathway
By Kyung-Ah Cho, Jee Won Suh, Kyung Ho Lee, Jihee Lee Kang and So-Youn Woo
In this paper, Woo and colleagues (p. 147) add IL-17 and/or IL-22 to human keratinocytes and demonstrate increased IL-1β production. This involves reactive oxygen species and inflammasomes. Caspase 1 is activated by inflammasomes and cleaves pro-IL-1β. IL-17/IL-22-induced skin inflammation is lower in caspase-1-deficient mice. The authors discuss how Th17 cells may potentiate IL-1β-mediated inflammatory skin disease via caspase 1.
Sulfatide inhibits α-galactosylceramide presentation by dendritic cells
By Mitsuhiro Kanamori, Yusuke Tasumi, Tomonori Iyoda, Maki Ushida and Kayo Inaba
Non-invariant NKT (non-iNKT) cells bind sulfatide and counteract iNKT cells. Inaba and colleagues (p. 129) report that, even in the absence of non-iNKT cells, sulfatide reduces formation of α-galactosyl ceramide (αGC)–CD1d complexes on dendritic cells (DCs) and thereby inhibits αGC-mediated iNKT cell activation. The authors conclude that sulfatide competes with αGC for loading onto CD1d in the endocytic pathway of DCs.
B cells and lymphotoxin-βR remodel the lymph node medulla
By Jun Abe, Satoshi Ueha, Hiroyuki Yoneyama, Yusuke Shono, Makoto Kurachi, Akiteru Goto, Masashi Fukayama, Michio Tomura, Kazuhiro Kakimi, and Kouji Matsushima
The medulla of lymph nodes contains most of their plasma cells. Matsushima and colleagues (p. 17) show that lymphotoxin-βR and polyclonal, non-cognate B cells mediate remodelling of the medulla in lymph nodes draining inflammatory sites. The authors conclude that this restructuring is crucial to create or expand niches for production of specific antibodies during inflammation.
Identification of a second mimicry epitope from Acanthamoeba castellanii that induces CNS autoimmunity by generating cross-reactive T cells for MBP 89–101 in SJL mice
By Chandirasegaran Massilamany, Oluwatoyin A. Asojo, Arunakumar Gangaplara, David Steffen and Jay Reddy
Previously, Reddy and colleagues identified an epitope in Acanthamoeba castellanii that mimics proteolipid protein 139–151 and induces autoimmunity in the CNS of SJL/J mice. They now report an amoebic NAD dehydrogenase subunit 2 peptide that mimics myelin basic protein 89–101. A single microbe therefore generates multiple epitopes that cross-react with myelin and cause encephalomyelitis.
IL-1β and TNFα-initiated IL-6–STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis
By Tomoaki Mori, Takeshi Miyamoto, Hideyuki Yoshida, Mayoko Asakawa, Miyuri Kawasumi, Takashi Kobayashi, Hideo Morioka, Kazuhiro Chiba, Yoshiaki Toyama, and Akihiko Yoshimura
Miyamoto and colleagues show that IL-1β, TNFα and IL-6 induce STAT3, IL-6-family cytokines and RANKL (receptor activator of NF-κB ligand). Pharmacological STAT3 inhibition reduces IL-6 and RANKL, and reduces inflammation and joint destruction in an arthritis model. STAT3 is therefore a key member of an amplification loop promoting inflammation and arthritis, and is a potential therapeutic target.
RhoB deficiency in thymic medullary epithelium leads to early thymic atrophy
By Arturo Bravo-Nuevo, Rebekah O'Donnell, Alexander Rosendahl, Jae Hoon Chung, Laura E. Benjamin, and Chikako Odaka
Odaka and colleagues show that RhoB is expressed in thymic medullary epithelium. RhoB-deficient mice have early thymic atrophy, with reduced thymic weight and cellularity. TGF-βRII expression is enhanced and fibronectin expression reduced in the medulla. Because RhoB expression does not normally change in the developing thymus, the authors suggest that Rho operates by inhibiting medullary TGF-β signalling.
The pre-TCR signal induces transcriptional silencing of the TCRγ locus by reducing the recruitment of STAT5 and Runx to transcriptional enhancers
By Shizue Tani-ichi, Masanobu Satake and Koichi Ikuta
In ab T cells, TCRc transcription must be repressed. Tani-ichi et al. show that pre-TCR-mediated signalling reduces transcription and histone acylation of the TCRc locus. Pre-TCR signalling inactivates TCRc enhancer elements indirectly, by reducing recruitment of Runx and STAT5 (signal transducer and activator of transcription 5). The authors propose that this mechanism is important for TCRc silencing.
Intracellular TLR4/MD-2 in macrophages senses Gram-negative bacteria and induces a unique set of LPS-dependent genes
By Takuma Shibata, Yuji Motoi, Natsuko Tanimura, Natsuko Yamakawa, Sachiko Akashi-Takamura and Kensuke Miyake
Here, Miyake and colleagues knock out PRAT4 (protein associated with TLR4A), a chaperone required for surface TLR4–MD-2 expression. Some responses to LPS (e.g. RANTES and MCP-1 production; CD40 and CD86 upregulation) remain intact in PRAT4–/– bone marrow derived macrophages. The authors conclude that intracellular TLR4–MD-2 interactions trigger a unique set of responses to LPS.
HIV-1 Nef impairs multiple T-cell functions in antigen-specific immune response in mice
By Hideki Fujii, Manabu Ato, Yoshimasa Takahashi, Kaori Otake, Shu-ichi Hashimoto, Tomohiro Kaji, Yasuko Tsunetsugu-Yokota, Mikako Fujita, Akio Adachi, Toshinori Nakayama, Masaru Taniguchi, Shigeo Koyasu and Toshitada Takemori
In this paper, Takemori and colleagues express HIV Nef in ovalbuminspecific peripheral CD4+ cells. Nef inhibits antigen-specific T cell proliferation, cytokine production and B cell helper activity; however, activation is not completely abrogated. The authors suggest a model in which Nef reduces T cell activity, thereby allowing low-level virus spread while avoiding cytopathic effects in host cells.
Antigen-independent development of Foxp31 regulatory T cells suppressing autoantibody production in experimental pemphigus vulgaris
By Tomoaki Yokoyama, Satoshi Matsuda, Yujiro Takae, Naoko Wada, Takeji Nishikawa, Masayuki Amagai and Shigeo Koyasu
Koyasu and colleagues examine CD4+CD25+Foxp3+ regulatory T cells (Tregs) in suppressing anti-desmoglein 3 (Dsg3)-mediated pemphigus vulgaris in Rag2–/– mice. Comparing Tregs from wild-type and Dsg3–/– mice, the authors show that target antigen expression is not required for Treg development; indeed a lack of antigen in the donor enhances the potency of Tregs in the host.
Mouse neutrophils are professional antigen-presenting cells programmed to instruct Th1 and Th17 T-cell differentiation
By Delbert S. Abi Abdallah, Charlotte E. Egan, Barbara A. Butcher and Eric Y. Denkers
Using mouse neutrophils, Denkers and colleagues (p. 317) show expression of MHC class II, CD80 and CD86 after coincubation with T cells. Neutrophils also process ovalbumin and present peptides on class II to valbumin-specific T cells. Finally, neutrophils prime Th1 and Th17 responses in the absence of exogenous cytokines. The authors conclude that neutrophils are bona fide antigen-presenting cells.
Extracellular heat shock protein 90 plays a role in translocating chaperoned antigen from endosome to proteasome for generating antigenic peptide to be cross-presented by dendritic cells
By J, Oura et al.
Tamura and colleagues (p. 223) use confocal microscopy to demonstrate that extracellular complexes of Hsp90 (heat-shock protein 90) and ovalbumin localise in cytosolic proteasomes. Antibody-mediated blocking of Hsp90 inhibits transporter associated with antigen presentation (TAP)-dependent cross-presentation of ovalbumin. The authors conclude that Hsp90 is important for translocation of chaperoned antigens into the cytosol before degradation and cross-presentation.
Abberant IL-4 production by SOCS3-over-expressing T cells during infection with Leishmania major exacerbates disease manifestations
By M. Nakaya et al
Deletion of SOCS3 (suppressor of cytokine signalling 3) in mouse T cells increases susceptibility to Leishmania major. Kobayashi and colleagues (p. 195) show that T cell SOCS3 overexpression also increases susceptibility. Levels of SOCS3 are thus crucial for disease control. IL-10, TGF-b and IFN-c production is unaffected.
The WSX-1 pathway restrains intestinal T-cell immunity
By Jeremy P. McAleer, Christiaan J. M. Saris and Anthony T. Vella
Vella and colleagues (p. 129) examine IL-12-family members in T cell responses to lipopolysaccharide. In particular, serum levels of IL-27 are increased and mice lacking IL-27R? have increased spleen and lamina propria Th17, but not Th1, cell numbers. IL-27R?-deficient regulatory T cells make more IL-17 and less IL-10. The authors hypothesise that blocking IL-27 will enhance mucosal vaccination.
IL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acid
By Masahiko Yabu, Hiroaki Shime, Hiromitsu Hara, Takashi Saito, Misako Matsumoto, Tsukasa Seya, Takashi Akazawa, and Norimitsu Inoue
Using mouse splenocytes, Inoue and colleagues (p. 29) show that macrophages and effector/memory CD4+ cells are essential for antigen-dependent IL-23 and IL-17 production in response to lactic acid. The authors suggest that a new cytokine that contains the IL-12/IL-23 p40 subunit plays a role in the enhanced lactic-acid-stimulated IL-17A production by effector/memory cells.
Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10
By Yoshiyasu Ueda, Hisako Kayama, Seong Gyu Jeon, Takashi Kusu, Yoshitaka Isaka, Hiromi Rakugi, Masahiro Yamamoto, and Kiyoshi Takeda
In this paper,Takeda and colleagues (p. 953)compare lamina propria macrophages and dendritic cells. Macrophages constitutively produce IL-10 and IL-10-regulated gene products. Large-intestineIL-10 comes mainly from macrophages (and regulatory T cells) and depends on commensal micro-organisms. Macrophages do not secrete cytokines in response to LPS unless IL-10 production is impaired. Commensals therefore induce IL-10 and suppress large-gut inflammation.
The Candida Th17 response is dependent on mannan- and β-glucan-induced prostaglandin E2
By Sanne P. Smeekens, Frank L. van de Veerdonk, Jos W. M. van der Meer, Bart Jan Kullberg, Leo A. B. Joosten, and Mihai G. Netea
Candida albicans stimulates strong Th17 responses. Netea and colleagues (p. 889) show that Candida is a potent inducer of prostaglandin E2 (PGE2) and that blocking PGE2 induction in human PBMCs decreases IL-6, IL-10, IL-17, IL-22 and IL-23 while increasing TNF production. PGE2 agonists restore IL-17 production. The authors identify mannan and β-glucan as important fungal components for PGE2 induction.
Neutrophil activation and survival are modulated by interaction with NK cells
By Claudio Costantini, Alessandra Micheletti, Federica Calzetti, Omar Perbellini, Giovanni Pizzolo, and Marco A. Cassatella
Using human cells, Cassatella and colleagues (p.827) show that NK cells treated with IL-2, IL-15 and/or IL-18 can prime superoxide production, increase neutrophil survival and upregulate activation markers. The authors identify some of the NK cell cytokines involved and the effects of NK–neutrophil contact. These novel and varied interactions could clearly influence neutrophil responses in inflammation.
Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells
By Hidetomo Matsushita, Shoichiro Ohta, Hiroshi Shiraishi, Shoichi Suzuki, Kazuhiko Arima, Shuji Toda, Hiroyuki Tanaka, Hiroichi Nagai, Masao Kimoto, Akira Inokuchi, and Kenji Izuhara
Previous exposure of cells to endotoxin or UT12 — an anti-TLR4 (Toll-like receptor 4) antibody — can induce endotoxin tolerance (ET). Ohta and colleagues (p. 739) use UT12 to suppress allergic inflammation in mice by directly inhibiting dendritic cell induction of antigen-specific Th2 and Th17 cells. The authors outline potential roles of ET and of UT12 in human asthma.
Accessibility control of TCR V region by STAT5
By Shizue Tani-ichi, Hai-Chon Lee, Sang-Kyu Ye, and Koichi Ikuta
Ikuta and colleagues (p. 693) report that STAT5 (signal transducer and activator of transcription 5) induces histone acetylation, germline transcription and increased chromatin accessibility around the TCR Vc5 region and the cis-acting HsA transcription element. STAT5 is recruited to HsA but does not bind the Vc5 promoter. STAT5 therefore mediates both direct and indirect control of TCRc transcription.
MicroRNA 125b inhibition of B cell differentiation in germinal centers
By Murali Gururajan, Christopher L. Haga, Sabyasachi Das, Chuen-Miin Leu, Daniel Hodson, Sajni Josson, Martin Turner, and Max D. Cooper
Here, Cooper and colleagues (p. 583) show that micro-RNA 125b (miR125b) is a member of a multigene family with miR125a, miR99a, miR99b, let-7a and let-7e. Expression patterns in centroblasts and binding to transcription factors pinpoint a role for miR125b inhibiting BLIMP-1 and IRF-4 and thereby promoting germinal centre B cell diversification and inhibiting plasma cell differentiation.
Contribution of IL-33 to induction and augmentation of experimental allergic conjunctivitis
By Saori Matsuba-Kitamura, Tomohiro Yoshimoto, Koubun Yasuda, Shizue Futatsugi-Yumikura, Yuuko Taki, Taichiro Muto, Tomohiro Ikeda, Osamu Mimura, and Kenji Nakanishi
IL-33, a member of the IL-1 family of cytokines, is the ligand for ST2 (IL-33Ra chain). IL-33 produce Th2 cytokine from Th2 cells, mast cells and basophils and augments allergic inflammation. In this study, the authors examined the pathological role of IL-33 in allergic conjunctivitis (AC). Ragweed pollen (RW)-immunized mice develop early-phase AC manifestation and late-phase conjunctival eosinophilic inflammation after challenge with RW. Additional IL-33 challenge significantly increased the late-phase response without affecting the early-phase response. Antigen challenge induced recruitment of ST2+CD4+ T cells and ST2+ eosinophils into the conjunctiva and additional IL-33 treatment significantly enhanced these responses. Furthermore, IL-5 induced IL-33R expression on evn splenic eosinophils and that these IL-5 and o/or GM-CSF-stimulated eosinophils produced IL-4 and chemokines in response to IL-33. Finally, IL-33 was shown to be constitutively expressed in conjunctival tissues, suggesting its crucial role in induction and augmentation of AC.
Zinc suppresses Th17 development via inhibition of STAT3 activation
By Chika Kitabayashi, Toshiyuki Fukada, Minoru Kanamoto, Wakana Ohashi, Shintaro Hojyo, Toru Atsumi, Naoko Ueda, Ichiro Azuma, Hiroshi Hirota, Masaaki Murakami, and Toshio Hirano
Here, Hirano and colleagues (p. 375) use the collagen-induced arthritis model to examine the effects of zinc on immune responses at a molecular level. Zinc attenuates IL-6-mediated STAT3 (signal transducer and activator of transcription 3)activation and inhibits development of Th17 cells. Zinc affects the secondary structure of STAT3 and thereby disrupts its interactions with several other signalling molecules.
Molecular analysis of IgD-positive human germinal centres
By Claudia Müller, Dörte Siemer, Götz Lehnerdt, Stephan Lang, and Ralf Küppers
Using microdissection and single-cell PCR, Küppers and colleagues (p. 289) investigate whether IgM+IgD+CD27+ B cells arise from IgD+ germinal centres (GCs). Six GCs were examined: one had a clone of large, IgM+IgD+ B cells; however, the other five were ‘IgD+-only’, having deleted Cl. The authors suggest that IgD+-only B cells may arise is specific immune responses.
Identification of TOSO/FAIM3 as an Fc receptor for IgM
By Hideaki Shima, Hiroyuki Takatsu, Shinji Fukuda, Masumi Ohmae, Koji Hase, Hiromi Kubagawa, Ji-Yang Wang, and Hiroshi Ohno
After searching EST (expressed sequence tag) databases, Ohno and colleagues (p.149) identify Fas apoptotic inhibitory molecule 3 (FAIM3 or TOSO) as a possible IgM receptor. In HeLa cells, it binds IgM specifically and internalises IgM-coated beads. FAIM3 is expressed after the pre-B cell stage and is thus a novel B cell receptor specific for opsonic IgM.
IL-6 positively regulates Foxp3+CD8+ T cells in vivo
By Takayuki Nakagawa, Mineko Tsuruoka, Hideki Ogura, Yuko Okuyama, Yasunobu Arima, Toshio Hirano, and Masaaki Murakami
The mechanisms inducing regulatory Forkhead box p3 (Foxp3)+CD8+ cells in vivo are unclear, but IL-6 does affect Foxp3+CD4+ cell induction. Murakami and colleagues (p. 129) show that IL-6 induces Foxp3+CD8+ cells in vitro that suppress autoimmune colitis and arthritis in vivo. In mice with enhanced IL-6 signalling in vivo, spontaneous Th17-cell-mediated arthritis is suppressed by Foxp3+CD8+ cells.
The specialized iNKT cell system recognizes glycolipid antigens and bridges the innate and acquired immune systems with potential applications for cancer therapy
By Masaru Taniguchi, Takuya Tashiro, Nyambayar Dashtsoodol, Naomi Hongo and Hiroshi Watarai
In this review, Taniguchi et al. (p. 1) describe the discovery, ligand recognition and rapid responsiveness of invariant NKT cells (iNKTcells). They detail how cytokine ‘second signals’ determine iNKT-cell-mediated effects: interaction with IL-12-producing cells enhances proinflammatory responses; whereas interaction with IL-10-producing cells promotes regulatory functions. Finally, the authors discuss using iNKT cells as adjuvant therapy for cancer.
Regulatory and pro-inflammatory phenotypes of myelin basic protein-autoreactive T cells in multiple sclerosis
By Jian Hong, Haiyan Li, Meiyue Chen, Ying C. Q. Zang, Sheri M. Skinner, James M. Killian, and Jingwu Z. Zhang
Autoreactive T cells specific for myelin antigens, such as MBP are considered to play an important role in the pathogenesis of multiple sclerosis (MS). This study showed that MBP83–99-specific T cells generated from MS patients (n = 7) contain pro-inflammatory and regulatory subsets of distinct phenotypes. The pro-inflammatory subset produced high amounts of IFN-y, IL-6, IL-21 and IL-17 with low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and showed potent regulatory functions. The regulatory subset of MBP-specific T cells appeared to expand from the CD4+CD25- T-cell pool. Their FOXP3 expression was stable, independent of the activation state, which correlated with suppressive function and inversely with the production of IFN-y, IL-6, IL-21 and IL-17. In contrast, the phenotype and function of FOXP3low MBP-specific T cells were adaptive and dependent on IL-6. Furthermore, FOXP3high MBP-specific T cells increased when IL-6 was neutralized in the culture of PBMC with MBP. These findings described here have therapeutic implications in MS and provide new insights into the understanding of the role of MBP-specific T cells in MS.
Critical role of IFN-y in CFA-mediated protection of NOD mice from diabetes development
By Yoshiko Mori, Tetsuro Kodaka, Takako Kato, Edith M. Kanagawa, and Osami Kanagawa
Complete Freund’s adjuvant (CFA) protects nonobese diabetic (NOD) mice from developing diabetes and prevents them rejecting transplanted pancreatic islets. Kanagawa and colleagues (p. 1291) show that IFN-y is essential for these protective effects and that diabetogenic effector cells appear to be refractory to regulatory T cell (Treg)-mediated inhibition, if IFN-y signalling is absent. The authors then discuss IFN-y’s role in autoimmunity.
Recombinant nucleocapsid-like particles from dengue-2 virus induce protective CD4+ and CD8+ cells against viral encephalitis in mice
By Lázaro Gil, Carlos López, Laura Lazo, Iris Valdés, Ernesto Marcos, Ruby Alonso, Ailyn Gambe, Jorge Martín, Yaremis Romero, María G. Guzmán, Gerardo Guillén, and Lisset Hermida
In this article, Gil et al. (p. 1175) use a particulate form of nucleocapsid-like particles (NLPs) from dengue virus as a subunit vaccine, combined with alum, in mice. Although no neutralising antibodies are produced, CD4+ and CD8+ cell-mediated immunity (CMI) is stimulated and protects mice against otherwise lethal challenge. The authors propose NLPs as a candidate vaccine against dengue fever.
A novel immunoregulatory protein in human colostrum, syntenin-1, for promoting the development of IgA-producing cells from cord blood B cells
By Mostafa M. Sira, Taketoshi Yoshida, Makoto Takeuchi, Yoshinori Kashiwayama, Takeshi Futatani, Hirokazu Kanegane, Akiko Sasahara, Yasunori Ito, Mineyuki Mizuguchi, Tsuneo Imanaka, and Toshio Miyawaki
Using human colostrum to stimulate naıve cord blood B cells and dendritic cells, Yoshida and colleagues (p. 1013) identify syntenin 1 as a potentially important stimulus for preferential induction of IgA production in cord blood B cells. The authors discuss the role of other factors, especially cytokines, in IgA-inducing activity in colostrum.
CCR1 expression and signal transduction by murine BMMC results in secretion of TNF-, TGFβ-1 and IL-6
By Nimita H. Fifadara, Cho Cho Aye, Sandeep K. Raghuwanshi, Ricardo M. Richardson, and Santa Jeremy Ono
Fifadara et al. (p. 991) report the novel finding that BMMCs (bone-marrow-derived mast cells) express CCR1 (C–C motif chemokine receptor 1). The CCR1+ cells express neurokinin receptor 1 and intercellular adhesion molecule 1. Ligand binding, together with crosslinking IgE receptors, enhances degranulation and cytokine release. The authors discuss how mast cells influence the trafficking of immune cells in inflammation.
Gfi1 negatively regulates Th17 differentiation by inhibiting RORv activity
By Kenji Ichiyama, Masayuki Hashimoto, Takashi Sekiya, Ryusuke Nakagawa, Yu Wakabayashi, Yuki Sugiyama, Kyoko Komai, Ingrid Saba, Tarik Möröy, and Akihiko Yoshimura
Yoshimura and colleagues (p. 881) show that growth factor independent 1 transcription repressor (Gfi1) is reduced in Th17 cells (and inducible regulatory T cells) but upregulated in Th1 and Th2 cells. Gfi1 is repressed by transforming growth factor B but enhanced by IFN-y or IL-4. The authors conclude that Gfi1 is a novel negative regulator of Th17 cell differentiation.
Prediction of HLA-DQ8 b cell peptidome using a computational program and its relationship to autoreactive T cells
By Kuan Y. Chang and Emil R. Unanue
To identify B-cell epitopes that bind HLA-DQ8 and affect autoimmune diabetes, Chang and Unanue (p. 705) adapted a computational program that then worked better than the others available. In mice many, but not all, peptides with strong binding-motifs were immunogenic; but some peptides with weak binding-motifs were immunogenic. Predictive programs are thus useful, but have limitations.
T cell sensitivity to TGF-β is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber
By Robert E. Cone, Subhasis Chattopadhyay, Roshanak Sharafieh, Yen Lemire, James O'Rourke, Richard A. Flavell, and Robert B. Clark
Injecting antigen into the anterior chamber of the eye induces splenic CD8+ regulatory T cells (Tregs) that suppress delayed-type hypersensitivity (DTH) responses; similar Tregs are generated after in vitro exposure to transforming growth factor β (TGF-β). In the in vivo system, Cone et al. (p.567) show that TGF-β appears non-essential for Treg induction, but that suppression of DTH does require TGF-β.
GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity
By Aya Yokota, Hajime Takeuchi, Naoko Maeda, Yoshiharu Ohoka, Chieko Kato, Si-Young Song, and Makoto Iwata
Dendritic cell (DC) aldehyde dehydrogenase genes (e.g. Aldh1a2) are needed for retinoic acid production, which has important effects on lymphocyte function. Iwata and colleagues (p.361) identify specific DC subsets expressing Aldh1a2 and show that granulocyte/macrophage colony-stimulating factor (GM-CSF) is crucial for DC retinoic acid production, in synergy with IL-4, Toll-like receptor ligands and retinoic acid itself.
GM-CSF-induced CD11c+CD8a—dendritic cells facilitate Foxp3+ and IL-10+ regulatory T cell expansion resulting in suppression of autoimmune thyroiditis
By Balaji B. Ganesh, Donald M. Cheatem, Jian Rong Sheng, Chenthamarakshan Vasu, and Bellur S. Prabhakar
Prabhakar and colleagues (p. 269) show that GM-CSF (granulocyte/macrophage colony-stimulating factor) is tolerogenic for CD8a– dendritic cells (DCs) but not CD8a+ DCs. In a mouse model of experimental autoimmune thyroiditis, GM-CSF-exposed CD8a– DCs stimulate Foxp3-expressing regulatory T cells and IL-10 production; the DCs appear to remain in a semi-mature state. Importantly, adoptive transfer of these DCs prevents thyroiditis in this model.
Ablation of type I hypersensitivity in experimental allergic conjunctivitis by eotaxin-1/CCR3 blockade
By Dai Miyazaki, Takao Nakamura, Masaharu Ohbayashi, Chuan Hui Kuo, Naoki Komatsu, Keiko Yakura, Takeshi Tominaga, Yoshitsugu Inoue, Hidemitsu Higashi, Meguru Murata, Shuzo Takeda, Atsuki Fukushima, Fu-Tong Liu, Marc E. Rothenberg, and Santa Jeremy Ono
Chemokines affect the late phase of immediate hypersensitivity. Using a mouse model of conjunctival allergic inflammation, Miyazaki et al. (p. 187) show that deficiency in eotaxin 1 or blockade of one of its receptors, CCR3 (C–C chemokine receptor 3) ablates IgE-mediated immediate hypersensitivity. The authors identify mature mast cell degranulation as the critical event affected.
A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation
By Stefen A. Boehme, Karin Franz-Bacon, Edward P. Chen, Roman Sásik, L. James Sprague, Tai Wei Ly, Gary Hardiman, and Kevin B. Bacon
In this article, Boehme et al. (p. 81) examine FITC-induced murine contact sensitivity and undertake gene-expression analysis after treatment with a CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) antagonist. Decreased transcription of a wide range of inflammatory mediators occurred. This correlated with decreased levels of many cytokines and chemokines. The authors conclude that CRTH inhibits multiple pathways.
Tribbles-2 is a novel regulator of inflammatory activation of monocytes
By Katalin Eder, Hongtao Guan, Hye Y. Sung, Jon Ward, Adrienn Angyal, Michelle Janas, Gabriella Sarmay, Erno Duda, Martin Turner, Steven K. Dower, Sheila E. Francis, David C. Crossman1 and Endre Kiss-Toth
The family of tribbles proteins has recently been identified as potent regulators of signal processing in a number of physiological and pathological processes. Here, Tribbles-2 (trb-2) was shown as a novel regulator of inflammatory activation of monocytes. Down-regulation of trb-2 levels potentiated LPS-induced IL-8 production via enhanced activation of the MAP Kinases such as ERK and JNK. In consitent with this, the endogenous level of trb-2 expression in human primary monocytes was inversely correlated to the cell’s ability to produce IL-8. Interestingly, Trb-2 was a binding partner and a negative regulator of selected MAPKs. Further, the kinase-like domain of trb-2 was sufficient for binding to MAPKKs, as well as to exert its bioactivity. Co-stimulation of THP-1 cells as well as human primary monocytes with LPS and modified low-density lipoprotein (LDL) leads to the enhancement of IL-8 production, probably via down-regulation of trb-2. Taken together, in vivo modulation of trb-2 expression may be an important regulatory mechanism in monocyte biology.
Deliberately provoking local inflammation drives tumors to become their own protective vaccine site
By Connie Jackaman, Andrew M. Lew, Yifan Zhan, Jane E. Allan, Biljana Koloska, Peter T. Graham, Bruce W. S. Robinson, and Delia J. Nelson
Here, Nelson and colleagues (p. 1467) use a mouse model of malignant mesothelioma to show that direct injection of IL-2 and anti-CD40 into large tumours eradicates both that tumour and distant ones. Tumour eradication requires collaboration between CD8+ T cells and neutrophils, and long-term memory responses are triggered. The authors discuss using solid tumours as an in situ ‘vaccine site’.
Arthritis and pneumonitis produced by the same T cell clones from mice with spontaneous autoimmune arthritis
By Chiaki Wakasa-Morimoto, Tomoko Toyosaki-Maeda, Takaji Matsutani, Ryu Yoshida, Shino Nakamura-Kikuoka, Miki Maeda-Tanimura, Hiroyuki Yoshitomi, Keiji Hirota, Motomu Hashimoto, Hideyuki Masaki, Yoshiki Fujii, Tsuneaki Sakata, Yuji Tsuruta, Ryuji Suzuki, Noriko Sakaguchi, and Shimon Sakaguchi
Rheumatoid arthritis (RA) is often accompanied by extra-articular manifestations, including interstitial lung disease. Sakaguchi and colleagues (p. 1331) isolated T cell clones from joints of SKG-strain mice (which model RA). The clones initiate arthritis and pneumonitis in nude mice but disease progression appears relatively T-cell-independent. The authors discuss this, and the susceptibility of certain tissues to immunopathology in RA.
IL-17A is produced by Th17, gd T cells and other CD4- lymphocytes during infection with Salmonella enterica serovar Enteritidis and has a mild effect in bacterial clearance
By Silke M. Schulz, Gabriele Köhler, Christoph Holscher, Yoichiro Iwakura and Gottfried Alber
The role of Th17 cells in intracellular bacteria infection remains unclear, especially at late stages. In this study, Alber and colleagues (p. 1129) show that IL-17A–/– mice survive infection with Salmonella Enteritidis but have a larger bacterial burden. Neutrophil and DTH reactions are reduced. IL-17A is produced by cd T cells and other CD4– cells, as well as CD4+ cells.
IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK Cells
By Molly D. Smithgall, Michael R. Comeau, Bo-Rin Park Yoon, Dawn Kaufman, Richard Armitage and Dirk E. Smith
IL-33 has several known effects on mast cells and Th2 responses. To extend this knowledge, Smith and colleagues (p.1019) examine IL-33-mediated cytokine production in basophils, NKT cells, NK cells and antigen-dependent or -independent Th2 cells. The implications for IL-33 in human Th1 and Th2 responses are detailed.
The NF-B, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes
By Xiuju Dai, Koji Sayama, Mikiko Tohyama, Yuji Shirakata, Lujun Yang, Satoshi Hirakawa, Sho Tokumaru, and Koji Hashimoto
The epidermis is important in interactions between viruses and innate immunity, and Sayama and colleagues (p. 901) demonstrated a wide range of cytokines and chemokines produced by keratinocytes in response to double-stranded RNA. The authors then showed that three major signalling pathways are each regulated by a different set of cytokines/chemokines.
IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD
By Alejandro V. Villarino, David Artis, Jelena S. Bezbradica, Omer Miller, Christiaan J. M. Saris, Sebastian Joyce and Christopher A. Hunter
IL-27 is one of the IL-12 family members, which comprises the p28 subunit and Epstein-Barr virus-induced gene 3 (EBI3). The present study demonstrates that IL-27 can promote the onset of colitis in mice. Unlike IL-10-/- mice, IL-10-/-IL-27R-/- mice exhibited prolonged survival associated with a profound defect in IFN-g production and only slight decreases in Th2- and Th17-type cytokines. These mice also became resistant to infection with Trichuris muris, a colon-dwelling nematode that induced severe intestinal pathology in IL-10-/- mice. Again, Th1-type cytokines were dramatically reduced following helminth infection but, in this case, there was evidence that exaggerated Th2 responses may have contributed to the phenotype of the dKO mice. Taken together, these studies demonstrate that IL-27 is an important regulator of intestinal T cell responses and suggest that it promotes the onset of IBD through effects on both Th1 and Th2 responses
Improved methods for detecting selection by mutation analysis of Ig V region sequences
By Uri Hershberg, Mohamed Uduman, Mark J. Shlomchik, and Steven H. Kleinstein
As a tool to examine the in vivo antigen-driven B cell V-gene repertoire, Hershberg et al. (p. 683) present improved statistical methodology that helps to eliminate cross-talk between positive and negative selection and increases the predictive power for detecting immunoglobulin-gene selection by antigen. The model also allows for some intrinsic biases of somatic hypermutation.
Dual role of Cbl links critical events in BCR endocytosis
By Michele Jacob, Leslie Todd, Maame F. Sampson, and Ellen Puré
Cbl promotes B cell receptor endocytosis through ubiquitination and cytoskeletal remodeling
CD4+CD25+ regulatory T cells in the small intestinal lamina propria show CD4+CD25+ an effector/memory phenotype
By Zijin Guo, Myoung Ho Jang, Kazuhiro Otani, Zhongbin Bai, Eiji Umemoto, Masanori Matsumoto, Mika Nishiyama, Mikako Yamasaki, Satoshi Ueha, Kouji Matsushima, Takako Hirata, and Masayuki Miyasaka
CpG oligodeoxynucleotides (CpG-ODN), potent inducers of Th1 responses, are known to improve symptoms of mouse airway hypersensitivity, a model of allergic asthma.
CpG-ODN inhibits airway inflammation at effector phase through down-regulation of antigen-specific Th2-cell migration into lung
By Shigeru Ashino, Daiko Wakita, Yue Zhang, Kenji Chamoto, Hidemitsu Kitamura, and Takashi Nishimura
Ashino et al. shows that CpG-ODN inhibit the effector phase of Th2-cell – dependent airway inflammation by blocking Th2 cell-migration into lung. The inhibition of both airway inflammation and Th2 migration appears to be dependent on production of IFN-a, IFN-b and IL-12 but not IFN-y.
Immunoadjuvant effects of polyadenylic:polyuridylic acids through TLR3 and TLR7
By Takahiro Sugiyama, Katsuaki Hoshino, Masuyoshi Saito, Takahiro Yano, Izumi Sasaki, Chihiro Yamazaki, Shizuo Akira, and Tsuneyasu Kaisho
Nucleic acids can activate innate immunity and function as potent immune adjuvants through pattern recognition receptors such as TLRS or RIG-I.Polyadenylic:polyuridylic acids [poly(A:U)] has been used as immune adjuvant. Authors clearly described in this study that poly(A:U) activates both pDCs and cDCs through TLR7 and TLR3. Authors clearly demonstrate that poly(A:U) functions as in vivo immunoadjuvant for CD8+ T-cell activation mainly through TLR3 and TLR7.
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