Toshiyuki Takai

Publications (86)723.07 Total impact

• Article: Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcγRIIB-deficient C57BL/6 mice.

  Shinya Kawano, Qingshun Lin, Hirofumi Amano, Toshiyuki Kaneko, Keiko Nishikawa, Hiromichi Tsurui, Norihiro Tada, Hiroyuki Nishimura, Toshiyuki Takai, Toshikazu Shirai, Yoshinari Takasaki, Sachiko Hirose
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  ABSTRACT: We previously established an IgG Fc receptor IIB (FcγRIIB)-deficient C57BL/6 (B6)-congenic mouse strain (KO1), which spontaneously develops rheumatoid arthritis (RA), but not systemic lupus erythematosus (SLE). Here we show that when Y chromosome-linked autoimmune acceleration (Yaa) mutation was introduced in KO1 strain (KO1.Yaa), the majority of KO1.Yaa mice did not develop RA, but instead did develop SLE. This phenotype conversion did not depend on autoantibody specificity, since KO1.Yaa mice, compared with KO1, showed a marked increase in serum levels of both lupus-related and RA-related autoantibodies. The increase in frequencies of CD69(+) activated B cells and T cells, and the spontaneously splenic GC formation with T follicular helper (T(FH) ) cell generation were manifest early in life of KO1.Yaa, but not KO1 and B6.Yaa, mice. Activated CD4(+) T cells from KO1.Yaa mice showed up-regulated production of IL-21 and IL-10, compared with the finding in KO1 mice, indicating the possibility that this aberrant cytokine milieu relates to the disease phenotype conversion. Thus, our model is useful to clarify the shared and the disease-specific mechanisms underlying the clinically distinct systemic autoimmune diseases RA and SLE.
  European Journal of Immunology 12/2012; · 5.10 Impact Factor
• Article: Inhibitory Receptor Paired Ig-like Receptor B Is Exploited by Staphylococcus aureus for Virulence.

  Masafumi Nakayama, Kenji Kurokawa, Kyohei Nakamura, Bok Luel Lee, Kazuhisa Sekimizu, Hiromi Kubagawa, Keiichi Hiramatsu, Hideo Yagita, Ko Okumura, Toshiyuki Takai, David M Underhill, Alan Aderem, Kouetsu Ogasawara
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  ABSTRACT: The innate immune system has developed to acquire a wide variety of pattern-recognition receptors (PRRs) to identify potential pathogens, whereas pathogens have also developed to escape host innate immune responses. ITIM-bearing receptors are attractive targets for pathogens to attenuate immune responses against them; however, the in vivo role of the inhibitory PRRs in host-bacteria interactions remains unknown. We demonstrate in this article that Staphylococcus aureus, a major Gram-positive bacteria, exploits inhibitory PRR paired Ig-like receptor (PIR)-B on macrophages to suppress ERK1/2 and inflammasome activation, and subsequent IL-6 and IL-1β secretion. Consequently, Pirb(-/-) mice infected with S. aureus showed enhanced inflammation and more effective bacterial clearance, resulting in resistance to the sepsis. Screening of S. aureus mutants identified lipoteichoic acid (LTA) as an essential bacterial cell wall component required for binding to PIR-B and modulating inflammatory responses. In vivo, however, an LTA-deficient S. aureus mutant was highly virulent and poorly recognized by macrophages in both wild-type and Pirb(-/-) mice, demonstrating that LTA recognition by PRRs other than PIR-B mediates effective bacterial elimination. These results provide direct evidence that bacteria exploit the inhibitory receptor for virulence, and host immune system counterbalances the infection.
  The Journal of Immunology 11/2012; · 5.79 Impact Factor
• Source

  Available from: Toshiki Yabe-Wada

  Article: Regulation of plasmacytoid dendritic cell responses by PIR-B.

  Yoshiya Mitsuhashi, Akira Nakamura, Shota Endo, Kazuya Takeda, Toshiki Yabe-Wada, Toshihiro Nukiwa, Toshiyuki Takai
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  ABSTRACT: Plasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α-mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.
  Blood 09/2012; 120(16):3256-9. · 9.90 Impact Factor
• Article: Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells.

  Won Fen Wong, Kazuyoshi Kohu, Akira Nakamura, Masahito Ebina, Toshiaki Kikuchi, Ryushi Tazawa, Keisuke Tanaka, Shunsuke Kon, Tomo Funaki, Akiko Sugahara-Tobinai, Chung Yeng Looi, Shota Endo, Ryo Funayama, Mineo Kurokawa, Sonoko Habu, Naoto Ishii, Manabu Fukumoto, Koh Nakata, Toshiyuki Takai, Masanobu Satake
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  ABSTRACT: The Runx1 transcription factor is abundantly expressed in naive T cells but rapidly downregulated in activated T cells, suggesting that it plays an important role in a naive stage. In the current study, Runx1(-/-)Bcl2(tg) mice harboring Runx1-deleted CD4(+) T cells developed a fatal autoimmune lung disease. CD4(+) T cells from these mice were spontaneously activated, preferentially homed to the lung, and expressed various cytokines, including IL-17 and IL-21. Among these, the deregulation of IL-21 transcription was likely to be associated with Runx binding sites located in an IL-21 intron. IL-17 produced in Runx1-deleted cells mobilized innate immune responses, such as those promoted by neutrophils and monocytes, whereas IL-21 triggered humoral responses, such as plasma cells. Thus, at an initial stage, peribronchovascular regions in the lung were infiltrated by CD4(+) lymphocytes, whereas at a terminal stage, interstitial regions were massively occupied by immune cells, and alveolar spaces were filled with granular exudates that resembled pulmonary alveolar proteinosis in humans. Mice suffered from respiratory failure, as well as systemic inflammatory responses. Our data indicate that Runx1 plays an essential role in repressing the transcription of cytokine genes in naive CD4(+) T cells and, thereby, maintains cell quiescence.
  The Journal of Immunology 05/2012; 188(11):5408-20. · 5.79 Impact Factor
• Article: [Osteoimmunology - Basic principles and Clinical applications - . Regulation of osteoclast development by immunoglobulin-like receptors.]

  Masanori Inui, Toshiyuki Takai
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  ABSTRACT: Immunoglobulin-like receptors (IgLR) , expressed in a wide range of cells in immune system, provide a positive and negative regulation of immune responses. Activation signals initiated by activating IgLR associating with ITAM-containing adapter proteins DAP12 and FcRγ are indispensable for the development of osteoclasts. On the other hand, ITIM signals induced by inhibitory IgLR regulate osteoclast development and activation. Thus, ITAM and ITIM play important roles in the maintenance of bone homeostasis.
  Clinical calcium 01/2012; 22(11):1651-1657.
• Source

  Available from: eurekalert.org

  Article: Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells.

  Masafumi Nakayama, Kazuyoshi Takeda, Mitsuko Kawano, Toshiyuki Takai, Naoto Ishii, Kouetsu Ogasawara
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  ABSTRACT: Natural killer (NK) cells contribute to not only innate but also to adaptive immunity by interacting with dendritic cells (DCs) and T cells. All activated human NK cells express HLA-DR and can initiate MHCII-dependent CD4(+) T-cell proliferation; however, the expression of MHCII by mouse NK cells and its functional significance are controversial. In this study, we show that NK-DC interactions result in the emergence of MHCII-positive NK cells. Upon in vitro or in vivo activation, mouse conventional NK cells did not induce MHCII transcripts, but rapidly acquired MHCII protein from DCs. MHCII H2-Ab1-deficient NK cells turned I-A(b)-positive when adoptively transferred into wild-type mice or when cultured with WT splenic DCs. NK acquisition of MHCII was mediated by intercellular membrane transfer called "trogocytosis," but not upon DAP10/12- and MHCI-binding NK cell receptor signaling. MHCII-dressed NK cells concurrently acquired costimulatory molecules such as CD80 and CD86 from DCs; however, their expression did not reach functional levels. Therefore, MHCII-dressed NK cells inhibited DC-induced CD4(+) T-cell responses rather than activated CD4(+) T cells by competitive antigen presentation. In a mouse model for delayed-type hypersensitivity, adoptive transfer of MHCII-dressed NK cells attenuated footpad swelling. These results suggest that MHCII-dressed NK cells generated through NK-DC interactions regulate T cell-mediated immune responses.
  Proceedings of the National Academy of Sciences 11/2011; 108(45):18360-5. · 9.68 Impact Factor
• Article: Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγ receptor type IIb-deficient C57BL/6 genetic background.

  Aya Sato-Hayashizaki, Mareki Ohtsuji, Qingshun Lin, Rong Hou, Naomi Ohtsuji, Keiko Nishikawa, Hiromichi Tsurui, Katsuko Sudo, Masao Ono, Shozo Izui, Toshikazu Shirai, Toshiyuki Takai, Hiroyuki Nishimura, Sachiko Hirose
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  ABSTRACT: Fcγ receptor type IIb (FcγRIIb) is a major negative regulator of B cells, and the lack of FcγRIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strain-derived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in FcγRIIb-deficient B6 mice. We established 2 lines of FcγRIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed FcγRIIb-deficient mice on a hybrid (129×B6) background into a B6 background. Although both lack FcγRIIb expression, the KO1 and KO2 strains carry different lengths of the 129 strain-derived telomeric chromosome 1 segment flanked to the null-mutated Fcgr2b gene; the KO1 strain carries a 129 strain-derived ∼6.3-Mb interval distal from the null-mutated Fcgr2b gene within the Sle16 locus, while this interval in the KO2 strain is of B6 origin. Unexpectedly, both strains failed to develop SLE; instead, the KO1 strain, but not the KO2 strain, spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90% at age 12 months. The current study shows evidence that the epistatic interaction between the Fcgr2b-null mutation and a polymorphic gene(s) in the 129 strain-derived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background, although the participation of other genetic polymorphisms cannot be totally excluded.
  Arthritis & Rheumatism 10/2011; 63(10):2930-8. · 7.87 Impact Factor
• Source

  Available from: Kiyotaka Nakamagoe

  Article: The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven adaptive immune responses.

  Takako Nakano-Yokomizo, Satoko Tahara-Hanaoka, Chigusa Nakahashi-Oda, Tsukasa Nabekura, Nadia K Tchao, Momoko Kadosaki, Naoya Totsuka, Naoki Kurita, Kiyotaka Nakamagoe, Akira Tamaoka, Toshiyuki Takai, Teruhito Yasui, Hitoshi Kikutani, Shin-ichiro Honda, Kazuko Shibuya, Lewis L Lanier, Akira Shibuya
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  ABSTRACT: DAP12, an immunoreceptor tyrosine-based activation motif-bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II-deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II-deficient B cells suppressed B cell receptor (BCR)-mediated proliferation. The chimeric MAIR-II-DAP12 receptor recruited the SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell-dependent and T cell-independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell-mediated adaptive immune responses.
  Journal of Experimental Medicine 08/2011; 208(8):1661-71. · 13.85 Impact Factor
• Article: Transcriptional activation of the Pirb gene in B cells by PU.1 and Runx3.

  Kojo Arita, Shota Endo, Tomonori Kaifu, Kohji Kitaguchi, Akira Nakamura, Hidetaka Ohmori, Kazuyoshi Kohu, Masanobu Satake, Toshiyuki Takai
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  ABSTRACT: Cells in the immune system are regulated positively or negatively by sets of receptor pairs that conduct balanced, activating, or inhibitory intracellular signaling. One such receptor pair termed paired Ig-like receptor (PIR) is composed of the inhibitory PIR-B and its activating isoform, PIR-A. Upon binding to their shared ligand, MHC class I molecules, these receptors control the threshold for immune cell activation. Gene-targeting studies on PIR-B in mice revealed the importance of the inhibition mediated by the PIR-B-MHC interaction in the immune system. Recent studies also revealed the significance of the interaction of PIR-B with neurite outgrowth inhibitors, including Nogo in the CNS. The coordinated regulation by PIR-B and PIR-A is considered to be primarily dependent on their expression balance in cells. However, the mechanism underlying transcriptional control of the genes for PIR-B and PIR-A (Pirb and Pira, respectively) remains to be clarified. In this study, we identified the major cis-acting promoter segment for Pirb and Pira in B cells as the -212 to -117 region upstream from the translation initiation codon. PU.1 and Runx3 were found to bind to this Pirb promoter. Truncation of the PU.1-binding motif significantly reduced the promoter activity, whereas the influence of elimination of the Runx3 site was marginal in B lymphoma BCL1-B20 cells. Unexpectedly, PU.1, but not Runx3, knockdown reduced the levels of both the Pirb and Pira transcripts. We conclude that the major promoter of Pirb, and probably Pira as well, is activated dominantly by PU.1 and marginally by Runx3 in B cells.
  The Journal of Immunology 06/2011; 186(12):7050-9. · 5.79 Impact Factor
• Article: Differential but competitive binding of Nogo protein and class i major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells.

  Haruka Matsushita, Shota Endo, Eiji Kobayashi, Yuzuru Sakamoto, Keisuke Kobayashi, Kohji Kitaguchi, Kimiko Kuroki, Arvid Söderhäll, Katsumi Maenaka, Akira Nakamura, Stephen M Strittmatter, Toshiyuki Takai
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  ABSTRACT: Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory role of PIR-B in neurite regeneration through binding to three axonal outgrowth inhibitors of myelin, including Nogo. Thus, it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here, we present data supporting the competition of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding only occurred with the N-terminal domains of PIR-B, whereas Nogo binding occurred with either the N- or C-terminal ectodomains. Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wild-type, but not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates Nogo-induced inhibition. Thus, we propose a novel mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the immune system.
  Journal of Biological Chemistry 06/2011; 286(29):25739-47. · 4.77 Impact Factor
• Article: Differential but competitive binding of Nogo and MHCI to PIR-B provides an inhibition of cells

  Haruka Matsushita, Shota Endo, Eiji Kobayashi, Yuzuru Sakamoto, Keisuke Kobayashi, Kohji Kitaguchi, Kimiko Kuroki, Arvid Soderhall, Katsumi Maenaka, Akira Nakamura, Stephen M. Strittmatter, Toshiyuki Takai
  [show abstract] [hide abstract]
  ABSTRACT: Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory role of PIR-B in neurite regeneration through binding to three axonal outgrowth inhibitors of myelin including Nogo. Thus, it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here we present data supporting the competition of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding only occurred with the N-terminal domains of PIR-B, whereas the Nogo binding occurred with either the N- or C-terminal ectodomains. Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wild-type, but not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates the Nogo-induced inhibition. Thus, we propose a novel mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the immune system.
  Journal of Biological Chemistry 06/2011; · 4.77 Impact Factor
• Source

  Available from: PubMed Central

  Article: Role of PIR-B in autoimmune glomerulonephritis.

  Toshiyuki Takai, Akira Nakamura, Shota Endo
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  ABSTRACT: PIR-B, an inhibitory receptor expressed on murine B cells and myeloid cells, regulates humoral and cellular immune responses via its constitutive binding to the ligand, MHC class I molecules, on the same cells (cis) or on different cells (trans). Although it has been speculated that PIR-B is important for maintaining peripheral tolerance, PIR-B single deficiency does not cause overt autoimmune diseases. Recently, however, the combination of its deficiency with the Fas lpr mutation was found to result in augmented production of autoantibodies such as IgG rheumatoid factor and anti-DNA IgG, leading to glomerulonephritis in mice. Although the precise molecular mechanism for the overall scenario is unclear, PIR-B was found to suppress TLR9-mediated production of naturally autoreactive antibodies by innate B cells or B-1 cells by inhibiting the activation of Bruton's tyrosine kinase. Thus, PIR-B is an important regulator of innate immunity mediated by TLR9 in B-1 cells, which can otherwise provoke autoimmunity when overactivated.
  Journal of Biomedicine and Biotechnology 01/2011; 2011:275302. · 2.44 Impact Factor
• Article: Characterization of leukocyte mono-immunoglobulin-like receptor 7 (LMIR7)/CLM-3 as an activating receptor: its similarities to and differences from LMIR4/CLM-5.

  Yutaka Enomoto, Yoshinori Yamanishi, Kumi Izawa, Ayako Kaitani, Mariko Takahashi, Akie Maehara, Toshihiko Oki, Reiko Takamatsu, Masunori Kajikawa, Toshiyuki Takai, Toshio Kitamura, Jiro Kitaura
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  ABSTRACT: Here we characterize leukocyte mono-Ig-like receptor 7 (LMIR7)/CLM-3 and compare it with an activating receptor, LMIR4/CLM-5, that is a counterpart of an inhibitory receptor LMIR3/CLM-1. LMIR7 shares high homology with LMIR4 in the amino acid sequences of its Ig-like and transmembrane domains. Flow cytometric analysis demonstrated that LMIR4 was predominantly expressed in neutrophils, whereas LMIR7 was highly expressed in mast cells and monocytes/macrophages. Importantly, LMIR7 engagement induced cytokine production in bone marrow-derived mast cells (BMMCs). Although FcRγ deficiency did not affect surface expression levels of LMIR7, it abolished LMIR7-mediated activation of BMMCs. Consistently we found significant interaction of LMIR7-FcRγ, albeit with lower affinity compared with that of LMIR4-FcRγ. Our results showed that LMIR7 transmits an activating signal through interaction with FcRγ. In addition, like LMIR4, LMIR7 synergizes with TLR4 in signaling. Analysis of several chimera receptors composed of LMIR4 and LMIR7 revealed these findings: 1) the transmembrane of LMIR7 with no charged residues maintained its surface expression at high levels in the absence of FcRγ; 2) the extracellular juxtamembrane region of LMIR7 had a negative effect on its surface expression levels; and 3) the strong interaction of LMIR4 with FcRγ depended on the extracellular juxtamembrane region as well as the transmembrane domain of LMIR4. Thus, LMIR7 shares similarities with LMIR4, although they are differentially regulated in their distribution, expression, and function.
  Journal of Biological Chemistry 11/2010; 285(46):35274-83. · 4.77 Impact Factor
• Article: Characterization of Leukocyte Mono-immunoglobulin-like Receptor 7 (LMIR7)/CLM-3 as an Activating Receptor

  Yutaka Enomoto, Yoshinori Yamanishi, Kumi Izawa, Ayako Kaitani, Mariko Takahashi, Akie Maehara, Toshihiko Oki, Reiko Takamatsu, Masunori Kajikawa, Toshiyuki Takai, Toshio Kitamura, Jiro Kitaura
  [show abstract] [hide abstract]
  ABSTRACT: Here we characterize leukocyte mono-Ig-like receptor 7 (LMIR7)/CLM-3 and compare it with an activating receptor, LMIR4/CLM-5, that is a counterpart of an inhibitory receptor LMIR3/CLM-1. LMIR7 shares high homology with LMIR4 in the amino acid sequences of its Ig-like and transmembrane domains. Flow cytometric analysis demonstrated that LMIR4 was predominantly expressed in neutrophils, whereas LMIR7 was highly expressed in mast cells and monocytes/macrophages. Importantly, LMIR7 engagement induced cytokine production in bone marrow-derived mast cells (BMMCs). Although FcRγ deficiency did not affect surface expression levels of LMIR7, it abolished LMIR7-mediated activation of BMMCs. Consistently we found significant interaction of LMIR7-FcRγ, albeit with lower affinity compared with that of LMIR4-FcRγ. Our results showed that LMIR7 transmits an activating signal through interaction with FcRγ. In addition, like LMIR4, LMIR7 synergizes with TLR4 in signaling. Analysis of several chimera receptors composed of LMIR4 and LMIR7 revealed these findings: 1) the transmembrane of LMIR7 with no charged residues maintained its surface expression at high levels in the absence of FcRγ; 2) the extracellular juxtamembrane region of LMIR7 had a negative effect on its surface expression levels; and 3) the strong interaction of LMIR4 with FcRγ depended on the extracellular juxtamembrane region as well as the transmembrane domain of LMIR4. Thus, LMIR7 shares similarities with LMIR4, although they are differentially regulated in their distribution, expression, and function.
  Journal of Biological Chemistry 11/2010; 285(46):35274-35283. · 4.77 Impact Factor
• Source

  Available from: PubMed Central

  Article: TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury.

  Yoshinori Yamanishi, Jiro Kitaura, Kumi Izawa, Ayako Kaitani, Yukiko Komeno, Masaki Nakamura, Satoshi Yamazaki, Yutaka Enomoto, Toshihiko Oki, Hisaya Akiba, Takaya Abe, Tadasuke Komori, Yoshihiro Morikawa, Hiroshi Kiyonari, Toshiyuki Takai, Ko Okumura, Toshio Kitamura
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  ABSTRACT: Leukocyte mono-immunoglobulin (Ig)-like receptor 5 (LMIR5)/CD300b is a DAP12-coupled activating receptor predominantly expressed in myeloid cells. The ligands for LMIR have not been reported. We have identified T cell Ig mucin 1 (TIM1) as a possible ligand for LMIR5 by retrovirus-mediated expression cloning. TIM1 interacted only with LMIR5 among the LMIR family, whereas LMIR5 interacted with TIM4 as well as TIM1. The Ig-like domain of LMIR5 bound to TIM1 in the vicinity of the phosphatidylserine (PS)-binding site within the Ig-like domain of TIM1. Unlike its binding to TIM1 or TIM4, LMIR5 failed to bind to PS. LMIR5 binding did not affect TIM1- or TIM4-mediated phagocytosis of apoptotic cells, and stimulation with TIM1 or TIM4 induced LMIR5-mediated activation of mast cells. Notably, LMIR5 deficiency suppressed TIM1-Fc-induced recruitment of neutrophils in the dorsal air pouch, and LMIR5 deficiency attenuated neutrophil accumulation in a model of ischemia/reperfusion injury in the kidneys in which TIM1 expression is up-regulated. In that model, LMIR5 deficiency resulted in ameliorated tubular necrosis and cast formation in the acute phase. Collectively, our results indicate that TIM1 is an endogenous ligand for LMIR5 and that the TIM1-LMIR5 interaction plays a physiological role in immune regulation by myeloid cells.
  Journal of Experimental Medicine 07/2010; 207(7):1501-11. · 13.85 Impact Factor
• Article: The study of allergy by Japanese researchers: a historical perspective.

  Toshiyuki Takai, Hajime Karasuyama
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  ABSTRACT: It has been over a hundred years since Shibasaburo Kitasato and Emil Adolf von Boehring's finding of a serum component that neutralizes bacterial toxins and the subsequent development of antiserum therapy. Over that time, many Japanese researchers have greatly contributed to our understanding of the molecular mechanisms for allergic and inflammatory diseases. This article is aimed at introducing such individual work and how these areas have contributed to our understanding of the mechanisms of allergic reactions.
  International Immunology 10/2009; 21(12):1311-6. · 3.41 Impact Factor
• Article: Ectopically expressed PIR-B on T cells constitutively binds to MHC class I and attenuates T helper type 1 responses.

  Michiyo Imada, Kyoko Masuda, Rumi Satoh, Yumi Ito, Yoshiyuki Goto, Takayuki Matsuoka, Shota Endo, Akira Nakamura, Hiroshi Kawamoto, Toshiyuki Takai
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  ABSTRACT: Activated mature T cells induce various inhibitory receptors implicated in maintaining peripheral tolerance in response to the trans-acting ligands. Interestingly, paired Ig-like receptor (PIR)-B, an inhibitory MHC class I receptor on B cells and myeloid cells, could be involved in regulating early T cell development because epitope for PIR is detected on pre-thymic T/NK progenitors but not on thymocytes or mature T cells. We hypothesized that PIR-B is not only a regulator for T cell development but is also detrimental if expressed on mature T cells. Here we demonstrated, using PIR-B-deficient fetuses, that PIR-B is indeed expressed on the T cell progenitors but failed to identify its distinctive roles in the development. Forced expression of PIR-B in thymocytes and mature T cells also resulted in no abnormalities in development. However, upon antigenic or allogeneic stimulation, peripheral T cells with the ectopic PIR-B showed reduced T(h) type 1 responses due to the suppression of proximal TCR signaling by constitutive binding of PIR-B to MHC class I on the same cell surface. Our findings suggest that T cell expression of PIR-B with the cis-interacting MHC class I is strictly prohibited in periphery so as to secure prompt immune responses.
  International Immunology 09/2009; 21(10):1151-61. · 3.41 Impact Factor
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  Available from: PubMed Central

  Article: Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity.

  Tomohiro Kubo, Yuki Uchida, Yuko Watanabe, Masahiro Abe, Akira Nakamura, Masao Ono, Shizuo Akira, Toshiyuki Takai
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  ABSTRACT: Pathogens are sensed by Toll-like receptors (TLRs) expressed in leukocytes in the innate immune system. However, excess stimulation of TLR pathways is supposed to be connected with provocation of autoimmunity. We show that paired immunoglobulin (Ig)-like receptor B (PIR-B), an immunoreceptor tyrosine-based inhibitory motif-harboring receptor for major histocompatibility class I molecules, on relatively primitive B cells, B-1 cells, suppresses TLR9 signaling via Bruton's tyrosine kinase (Btk) dephosphorylation, which leads to attenuated activation of nuclear factor kappaB p65RelA but not p38 or Erk, and blocks the production of natural IgM antibodies, including anti-IgG Fc autoantibodies, particularly rheumatoid factor. The autoantibody production in PIR-B-deficient (Pirb(-/-)) mice was further augmented in combination with the Fas(lpr) mutation, which might be linked to the development of autoimmune glomerulonephritis. These results show the critical link between TLR9-mediated sensing and a simultaneously evoked, PIR-B-mediated inhibitory circuit with a Btk intersection in B-1 cells, and suggest a novel way toward preventing pathogenic natural autoantibody production.
  Journal of Experimental Medicine 09/2009; 206(9):1971-82. · 13.85 Impact Factor
• Article: Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin.

  Karel Otero, Isaiah R Turnbull, Pietro Luigi Poliani, William Vermi, Elisa Cerutti, Taiki Aoshi, Ilaria Tassi, Toshiyuki Takai, Samuel L Stanley, Mark Miller, Andrey S Shaw, Marco Colonna
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  ABSTRACT: Macrophage colony-stimulating factor (M-CSF) influences the proliferation and survival of mononuclear phagocytes through the receptor CSF-1R. The adaptor protein DAP12 is critical for the function of mononuclear phagocytes. DAP12-mutant mice and humans have defects in osteoclasts and microglia, as well as brain and bone abnormalities. Here we show DAP12 deficiency impaired the M-CSF-induced proliferation and survival of macrophages in vitro. DAP12-deficient mice had fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerated myeloid cells inefficiently after bone marrow transplantation. Signaling by M-CSF through CSF-1R induced the stabilization and nuclear translocation of beta-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of beta-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.
  Nature Immunology 08/2009; 10(7):734-43. · 26.01 Impact Factor
• Article: An activating and inhibitory signal from an inhibitory receptor LMIR3/CLM-1: LMIR3 augments lipopolysaccharide response through association with FcRgamma in mast cells.

  Kumi Izawa, Jiro Kitaura, Yoshinori Yamanishi, Takayuki Matsuoka, Ayako Kaitani, Masahiro Sugiuchi, Mariko Takahashi, Akie Maehara, Yutaka Enomoto, Toshihiko Oki, Toshiyuki Takai, Toshio Kitamura
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  ABSTRACT: Leukocyte mono-Ig-like receptor 3 (LMIR3) is an inhibitory receptor mainly expressed in myeloid cells. Coengagement of Fc epsilonRI and LMIR3 impaired cytokine production in bone marrow-derived mast cells (BMMCs) induced by Fc epsilonRI crosslinking alone. Mouse LMIR3 possesses five cytoplasmic tyrosine residues (Y241, Y276, Y289, Y303, Y325), among which Y241 and Y289 (Y241/289) or Y325 fit the consensus sequence of ITIM or immunotyrosine-based switch motif (ITSM), respectively. The inhibitory effect was abolished by the replacement of Y325 in addition to Y241/289 with phenylalanine (Y241/189/325/F) in accordance with the potential of Y241/289/325 to cooperatively recruit Src homology region 2 domain-containing phosphatase 1 (SHP)-1 or SHP-2. Intriguingly, LMIR3 crosslinking alone induced cytokine production in BMMCs expressing LMIR3 (Y241/276/289/303/325F) mutant as well as LMIR3 (Y241/289/325F). Moreover, coimmunoprecipitation experiments revealed that LMIR3 associated with ITAM-containing FcRgamma. Analysis of FcRgamma-deficient BMMCs demonstrated that both Y276/303 and FcRgamma played a critical role in the activating function of this inhibitory receptor. Importantly, LMIR3 crosslinking enhanced cytokine production of BMMCs stimulated by LPS, while suppressing production stimulated by other TLR agonists or stem cell factor. Thus, an inhibitory receptor LMIR3 has a unique property to associate with FcRgamma and thereby functions as an activating receptor in concert with TLR4 stimulation.
  The Journal of Immunology 07/2009; 183(2):925-36. · 5.79 Impact Factor