Editor's choice: featured articles (free access)
July 2009
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.
June 2009
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.
May 2009
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.
April 2009
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.
March 2009
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.
February 2009
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.
January 2009
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.
December 2008
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.
November 2008
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’.
October 2008
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.
September 2008
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.
August 2008
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.
July 2008
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.
June 2008
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
May 2008
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.
April 2008
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
March 2008
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.
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.
February 2008
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
CpG oligodeoxynucleotides (CpG-ODN), potent inducers of Th1 responses, are known to improve symptoms of mouse airway hypersensitivity, a model of allergic asthma.
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.
January 2008
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.
December 2007
Allergen-induced CD11b+ CD11cint CCR3+ macrophages in the lung promote eosinophilic airway inflammation in a mouse asthma model
By Keun-ai Moon, So Young Kim, Tae-Bum Kim, Eun Suk Yun, Chan-Sun Park, You Sook Cho, Hee-Bom Moon, and Ki-Young Lee
Macrophages are recruited to the lung in the airway inflammation but their function in ongoing Th2 cell-mediated eosinophilic airway inflammation remains controversial. The authors have demonstrated that the allergen-induced CD11b+ CD11cint macrophage expressing CCR3 in the lung plays a crucial role in the induction of eosinophilic asthma in a murine model.
In the lungs of normal mice, residential cells evidencing high granularity phenotypically evidenced CD11bint CD11c+ or CD11b+ CD11cint cells, appearing at a 2:1 ratio. Allergen challenge reversed the ratio of one to six. Approximately 91% of increased CD11b+ CD11cint cells expressed the CCR3 eotaxin receptor, but not other chemokine receptors, such as CCR5 and CXCR4. Interestingly, the CD11b+ CD11cint cells purified from the lungs of OVA (ovalbumin)-sensitized and challenged mice showed higher antigenpresenting activity than was observed in CD11bint CD11c+ cells. To examine the in vivo function of CD11b+ CD11cint cells, the cells were isolated from the lungs of OVA-sensitized and challenged mice and then adoptively transferred prior to the allergen challenge of normal mice. In the CD11b+ CD11cint-transferred mice airway hyperresponsiveness, eosinophilic inflammation in the lung and Th2 cytokine secretion in the bronchoalveolar lavage fluids were significantly enhanced as the result of OVA challenge, as compared with the mice that received OVA-primed CD901 T cells or CD11bint CD11c+ cells. Thus, CD11b+ CD11cint macrophages expressing CCR3 as key pro-inflammatory cells play a crucial role not only in the stimulation of allergen-specific T cells but also in the promotion of eosinophilic airway inflammation.
November 2007
Tetramer-guided epitope mapping reveals broad, individualized repertoires of tetanus toxin-specific CD4+ T cells and suggests HLA-based differences in epitope recognition
By Eddie A. James, John Bui, DeAnna Berger, Laurie Huston, Michelle Roti, and William W. Kwok
In developed countries, most healthy people, who have been vaccinated with tetanus toxoid (TT), exhibit both humoral and cellular TT immune responses. By extensive epitope mapping using class II tetramer staining, James et al. reveal that the majority of the identified epitopes is shared by one or two alleles, which contrasts with the perceived notion that TT responses are dominated by universal T cell epitopes.
October 2007
Forced expression of Id2 in fetal thymic T cell progenitors allows some of their progeny to adopt NK cell fate
By Shinji Fujimoto, Tomokatsu Ikawa, Tatsuo Kina and Yoshifumi Yokota
While the E proteins are indispensable for early T cell development, their inhibitor Id2 is essential for NK lineage commitment from bipotent progenitors generating both T and NK cells (p-T/NK). To examine the role of E proteins and Id2 in the development of early intrathymic progenitors, individual fetal thymic CD42CD82CD441CD252CD1222 (DN1CD1222) cells were retrovirally transduced with an Id2-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) (Id2-GFP) gene or a control IRES-GFP (GFP) gene, and cultured in a modified fetal thymus organ culture able to support T and NK cell development. After the culture, both T and NK cells, T cells and no NK cells, NK cells and no T cells, or completely no cells were generated from single cells in each lobe. Hence, the seeded cells were regarded as p-T/NK, unipotent progenitors generating T cells (p-T), unipotent NK progenitors, or cells without progenitor activity, respectively. With Id2-GFP transduction, p-T disappeared and more p-T/NK emerged than with GFP transduction. This increase corresponded to the number of p-T that was counted when the vector-transduced-DN1CD1222 cells of the same number were examined. Additionally, a fraction of GFP2 NK cells obtained after Id2-GFP transduction underwent TCRb D–J rearrangement. Thus, the authors clearly showed that inhibiting the function of E proteins in p-T allows some of their progeny to adopt an NK cell fate.
September 2007
Plasmacytoid dendritic cells employ multiple cell adhesion molecules sequentially to interact with high endothelial venule cells – molecular basis of their trafficking to lymph nodes
By Takahiro Matsutani, Toshiyuki Tanaka, Kazuo Tohya, Kazuhiro Otani, Myoung Ho Jang, Eiji Umemoto, Kanako Taniguchi, Haruko Hayasaka, Koichi Ueda, and Masayuki Miyasaka
Authors investigated direct interactions between plasmacytoid dendritic cells (pDC) and high endothelial venules (HEVs) using puuried pDCs and HEV endothelial cell lines. They clearly demonstrate that pDCs have the full capacity to adhere to and transmigrate beneath HEV endothelial cells and that pDCs interact with HEVs through a precise order of events using specific pairs of multiple adhesion molecules. Their assay system may provide a useful new tool for studing the entire process of pDC transmigration more in detail.
August 2007
Ifi202, an IFN-inducible candidate gene for lupus susceptibility in NZB/W F1 mice, is a positive regulator for NF-B activation in dendritic cells
By Moriyasu Yamauchi, Masayuki Hashimoto, Kenji Ichiyama, Ryoko Yoshida, Toshikatsu Hanada, Tatsushi Muta, Shizuo Komune, Takashi Kobayashi, and Akihiko Yoshimura
An IFN-inducible gene, Ifi202, is one of major susceptibility genes for murine lupus. Yamauchi et al. demonstrate that Ifi202 positively regulates the expression of the IkB-z And IL-12p40 genes, suggesting that Ifi202 may be responsible for a Th1-prone phenotype of the (NZBxNZW) F1 mouse.
July 2007
Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function
By Seigo Terawaki, Yoshimasa Tanaka, Tomokazu Nagakura, Tamon Hayashi, Shiro Shibayama, Kaori Muroi, Taku Okazaki, Bunzo Mikami, David N. Garboczi, Tasuku Honjo, and Nagahiro Minato
The negative co-stimulatory receptor, programmed cell death 1 (PD-1), is induced on activated T cells and delivers inhibitory signals upon engagement with its ligands PD-L1 and PD-L2, which are expressed on various somatic cells and certain cancers. In the present study, the authors established strategies to prepare soluble recombinant extracellular domains of PD-1 and of PD-L1 capable of binding to PD-L1 and PD-1, respectively. Tetramerized PD-1 or PD-L1 bound to ligand or receptor with higher affinity than do monomers and provide evidence that the mouse PD-L1 (mPD-L1) tetramer may antagonize the negative signal mediated by PD-1 to enhance T cell functions. These results suggested that oligomeric PD-L1 extracellular domains may provide a potential means to restore T cell functions in cancer and viral infection in humans.
June 2007
IL-6–gp130–STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state
By Mika Nishihara, Hideki Ogura, Naoko Ueda, Mineko Tsuruoka, Chika Kitabayashi, Fumio Tsuji, Hiroyuki Aono, Katsuhiko Ishihara, Eric Huseby, Ulrich A. K. Betz, Masaaki Murakami and Toshio Hirano
L-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are thought to be major contributors to autoimmune diseases. IL-6 and transforming growth factor
May 2007
Preferential recognition of a microbial metabolite by human Vg2Vd2 T cells
By Kia-Joo Puan, Chenggang Jin, Hong Wang, Ghanashyam Sarikonda, Amy M. Raker, Hoi K. Lee, Megan I. Samuelson, Elisabeth Märker-Hermann, Ljiljana Pasa-Tolic, Edward Nieves, José-Luis Giner, Tomohisa Kuzuyama, and Craig T. Morita
T cells expressing gd TCR heterodimers recognize non-peptide bacterial antigens and play important roles in immunity against microbial pathogens. Puan et al. report that human Vg2Vd2 T cells recognize (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), a microbial metabolite that is produced by many bacteria including Mycobacterium tuberculosis, Yersinia enterocolitica and Escherichia coli.
April 2007
The proto-oncogene Bcl-6 is essential not only for generation of high-affinity memory B cells but also for generation and maintenance of memory CD8+ T cells.
By Hirohito Ichii, Akemi Sakamoto, Masafumi Arima, Masahiko Hatano, Yoshikazu Kuroda, and Takeshi Tokuhisa
Ichii et al. report that Bcl-6 is also necessary for maintenance of long-term memory CD4+ T cells.
March 2007
AsialoGM1+CD8+ central memory-type T cells in unimmunized mice as novel immunomodulator of IFN-[gamma]-dependent type 1 immunity
By Akemi Kosaka, Daiko Wakita, Naoki Matsubara, Yuji Togashi, Shin-Ichiro Nishimura, Hidemitsu Kitamura and Takashi Nishimura
There are unique memory-type CD8+ T cell populations expressing asialoGM1 (ASGM1) in unimmunized specific pathogen-free mice. ASGM1+CD8+T cells were central memory-type CD8+ T cells (TCMT) expressing CD44, IL-2Rb, CD62L and CCR7 cell-surface markers and exhibited the highest responsiveness to immobilized anti-CD3 mAb stimulation among CD44+CD8+memory T cell population. ASGM1+CD8+ TCMT as well as NKT and NK cells were early IFN-gamma] source in anti-CD3 mAb administered mice and accelerated the generation of IFN-gamma]-producing Th1 from naive CD4+ T cells. Th1-prone C57BL/6 mice possessed higher frequency of IFN-gamma]-producing ASGM1+CD8+ TCMT compared with Th2-prone BALB/c mice. Thus, ASGM1+CD8+ TCMT appear to play a critical role in the control of type 1 immunity, which is essential for therapy of tumors and infectious diseases.
February 2007
TGF-[beta] type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody
By Michitomo Sakuma, Kyosuke Hatsushika, Kensuke Koyama, Ryohei Katoh, Takashi Ando, Yoshiyuki Watanabe, Masanori Wako, Mirei Kanzaki, Shinichi Takano, Hajime Sugiyama, Yoshiki Hamada, Hideoki Ogawa, Ko Okumura and Atsuhito Nakao
TGF-[beta] is a multifunctional cytokine. It is still controversial how TGF-[beta] is involved in inflammatory diseases such as rheumatoid arthritis (RA). Sakuma et al. report that TGF-[beta] induces proliferation and production of IL-6 and VEGF in RA synovial fibroblasts. Furthermore, the TGF-[beta] type I receptor kinase inhibitor not only suppresses the effects of TGF-[beta] on RA synovial fibroblasts but also prevents anti-collagen antibody-induced arthritis.
January 2007
IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells
By Ulla-Angela Temann, Yasmina Laouar, Elizabeth E. Eynon, Robert Homer and Richard A. Flavell
Constitutive expression of IL9 in the lungs of transgenic (Tg) mice resulted in an asthma-like phenotype consisting of lymphocytic and eosinophilic lung inflammation, mucus hypersecretion and mast cell hyperplasia. Several Th2 cytokines including IL4, IL5 and IL13 were expressed in the lung in response to Tg IL9. IL13 was absolutely necessary for the development of lung pathology. To investigate how IL9 induces pathology resulting from Th2 cytokine expression, the authors tried to identify potential target cells for the action of IL9. Surprisingly, the elimination of T cells did not abolish lung pathology in IL9 Tg mice. Airway epithelial cells were the major producers of IL13 in response to the IL9 transgene expression in the lung, in the absence of inflammatory cells such as T cells and eosinophils. Thus, airway epithelial cells might represent a potential target cell for IL9 in the lung and an important source of pathologic cytokines in asthma.
December 2006
Diversity in lectins enables immune recognition and differentiation of wide spectrum of pathogens
By Yong Zhu, Patricia M. L. Ng, Lihui Wang, Bow Ho and Jeak Ling Ding
Carbohydrate-binding lectins play essential roles as pattern recognition receptors in innate immunity. The carcinolectins 5 (CL5a and CL5b, the CL5 isoforms of horseshoe crab, Carcinoscopius rotundicauda) are prominent plasma lectins that bind all representative microbes and pathogen-associated molecular pattern molecules. Authors isolated different cDNA isoforms of both CL5a and CL5b, characterized their binding to microbial cell surfaces, and found that the resolution patterns of the isoforms that associate with fungus differ from those that associate with bacteria, suggesting the unique roles these lectins play in the recognition and differentiation of microbes.
November 2006
An MHC-liked locus modulate thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes
By Julie Tellier, Joost P. M. van Meerwijk and Paola Romagnoli
CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a crucial role in immunological tolerance. Tellier et al. report that different levels of Tregs are found in the thymi of distinct laboratory mouse strains. Interestingly, one of the genetic loci responsible for the modulation of thymic Treg development is mapped to the region close to the MHC.
October 2006
IL-4R signaling is required to induce IL-10 for the establishment of Th2 dominance
By Adam Balic, Yvonne M. Harcus, Matthew D. Taylor, Frank Brombacher and Rick M. Maizels
The requirement of IL-4 for differentiation of naive CD4+ T cells into Th2 effector cell populations has been extensively reported in various in vitro studies. However, a recent study indicated that signaling through the IL-4R is not essential for acquisition of the Th2 phenotype. Here, the authors showed that the initial development of IL-4-producing T cells is independent of IL-4R signaling but that the subsequent expansion of IL-4-producing CD4+ T cells is positively influenced by IL-4R signaling in the Nippostrongylus brasiliensis infection. IL-10 production by CD4+ T cells was dependent on intact IL-4R signaling, and that this in turn is responsible for the maintenance of a dominant Th2 population in the face of an emerging Th1-type response. The authors concluded that Th2 cell development in response to N. brasiliensis antigen requires both IL-4 and IL-10 to act in concert on incipient populations of both Th1 and Th2 types.
September 2006
CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8+ T cells in a manner dependent on IL-4
Naoko Ueda, Hiroko Kuki, Daisuke Kamimura, Shinichiro Sawa, Kenichiro Seino, Takuya Tashiro, Ken-ichi Fushuku, Masaru Taniguchi, Toshio Hirano and Masaaki Murakami
Authors investigated a role of NKT cells and cytokines for homeostatic proliferation of CD8+ T cells. They clearly show that activated NKT cells by {alpha}-GalCer enhance homeostatic proliferation of CD8+ T but not CD4+ T cells in an IL-4 dependent manner. They also demonstrate that IL-4, produced by NKT cells, directly acts on CD8+ T cells through IL-4R{alpha}/STAT6 signaling to lead their homeostatic proliferation.
August 2006
Human germinal center T cells are unique Th cells with high propensity for apoptosis induction
By Ekaterina Marinova, Shuhua Han and Biao Zheng
Although it is well established that germinal center (GC) reaction is a T cell-dependent process, little is known about T helper cells in GC. Marinova et al. demonstrate that a significant number of T cells residing in GC are undergoing apoptosis in vivo. These GC T cells are more sensitive to various apoptotic signals than naïve or memory/effector T cells, which is also supported by their unique expression profile of genes that control apoptosis and cell cycle.
July 2006
JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells
By Eggi Arguni, Masafumi Arima, Nobuhide Tsuruoka, Akemi Sakamoto, Masahiko Hatano and Takeshi Tokuhisa
Bcl6 is a transcriptional repressor, which is ubiquitously expressed and predominantly in germinal center (GC) B cells. Although the promoter region of the human Bcl6 gene has been reported, enhancer molecules for its high expression in GC B cells were largely unknown. Here, the authors identified the transcriptional start sites, the enhancer and silencer elements in the promoter region of the mBcl6 gene. The new promoter region is highly conserved between mice and humans. JunD/AP-1 and STATs, especially STAT3, are crucial molecules to induce high Bcl6 expression in GC B cells. Since IL-21 stimulation induces high Bcl6 expression in splenic B cells with induction of JunD/AP-1 and activation of STAT3, IL-21 may be a crucial inducer for high Bcl6 expression in GC B cells.
June 2006
Contribution of IL-18-induced innate T cell activation to airway inflammation with mucus hypersecretion and airway hyperresponsiveness
By Yuriko Ishikawa, Tomohiro Yoshimoto and Kenji Nakanishi
Human bronchial asthma is characterized by airway hyperresponsiveness (AHR), eosinophilic airway inflammation, mucus hypersecretion and high serum level of IgE. Although IL-18 was originally regarded to induce Th1-related cytokines from Th1 cells in the presence of IL-12, the authors previously demonstrated that IL-18 is closely related with the induction of Th2 responses. Here, the authors examined the capacity of IL-2 and IL-18 to induce AHR, airway eosinophilic inflammation and goblet cell metaplasia. CD4+ T cells were prerequisite for this IL-2 plus IL-18-induced CD4+ bronchial asthma. The authors also demonstrated that IL-13 but not IL-4 is produced abundantly and plays a critical role in the pathogenesis of bronchial asthma in this model. All these data suggested the biological relevance of IL-18 in antigen-independent bronchial asthma following viral or bacterial airway infection.
May 2006
Essential role for cholesterol in the delivery of exogenous antigens to the MHC class I-presentation pathway
By Imke Albrecht, John Gatfield, Thierry Mini, Paul Jeno and Jean Pieters
Cross-presentation is crucial for the establishment of immunity against virus infected and tumor cells. Albrecht et al. demonstrate that cholesterol is essential for cross- presentation of antigens loaded via macropinocytosis in antigen-presenting cells. Furthermore, palmitoylation of antigens, which targets antigens to cholesterol-enriched plasma membrane domains, results in a significant enhancement of T cell activation, suggesting that such modification of antigens to increase their affinity to cholesterol may be useful to enhance immunity.
April 2006
Recovery from experimental allergic encephalomyelitis is TGF-{beta} dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells
By Xingmin Zhang, Jayagopala Reddy, Hirofumi Ochi, Dan Frenkel1, Vijay K.
Kuchroo and Howard L. Weiner
SJL mice are highly susceptible to proteolipid protein (PLP) 139-151-induced experimental allergic encephalomyelitis (EAE). Authors found that FoxP3-expressing CD4+CD25+ T cells were increased in the blood, draining lymph node and spleen of EAE-recovered SJL mice. In addition, transforming growth factor-{beta} (TGF-{beta}) was shown to be involved in the recovery from EAE.
Their results demonstrate that both CD4+CD25+ and CD4+LAP+ regulatory T cells mediate recovery from PLP 139-151-induced EAE in SJL mice in which TGF-{beta} plays an important role.
March 2006
The Proliferative response of CD4 T cells to steady-state CD8+ dendritic cells is restricted by post-activation death
By Alexandra Rizzitelli, Edwin Hawkins, Hilary Todd, Philip D. Hodgkin and Ken Shortman
Despite many similarities in surface levels of MHC class II and co-stimulatory molecules, CD8+ subsets of dendritic cells (DCs) from steady state mice are less effective than CD8- DC subsets in their capacity to stimulate CD4 T cell proliferation in culture. By focusing on the fate of the responding T cells in an antigen-specific TCR-transgenic T cell system, the authors showed an insight into the basis of the difference between CD8+ and CD8- DCs. They show that differences in the CD4 T cell response are only apparent after cell division commences, and an increased rate of T cell death during each division cycle is an important factor limiting the response to CD8+ DCs.
February 2006
Transfer of regulatory T cells generated ex vivo modifies graft rejection of through induction of tolerogenic CD4+CD25+ cells in the recipient
By Song Guo Zheng, Lingzhong Meng, Ju Hua Wang, Meguru Watanabe, Mark L. Barr, Donald V. Cramer, J. Dixon Gray, and David A. Horwitz
CD4+CD25+ regulatory T cells play a critical role in maintenance of self-tolerance and immune homeostasis but also have therapeutic potential in organ transplantation and various autoimmune diseases. Zeng et al. show that the transfer of regulatory T cells, which are induced ex vivo by alloantigens and TGF-, with transplantation of a histo-incompatible heart results in prolongation of allograft survival. Interestingly, This effect appears to be secondary to the ability of the transferred regulatory cells to educate donor CD4+ cells to become CD25+ cells.
January 2006
TRAF1 regulates Th2 differentiation, allergic inflammation and nuclear localization of the Th2 transcription factor, NIP45
By Paul J. Bryce, Michiko K. Oyoshi, Seiji Kawamoto, Hans C. Oettgen, and Erdyni N. Tsitsikov
Tumor necrosis factor-associated factor 1 (TRAF1) regulates TNF-induced NF-B and AP-1 signaling as well as TCR-triggered responses in T cells. Using TRAF1-deficient mice, authors clearly demonstrated that TRAF1 regulates Th2 differentiation, allergic inflammation and nuclear localization of the Th2 transcription factor, NIP45. The results suggest that TRAF1 may limit the induction of Th2 responses by decreasing NIP45 concentration to the nucleus.
December 2005
CpG oligodeoxynucleotides induce IL-8 expression in CD34+ cells via mitogen-activated protein kinase-dependent and NF-{kappa}B-independent pathway
By Jung Mogg Kim, Nam In Kim, Yu-Kyoung Oh, Young-Jeon Kim, Jeehee Youn, and Myung-Ju Ahn
Primitive hematopoiesis stem cells express CD34 in their surfaces. The authors previously demonstrated that E. coli provokes the expression of several proinflammatory cytokines in CD34+ cells. Here they show that CD34+ cells constitutively expressed TLR9 and induced IL-8 in response to CpG ODN via MAPK-dependnet and NF-B independet pathway. The fact that expression plasmid has a direct CpG-mediated biological effect on CD34+ cells raises not only a safety concern, but also suggests caution in interpreting experimental data. Furthermore, attention should be paid to distinguish the therapeutic gene-mediated biological effect from the CpG-mediated non-specific effect.
November 2005
Regulation of the type I IFN induction: a current view
By Kenya Honda, Hideyuki Yanai, Akinori Takaoka and Tadatsugu Taniguchi
Type I interferons play critical roles not only in anti-viral innate responses, but also in regulation of adaptive immune responses. Professor Tadatsugu Taniguchi and his colleagues overview and discuss recent advances in the research field of regulation of interferon responses, particularly the regulatory mechanisms of type I interferon gene induction by toll-like receptors and viruses.
October 2005
Requirement for CD100–CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment
By Atsushi Kumanogoh, Takashi Shikina, Chie Watanabe, Noriko Takegahara, Kazuhiro Suzuki, Midori Yamamoto, Hyota Takamatsu, Durbaka V. R. Prasad, Masayuki Mizui, Toshihiko Toyohuku, Manabu Tamura, Dai Watanabe, Jane R. Parnes and Hiroshi Kikutani
The authors previously reported that the transmembarane semaphorin CD100/Sema4D, a natural ligand for CD72, enhances B-cell responses by blocking negative signals of CD72. Here, they showed how and to what extent the CD100-CD72 interaction regulates BCR signals and B-cell homeostasis. CD100 regulates the sensitivity of the BCR by preventing the association of the CD72 with BCR and this interaction is required for proper B-cell homeostasis. As a result, CD100-deficient mice developed autoimmunity with age. These results demonstrated that CD100-CD72 interaction fine-tunes the strength of B-cell signals and maintains immunological homeostasis.
September 2005
Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease
By D. Wang, S.A. John, J.L. Clements, D.H. Percy, K.P. Barton, and L.A. Garrett-Sinha
Dr. Wang et al. demonstrated that mice expressing low level of Ets-1 protein possess few marginal zone B cells and have increased expression of activation markers on follicular B cells, Cell transfer experiments revealed that Ets-1 deficiency leads to altered B cell differentiation, increased responsiveness to a TLR ligand and autoimmune disease.
August 2005
Asthmatic changes in mice lacking T-bet are mediated by IL-13
By Susetta Finotto, Michael Hausding, Aysefa Doganci, Hans A. Lehr, Cornelia Luft, Peter R. Galle and Laurie H. Glimcher
The authors previously identified T-bet as a Th1-specific transcription factor, and showed that mice lacking T-bet gene have profound defects in Th1 development and exhibit spontaneous airway hyperresponsiveness. Here they investigated mechanisms of this chronic airway remodeling. They demonstrate that blockade of IL-13, but not IL-4, resulted in amelioration of the diseases and decreased vimentin, TGF-b and aSMA levels. TGF-b is also partly involved in the chronic airway remodeling. These results demonstrate that IL-13 derived from hyperactivated memory T cells controls asthmatic phenotype observed in T-bet deficiency.
June 2005
Co-infection with Trypanosoma brucei brucei prevents experimental autoimmune encephalomyelitis in DBA/1 mice through induction of suppressor APCs
M. Wallberg and R. A. Harris
Authors investigated how infection with protozoan parasite Trypanosoma brucei brucei (Tbb) modulates the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in DBA/1 mice. They clearly demonstrated that mice harbouring a Tbb infection do not develop experimental autoimmune encephalomyelitis induced by MOG. They also presented data that APCs from spleen of Tbb-infected mice show the impaired MOG presentation to MOG-specific T cells. This suppressive effect is partly due to increased release of IL-10. These findings indicate that infection can prevent autoimmunity through induction of suppressor APCs.
May 2005
Critical contribution of CD80 and CD86 to induction of anterior chamber-associated immune deviation
Rintaro Tsukahara, Masaru Takeuchi, Hisaya Akiba, Takeshi Kezuka, Kazuyoshi Takeda, Yoshihiko Usui, Masahiko Usui, Hideo Yagita, and Ko Okumura
Intraocular inoculation of antigens elicits a uniquely deviated systemic immune response, termed anterior chamber-associated immune deviation (ACAID), which is characterized by the suppression of inflammatory Th1 responses. Tsukahara et al. showed that blockade of CD80 and CD86 at intraocular antigen inoculation inhibits the induction of regulatory cells and the development of ACAID. This reveals an immunoregulatory function of CD88 and CD86 in ocular immune privilege.
April 2005
CD25 CD4 regulatory T cells exert in vitro suppressive activity independent of CTLA-4
Hiroshi Kataoka, Shigekazu Takahashi, Kan Takase, Sho Yamasaki, Tadashi Yokosuka,Takao Koike and Takashi Saito
Although the constitutive expression of CTLA-4 is one of characteristics for naturally arising CD25+CD4+ regulatory T cells, a role of CTLA-4 in regulatory T cells is still controversial. Kataoka et al. demonstrate that CTLA-4 is not necessary for CD25+CD4+ regulatory T cells to exert a suppressive activity in vitro.
March 2005
Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development Meredith O'Keeffe, Thomas C. Brodnicki, Ben Fancke, David Vremec, Grant Morahan, Eugene Maraskovsky, Raymond Steptoe, Leonard C. Harrison, and Ken Shortman
February 2005
PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor ccells by enhanced recruitment of effector T cells
Yoshiko Iwai, Seigo Terawaki and Tasuku Honjo
Iwai et al. demonstrate that PD-1 blocake by genetic manipulation or antibody treatment inhibited hematogenous dissemination of poorly immunogenic tumor cells. This involves augmented homing of effector T cells to the tumor sites. This finding suggests that PD-1 blockade immunotherapy may be a powerful tool for treatment of hematogenous spread of various tumor cells.
January 2005
Toll-like receptors in innate immunity
Kiyoshi Takeda and Shizuo Akira
Professor Shizuo Akira of Osaka University, the front runner in TLR research and Associate Editor of International Immunology, overviews the recent development of this exciting field. This is an essential reference article for any immunologist/microbiologist/oncologist interested in the role of TLR in health and disease.
December 2004
The role of antigenic peptide in CD4+ T helper phenotype development in a T cell receptor transgenic model
Toshiki Tamura, Haruyuki Ariga, Tatsuo Kinashi, Shuichiro Uehara, Takeshi Kikuchi, Makiyo Nakada, Takeshi Tokunaga, Wen Xu, Ai Kariyone, Takashi Saito, Toshio Kitamura, Gavin Maxwell, Satoshi Takaki and Kiyoshi Takatsu
Strength of interaction mediated through TCR and MHC/peptide complex is suspected to affect the lineage commitment of naive Th cells to Th1 cells; however, it remains unclear whether Th1 can develop from naive CD4+ T cells upon antigenic peptide stimulation in the presence of APC under neutral
conditions. The authors generated TCR transgenic mice (P25 TCR-Tg) expressing TCR alpha- and beta-chains specific for Peptide-25:I-Ab complex and analyzed the role of TCR signals in Th1 development. They clearly demonstrated that naive CD4+ T cells from P25 TCR-Tg preferentially develop Th1 cells upon Peptide-25 stimulation in the presence of I-Ab splenic antigen-presenting cells under neutral conditions. In contrast, a mutant of Peptide-25 can induce solely Th2 differentiation. Intriguingly, Peptide-25-loaded I-Ab-transfected Chinese hamster ovary cells induce Th1 differentiation of naive CD4+ T cells from P25 TCR-Tg in the absence of IFN-gamma or IL-12. The authors propose that interaction between Peptide-25/I-Ab and TCR may primarily influence determination of the fate of naive CD4+ T cells in differentiation towards Th1 subset in the absence of IL-12, IFN-gamma and co-stimulatory signals.
November 2004
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
Haruhiko Yagi, Takashi Nomura, Kyoko Nakamura, Sayuri Yamazaki, Toshio Kitawaki, Shohei Hori, Michiyuki Maeda, Masafumi Onodera, Takashi Uchiyama, Shingo Fujii and Shimon Sakaguchi
Shimon Sakaguchi's group showed that FOXP3 is a master regulatory gene for development and function of CD25+CD4+ regulatory T cells in humans. The role of FOXP3 has been established, but the role in humans was not confirmed so far. The FOXP3 gene and its protein were preferentially expressed in human CD25+CD4+ regulatory T cells. Ex vivo retroviral gene transfer of FOX3 converted peripheral naive CD4+ T cells into a regulatory T cell phenotype. This finding demonstrates that FOXP3 induction alone is sufficient to induce a regulatory phenotype in naive human T cells.
October 2004
Marginal zone B cells transport and deposit IgM-containing immune complexes onto follicular dendritic cells
Andrew R. Ferguson, Michele E. Youd and Ronald B. Corley
Ferguson et al. identify a novel role of marginal zone (MZ) B cells in T-dependent humoral immune responses. They demonstrate that IgM-immune complexes (IgM-IC) bind to MZ B cells in a complement and complement receptor dependent process. MZ B cells then transport the IgM-IC into the follicle for deposition onto follicular dendritic cells. This MZ B cell mediated transport and deposition of IgM-immune complex onto FDC may be an important first step in initiating adaptive immune responses.
September 2004
Differential B cell expression of mouse Fc receptor homologs
Randall S. Davis, Robert P. Stephan, Ching-Cheng Chen, Glynn Dennis Jr and Max D. Cooper
A family of human Fc receptor homologs (FcRH1-5) that possess immunoreceptor tyrosine-based activation motifs (ITAM), inhibition motifs (ITIM), or both, are differentially expressed during B cell differentiation in humans. In this study authors identified mouse orthologs (moFcRH1-3) of FcRH1-5 and described their chromosomal localization, genomic configuration, sequence and cellular expression patterns. They suggest that members of the phylogenetically conserved FcRH family have an important immunoregulatory role in marginal zone B cells.
August 2004
Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger
Xuemei Zhong, Chunyan Bai, Wenda Gao, Terry B. Strom and Thomas L. Rothstein
PD-1 is thought to negatively influence lymphocyte activation. PD-1 expression on naive B cells is low, but increased following activation. Anti-IgM-induced PD-1 expression on B cells is diminished by treatment with LPS, CpG and cytokines such as IL-4, IL-12, IL-18, and IFN-gamma, and accompanied by loss of PD1 ligand-induced inhibition of B cell receptor-stimulated proliferation. This finding indicates that danger signal-triggered reduction of PD-1 expression may be associated with enhanced B cells responses seen in normal and aberrant immune responses.
July 2004
Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules
Hiroyuki Yoneyama, Kenjiro Matsuno, Yanyun Zhang, Tetsu Nishiwaki, Masahiro Kitabatake, Satoshi Ueha, Shosaku Narumi, Shunichi Morikawa, Taichi Ezaki, Bao Lu, Craig Gerard, Sho Ishikawa and Kouji Matsushima
Dendritic cells (DC) are known to enter lymph nodes through afferent lymphatics. Yoneyama et al. show that plasmacytoid DC precursors can transmigrate across high endothelial venules to enter inflamed lymph nodes, demonstrating a novel pathway of DC trafficking.
June 2004
Unexpected role of TNF-alpha in graft versus host reaction (GVHR): donor-derived TNF-alpha suppresses GVHR via inhibition of IFN-gamma-dependent donor type-1 immunity
Satoshi Yamamoto, Takemasa Tsuji, Junko Matsuzaki, Yue Zhange, Kenji Chamoto, Akemi Kosaka, Yuji Togashi, Kenji Sekikawa, Ken-ichi Sawada, Tsuguhide Takeshima, Takao Koike and Takashi Nishimura
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, leading to significant morbidity and mortality. It has been shown that TNF-alpha plays a role in the induction of allo-reactive donor T cell activation and the pathogenesis of GVHD; however, the precise role of donor-derived TNF-alpha in GVHD remains unclear. Authors demonstrate, for the first time, that donor-derived TNF-alpha suppresses GVHR by inhibiting IFN-gamma-dependent donor type-1 immunity which is
essential for host TNF-alpha elevation.
May 2004
Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist
Ken-ichiro Seino, Toshihiko Yamauchi, Kohdoh Shikata, Seiichi Kobayashi, Mitsuo Nagai, Masaru Taniguchi and Katashi Fukao
It remains difficult to regulate rejective responses in organ transplantation. Seino et al. have evaluated the effects of a novel retinoic acid receptor (RAR) agonist, ER-38925. The reagent prevented acute rejection of the cardiac allograft by inhibiting cytotoxic T cell function. Furthermore, it could also improve arteriosclerosis status in the chronic rejection model. This study has clarified that RAR agonists are useful immunosuppressive reagents in organ transplantation.
April 2004
Immune modulation with high dose of heat shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis
Rajiv Y. Chandawarkar, Mihir S. Wagh, Joseph T. Kovalchin and Pramod Srivastava
Immunization with heat shock protein gp96 elicits protective immunity to the cancer or virus-infected cells from which it is derived. Chandawarkar et al. demonstrate that immunization with high doses of gp96 prevents experimental autoimmune encephalomyelitis in SJL mice and diabetes in NOD mice. This suppression can be transferred with CD4+ T cells.
March 2004
The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis
Katsuhiko Ishihara, Shin-ichiro Sawa, Hideto Ikushima, Seiichi Hirota, Toru Astumi, Daisuke Kamimura, Sung-Joo Park, Masaaki Murakami, Yukihiko Kitamura, Yoichiro Iwakura and Toshio Hirano
The authors generated a double-mutant mouse by crossing two murine models of rheumatoid arthritis (RA), a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg) in a C57BL/6 background and demonstrated that the mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and a much higher incidence than the pX-Tg mice. They clearly show that the arthritis in the gp130F759/F759/pX-Tg mice is IL-6 dependent and a unique mouse model for RA.
February 2004
Roles of caspase-1 in Listeria infection in mice
Noriko M. Tsuji, Hiroko Tsutsui, Ekihiro Seki, Keisuke Kuida, Haruki Okamura, Kenji Nakanishi and Richard A. Flavell
It remains largely unknown how the host copes with infection of an intracellular parasitic bacteria. Tsuji et al. have analyzed the mutant mice lacking caspase-1, which is a critical enzyme for generating the active form of IL-1 and IL-18. The findings clearly demonstrate that IL-18, not IL-12, is critical for IFN-gamma production and pathogen clearance during the innate phase of infection.
January 2004
Regulation of chronic colitis in athymic nu/nu (nude) mice
F. Stephen Laroux, Hillary H. Norris, Jeff Houghton, Kevin P. Pavlick, Sulaiman Bharwani, Dana M. Merrill, John Fuseler, Robert Chervenak and Matthew B. Grisham
It is well known that transfer of CD4+CD45RBhigh T-cells can induce chronic colitis in scid or RAG-deficient mice lacking lymphocytes. By transfer of CD4+CD45RBhigh T-cells into BALB/c nude mice reconstituted with bone marrow derived from different immunodeficient mice, Laroux et al. demonstrate that intraepithelial lymphocytes play an important role in suppressing the development of chronic colitis.
December 2003
Impaired signaling via the high affinity IgE receptor in Wiskott-Aldrich Syndrome protein deficient mast cells
Vadim I. Pivniouk, Scott B. Snapper, Alexander Kettner, Harri Alenius, Dhafer Laouini, Hervé Falet, John Hartwig, Frederick W. Alt and Raif S. Geha
Wiskott-Aldrich Syndrome protein (WASP) is the product of the gene deficient in boys with X-linked Wiskott-Aldrich Syndrome. Authors assessed the role of WASP in signaling through the high affinity IgE receptor (FceRI) using WASP deficient mast cells, and report important findings that WASP regulates FceRI-mediated granule exocytosis, cytokine production and cytoskeletal changes in mast cells.
November 2003
Dominant-negative effect of the c-fos family gene products on inducible NO synthase expression in macrophages
Seiji Okada, Shintaro Obata, Masahiko Hatano and Takeshi Tokuhisa
Inducible nitric oxide synthase (iNOS) production by macrophages is a critical step for inflammation. Okada et al. have assessed roles of the c-fos family gene products in this step. Overexpression of c-fos, c-jun or junB inhibited the production of iNOS. Furthermore, the regulatory effect of c-fos was independent of the AP-1 binding site in the iNOS promoter and diminished by coexpression of c-jun or C/EBPß. Thus, although the mechanism is still unclear, c-fos family proteins can regulate iNOS expression activated macrophages.
October 2003
Transitional and marginal zone B cells have a high proportion of unmasked CD22: implications for BCR signaling
Claus-Peter Danzer, Brian E. Collins, Ola Blixt, James C. Paulson and Lars Nitschke
CD22 is an inhibitor of B cell signaling. Its binding to endogenous sialylated ligands on the B cell surface in cis reduces the BCR signal strength. Danzer et al. examined unbound (unmasked) CD22 on B cells by using an oligomeric streptoavidin-based sialylated probe as an artificial CD22 ligand. They found that transitional and marginal zone B cells contain 2-fold more B cells with unmasked CD22 than mature follicular B cells. Furthermore, B cells with unmasked CD22 have an activated phenotype.
September 2003
Human anti-idiotypic T cells induced by TCR peptides corresponding to a common CDR3 sequence motif in myelin basic protein-reactive T cells
Ying C. Q. Zang, Jian Hong, Victor M. Rivera, James Killian and Jingwu Z. Zhang
T cells recognizing myelin basic protein (MBP) are involved in the pathogenesis of multiple sclerosis (MS). Using TCR peptides corresponding to a CDR3 sequence motif preferentially expressed among T cells recognizing the 83-99 immunodominant MBP peptide, authors examined anti-idiotypic immune responses and the functional properties of anti-idiotypic T cells in MS patients. They demonstrated that anti-idiotypic T cells could be induced in vitro by the peptides. The CD4+ anti-idiotypic T cells recognizing 15-mer TCR peptide produce predominantly IL-10 and inhibit the proliferation of autologous T cells recognizing the MBP peptides, while the C
August 2003
CD69-null mice protected from arthritis induced with anti-type II collagen antibodies
Kaoru Murata, Masamichi Inami, Akihiro Hasegawa, Shuichi Kubo, Motoko Kimura, Masakatsu Yamashita, Hiroyuki Hosokawa, Tomokazu Nagao, Kazuo Suzuki, Kahoko Hashimoto, Hiroshi Shinkai, Haruhiko Koseki, Masaru Taniguchi, Steven F. Ziegler and Toshinori Nakayama
Arthritis is an obstinate immune disorder in humans. Murata et al. have shown that CD69 is critical for development of murine collagen arthritis. Cell transfer experiments implied critical roles of CD69 on neutrophils, but not on T cells or splenocytes. Thus, CD69 would be a possible therapeutic target for arthritis.
July 2003
Specific depletion of autoreactive B lymphocytes by a recombinant fusion protein in vitro and in vivo
Marcel Zocher, Patrick A. Baeuerle, Torsten Dreier and Antonio Iglesias
In many autoimmune diseases, autoreactive antibodies cause severe damage and malfunction of target tissues. Zocher et al. have generated a MOG-Fc fusion protein, composed of the human myelin-oligodendrocyte glycoprotein and Fc region of human IgG1 heavy chain. They show that MOG-Fc could eliminate MOG-specific autoreactive B cells in vitro and in vivo.
June 2003
Distinct antigen trafficking from skin in the steady and active states
M. Yoshino, H. Yamazaki, H. Nakano, T. Kakiuchi, K. Ryoke, T. Kunisada and S.-I. Hayashi
Mechanisms underlying the capturing exogeneous antigens, up-regulation of the chemokine receptor expression, and migration into lymphoid organs of langerhans cells/dendritic cells remains still elusive. Yoshino et al. demonstrate a distinct pathway of antigen-trafficking from skin in the steady state that is independent of CCL21-CCR7 signaling.
May 2003
Glia maturation factor produced by thymic epithelial cells play a role in T cell differentiation in the thymic environment
M. Utsuyama, J. Shiraishi, H. Takahashi, M. Kasai and K. Hirokawa
Utsuyama et al. have discovered a protein that affects T cell development in the thymus. They generated a panel of antibodies that stained thymic epithelial cells. One of them blocked maturation of T cells. They cloned the cDNA encoding the molecule recognized by the antibody and showed that the protein is identical to glia maturation factor. Their data suggest that glia maturation factor is produced by thymic epithelial cells and play a role in CD4+ T cell development in the thymus.
April 2003
Human germinal center B cells differ from naïve and memory B cells by their aggregated MHC class II rich compartments lacking HLA-DOC
Chalouni, J. Banchereau, A.B. Vogt, V. Pascual and J. Davoust
B cells act as antigen presenting cells at each stage of differentiation. Antigenic peptides are loaded onto MHC class II molecules in MHC class II rich compartments (MIIC). Chalouni et al. report that human germinal center B cells differ from naïve and memory B cells in terms of intracellular localization and HLA-DO content of MIIC.
March 2003
Expression of recombination-activating gene in mature peripheral T cells in Peyer's patch
Kondo, E., Wakao, H., Koseki, H., Takemori, T., Kojo, S., Harada, M., Takahashi, M., Sakata, S., Shimizu, C., Ito, T., Nakayama, T., and Taniguchi, M.
Recombination activating gene 1 and 2 (Rag1 and Rag2) are essential for the gene rearrangement of antigen receptor of both B and T cells. Authors established mice in which a green fluorescent protein (GFP) gene is knocked in the Rag2 gene locus and found that only a fraction of Thy1.2+ cells in the Peyer's patch is GFP-positive amongst the peripheral lymphoid organs and express TCR-beta and CD3 and shows activated/memory phenotypes. The results imply a potential for a secondary rearrangement of TCR in extra thymic tissues.
February 2003
SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen, mediates uptake of the polysaccharide dextran
Young-Sun Kang, Sayuri Yamazaki, Tomori Iyoda, Maggie Pack, Sandra A. Bruening, Jae Y. Kim, Kazuhiko Takara, Kayo Inaba, Ralph M. Steinman and Chae Gyu Park
Splenic marginal zone macrophages are involved in the clearance of the polysaccharides, but the molecular mechanism remains largely unknown. According to Kang et al., a C-type lectin, SIGN-R1, is selectively expressed in the macrophages and critically functions as a responsible endocytic receptor.
January 2003
Potential preventive effectos of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis
Masao Tanaka, Shoichi Ozaki, Daisuke Kawabata, Masaaki Kishimura, Fumio Osakada, Mitsuo Okubo, Masao Murakami, Kazuwa Nakao and Tsuneyo Mimori
Follistatin-related protein (FRP)/TSC-36 is one of target antigens of autoantibodies in rheumatoid arthritis (RA). Tanaka et al. demonstrate that FRP reduces synovial production of matrix metalloproteinase (MMP)-1, MMP-3 and prostaglandin E2, potent agonists of joint destruction in RA while autoantibodies to FRP increase their production by blocking FRP activity. Thus, both FRP and its autoantibody appear to be involved in pathogenesis of RA.
December 2002
Evidence for shared recognition of a peptide ligand by a diverse panel of nonobese diabetic (NOD) nice-derived, islet, diabetogenic T cell clones
Yoshida K., Martin, T., Yamamoto, K., Dobbs, C., Munz, C., Kamikawaji, N., Nakano, N., Rammensee, H.-G., Sasazuki, T., Haskins, K. and Kikutani, H.
Panels of islet-reactive mouse CD4+ T cell clones from prediabetic nonobese diabetic (NOD) mice have been shown to cause insulitis and diabetes when transferred to recipient mice, however, antigen specificities of these T cell clones have not been determined. In this paper, authors examined peptide mixtures to identify peptide ligands reactive T cell clones and identified HLAI-RM and HIPI-RM. This paper may suggest that iselet-reactive T cells recognize islet beta cells as a natural ligand.
November 2002
A regulatory role for SOCS-1 in T helper polarization in vivo. Suppressor of Cytokine Signaling (SOCS)s are a family of inhibitors of JAK-STAT signaling pathways
M. Fujimoto, H. Tsutsui, S. Y. Futatsugi, H. Ueda, O. Xingshou, T. Abe, I. Kawase, K. Nakanishi, T. Kishimoto and T. Naka
Fujimoto et al. demonstrate that SOCS-1 is a key regulator in Th differentiation. CD4+ T cells lacking SOCS-1 are dramatically accelerated to differentiate into Th1 or Th2 cells, depending on the Th-polarizing stimulation. Interestingly, this phenomenon is observed even in T cells from SOCS-1 heterozygous mice. These results may imply the role of SOCS-1 in the pathogenesis of Th1- and Th2-related diseases such as autoimmune diseases and allergy.
October 2002
Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1)+CD11b+ immature myeloid suppressor cells
O. Goñi, P. Alcaide and M. Fresno
Like many other pathogens, Trypanosoma cruzi, a causative agent of Chaga's disease, suppresses host immune responses during infection. Goñi et al. have identified Gr-1+, CD11b+ immature myeloid suppressor cells that increase in T. cruzi-infected mice and caninhibit T cell proliferation. In the same issue, Van Overtveldt et al. also report that T. cruzi infection inhibits LPS-induced up-regulation of MHC class I molecules on human dendritic cells.
September 2002
Regulation of Ig class switch recombination by NF-kappaB: retroviral expression of ReIB in activated B cells inhibits switching to IgG1, but not to IgE
D. Bhattacharya, D. U. Lee and W. C. Sha
NF-kB/Rel family member proteins have been shown to regulate class switch recombination (CSR). The manuscript first described that RelB complexes can specifically inhibit CSR to IgG1, but not IgE in activated primary B cells.
August 2002
Th1/Th2 cell differentiation of developing CD4 single-positive thymocytes
K. Kikkawa, M. Yamashita, M. Kimura, M. Omori, K. Sugaya, C. Shimizu, T. Katsumoto, M. Ikekita, M. Taniguchi and T. Nakayama
T lymphocytes mature from double positive cells to CD4+ or CD8+ cells in the thymus. Furthermore, CD4+ thymocytes develop from immature HSA+ to mature HAS- CD4 cells. Kikkawa et al. demonstrate a dramatic difference between HSA+ and HAS- CD4 thymocytes in the efficiency for Th1 differentiation. The poor capacity of HAS+ CD4 thymocytes to proceed to Th1 cells is due to low IL-12 receptor expression as well as defective activation of signaling molecules and transcription factors involved in Th1 development.
July 2002
A variety of microbial components induce tolerance to lipoplysaccharide by differentially affecting MyD88-dependent and -independent pathways
S. Sato, O. Takeuchi, T. Fujita, H. Tomizawa, K. Takeda and S. Akira
A prior exposure to a given bacterial component results in a state of reduced responsiveness to other components, and this protects the host against subsequent inflammatory stimuli leading to shock. Here Sato et al. investigate the molecular mechanism by which the pre-exposed compound modulates the cytokine production profile in such cross-tolerance.
