担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/psyg.12786

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1089/jpm.2021.0245

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/tkm2.1294

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記述言語：日本語  

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記述言語：日本語  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11258/jjghp.31.207

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bcr-2018-224431

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   出版者・発行元：BLACKWELL PUBLISHING INC  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

A complex mechanism may be operational for dendritic cell (DC) maturation, wherein Toll-like receptor and other signaling pathways may be coordinated differently depending on the nature of the pathogens, in order for DC maturation to be most effective to a given threat. Here, we show that IFN-alpha/beta signaling is selectively required for the maturation of DCs induced by double-stranded RNA or viral infection in vitro. Interestingly, the maturation is still observed in the absence of either of the two target genes of IFN-alpha/beta, TLR3 and PKR (double-stranded-RNA-dependent protein kinase R), indicating the complexity of the IFN-alpha/beta-induced transcriptional program in DCs. We also show that the DCs stimulated in vivo by these agents can migrate into the T cell zone of the spleen but fail to mature without the IFN signal. The immune system may have acquired the selective utilization of this cytokine system, which is essential for innate antiviral immunity, to effectively couple with the induction of adaptive immunity.

DOI： 10.1073/pnas.1934678100

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Type I interferons (IFN-alpha/beta) affect many aspects of immune responses. Many pathogen-associated molecules, including bacterial lipopolysaccharide (LPS) and virus-associated double-stranded RNA, induce IFN gene expression through activation of distinct Toll-like receptors (TLRs). Although much has been studied about the activation of the transcription factor IRF-3 and induction of IFN-beta gene by the LPS-mediated TLR4 signaling, definitive evidence is missing about the actual role of IRF-3 in LPS responses in vitro and in vivo. Using IRF-3 deficient mice, we show here that IRF-3 is indeed essential for the LPS-mediated IFN-beta gene induction. Loss of IRF-3 also affects the expression of profile of other cytokine/chemokine genes. We also provide evidence that the LPS/TLR4 signaling activates IRF-7 to induce IFN-beta, if IRF-7 is induced by IFNs prior to LPS simulation. Finally, the IRF-3-deficient mice show resistance to LPS-induced endotoxin shock. These results place IRF-3 as a molecule central to LPS/TLR4 signaling. (C) 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(03)01049-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Interleukin (IL)-12 plays a central role in the initiation and regulation of T cell-mediated immune responses. The present study investigated how IL-12, endogenously produced during tumor vaccination, functions for anti-tumor immune responses. Mice were given anti-IL-12 monoclonal antibody during immunization with attenuated syngeneic tumor cells. Spleinic T cells from anti-IL-12-treated immunized mice exhibited comparable levels of tumor-neutralizing activity with those from tumor-immunized mice without anti-IL-12 treatment. When these two groups of mice were directly challenged with viable tumor cells, tumor rejection was induced only in anti-IL-12-untreated mice. T cell infiltration was observed at the site of tumor challenge in these mice, whereas such a T cell infiltration did not occur in anti-IL-12-treated mice. The tumor-migratory capacity was directly assessed by transferring spleen cells from tumor-immunized mice into syngeneic, tumor-bearing recipient mice and by quantitating donor cells migrating into recipients' tumor masses. T cells from anti-IL-12-treated tumor-immunized. mice were found to exhibit a markedly reduced tumor-migratory capacity when compared with that of anti-IL-12-untreated mice. Moreover, the migration of T cells from anti-IL-12-untreated mice to tumor masses prepared in anti-IL-12-treated mice was severely reduced. These results indicate that endogenously produced IL-12 has dual roles in anti-tumor-immune resistance: One is to confer T cells with a tumormigratory capacity, and the other is to allow tumor masses to develop the capacity to accept tumor-migrating T cells.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

The chemokine receptor CXCR3 has been shown to play a key role in the recruitment of T cells to sites of inflammation such as allografts. Here, we investigated which signals and conditions are responsible for CXCR3 induction. CXCR3 was induced on T cells that were stimulated with anti-CD3 plus anti-CD28 monoclonal antibodies and then recultured without any external stimuli. CXCR3 expression was inhibited when TCR stimulation was persistent in the reculture. CXCR3 induction also depended on the stimulation with IFN-gamma because CXCR3 expression was not induced in IFN-gamma-deficient T cells. The induction of another Th1 chemokine receptor CCR5 absolutely required IL-12 stimulation and STAT4 involvement. In contrast, CXCR3 was induced on STAT4-deficient T cells independently of IL-12 stimulation as long as IFN-gamma was produced as a result of potent TCR stimulation. These results show that CXCR3 induction on TCR-triggered T cells requires the release of these T cells from persistent TCR signaling and the stimulation with IFN-gamma and also indicate the differential regulatory mechanisms underlying the induction of two Th1 chemokine receptors.

DOI： 10.1002/1521-4141(200206)32:6<1792::AID-IMMU1792>3.0.CO;2-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

IL-12 was recently shown to induce CCR5 on TCR-triggered mouse T cells. Considering that STAT4 is the most critical of IL-12 signaling molecules, this study investigated the role for STAT4 in the induction of CCR5 expression. IL-12R was induced by stimulation with anti-CD3 plus anti-CD28 mAb similarly on T cells from wild-type (WT) and STAT4-deficient (STAT4(-/-)) mice, but the levels of IL-12R induced on IFN-gamma -deficient (IFN-gamma (-/-)) T cells were lower compared with WT T cells. Exposure of TCR-triggered WT T cells to IL-12 induced CCR5 expression. In contrast, TCR-triggered STAT4(-/-) T cells failed to express CCR5 in response to IL-12. IL-12 stimulation induced detectable albeit reduced levels of CCR5 expression on IFN-gamma (-/-) T cells. Addition of rIFN-gamma to cultures of IFN-gamma (-/-) T cells, particularly to cultures during TCR triggering resulted in restoration of CCR5 expression. However, CCR5 expression was not induced in STAT4(-/-) T cells by supplementation of rIFN-gamma. These results indicate that for the induction of CCR5 on T cells, 1) STAT4 plays an indispensable role; 2) such a role is not substituted by simply supplementing IFN-gamma; and 3) IFN-gamma amplifies CCR5 induction depending on the presence of STAT4.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

Despite increasing evidence for the role of the chemokine system in leukocyte trafficking, the mechanism underlying the induction of chemokine receptors is poorly understood. Here, we investigated how CCR5, a chemokine receptor implicated in T cell migration to inflammatory sites, is induced in the T cell. CCR5 mRNA was hardly detected in resting T cells and marginally induced following T cell receptor (TCR) stimulation. However, TCR-triggered T cells expressed IL-12 receptor, and stimulation with recombinant IL-12 resulted in high levels of CCR5 expression on both CD4(+) and CD8(+) T cells. In contrast, IL-2 failed to up-regulate CCR5 expression. The effect of IL-12 was selective to CCR5 because IL-12 did not upregulate CXCR3 expression. Surface expression of CCR5 was shown by staining with anti-CCR5 monoclonal antibody. Stimulation of these CCR5-positive T cells with the relevant chemokine MIP-1 alpha elicited Ca2+ influx, showing that IL-12-induced CCR5 is functional. These results indicate a critical role for IL-12 in the induction of CCR5 on TCR-triggered T cells.

DOI： 10.1002/1521-4141(200108)31:8<2411::AID-IMMU2411>3.0.CO;2-Y

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

IFN-gamma -deficient (IFN-gamma (-/-)) mice induce potent in vitro immune responses such as anti-allo mixed lymphocyte reaction and CTL responses, whereas they often fail to exhibit in vivo immunity. Here, we investigated whether there exists a defect in tumor rejection responses and if so, which process of responses is impaired. IFN-gamma (-/-) and wild-type (WT) BALB/c mice were immunized with attenuated syngeneic CSA1M tumor cells. The capacity of T cells to mediate tumor protection was examined in Winn assays to assess the growth of tumor cells admired with tumor-sensitized T cells. Splenic T cells from both groups of mice exhibited comparable levels of tumor-neutralizing activity. When portions of immunized mice were directly challenged with viable tumor cells, tumor rejection was induced only in WT mice. CD4(+) and CD8(+) T-cell infiltration were observed at the site of tumor challenge in WT mice, whereas such a T-cell infiltration did not occur in IFN-gamma (-/-) mice, Similarly, splenic T cells from interleukin 12-treated CSA1M-bearing IFN-gamma (-/-) and WT mice neutralized tumor cells at comparable efficacies in Winn assays. However, the migration of these T cells to tumor masses and the resultant interleukin 12-induced tumor regression took place in WT mice, but neither intratumoral T-cell infiltration nor tumor regression occurred in IFN-gamma (-/-) mice, These results indicate a critical requirement for IFN-gamma in the process of inducing T-cell migration to tumor sites rather than of generating antitumor protective T cells.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Interleukin-12 (IL-12) treatment is effective in the CSA1M but not in the Meth A and CSA1M-variant tumor models. The authors investigated the cause by which IL-12 treatment fails to induce tumor regression in these two tumor models. T cells from CSA1M-bearing mice have high levels of IL-12 responsiveness, whereas cells from Meth A-bearing mice display marginal levels of responsiveness. Because IL-12 responsiveness in T cells is induced after T-cell receptor stimulation, the lack of IL-12 responsiveness suggests that T cells in Meth A-bearing mice are not sensitized to Meth A tumor antigen. Immunization of normal mice with attenuated Meth A tumor cells resulted in a protective immunity, as shown by the rejection of challenged viable Meth A cells. Such an immunization, when performed in Meth A-bearing mice, induced potent IL-12 responsiveness in T cells. Nevertheless, IL-12 treatment in these mice did not inhibit tumor growth. In another IL-12-incurable (CSA1M-variant) model, IL-12 responsiveness was observed before tumor cell immunization. However, IL-12 treatment was ineffective regardless of whether tumor cell immunization was performed. In these two models, the failure of IL-12 treatment to induce tumor regression was associated with the lack of T-cell migration to tumor sites. These results indicate that the sensitization of T cells to tumor antigens and generation of IL-12 responsiveness are insufficient to induce tumor regression when these sensitized T cells are not allowed to migrate to tumor sites.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

While IL-12 administration induces tumor regression through stimulating T cells in tumor-bearing mice, this IL-12 effect is observed in some but not all tumor models. The present study aimed to compare IL-12 responsiveness of T cells from tumor-bearing mice in IL-12-responsive (CSA1M and OV-HM) and -unresponsive (Meth A) tumor models, Tumor regression in IL-12-responsive tumor models required the participation of T cells, but not of NK1.1(+) cells. Because a NK1.1(+) cell population was the major producer of IFN-gamma, comparable levels of IFN-gamma production were induced in IL-12-responsive and -unresponsive tumor-bearing mice. This indicates that the amount of IFN-gamma produced in tumor-bearing individuals does not correlate with the anti-tumor efficacy of IL-12, In contrast, IL-12 responsiveness of T cells differed between the responsive and unresponsive models: purified T cells from CSA1M/OV-HM-bearing or Meth A-bearing mice exhibited high or low IL-12 responsiveness respectively, when evaluated by the amounts of IFN-gamma produced in response to IL-12, T cells from CSA1M- or OV-HM-bearing but not from Meth A-bearing mice exhibited enhanced levels of mRNA for the IL-12 receptor (IL-12R), These results indicate that a fundamental difference exists in IL-12 responsiveness of T cells between IL-12-responsive and -unresponsive tumor models, and that such a difference is associated with the expression of IL-12R on T cells.

DOI： 10.1093/intimm/12.5.701

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Interleukin (IL) 12 has been shown to elicit tumor regression when this cytokine induces the migration of T cells to tumor sites. The present study investigates the role of a peritumoral stromal reaction in IL-12-induced T-cell migration. In the CSA1M and OV-HM tumor models, IL-12 treatment induced tumor regression that is associated with T-cell migration, Neither T-cell migration nor tumor regression was observed in the Meth A and MCH-1-A1 models. Stromal tissue containing neovascular blood vessels developed at the peritumoral area of the former two IL-12-responsive tumors but not at the peritumoral area of the latter two IL-12-unresponsive tumors. The significance of stroma development was investigated using a pair of tumor models (CSA1M and a subline derived from CSA1M designated the CSA1M variant), both of which exhibit the same tumor immunogenicity. In contrast to the parental CSA1M cell line, the variant cell line was not responsive to IL-12, and neither stroma development nor T-cell migration was observed, even after IL-12 treatment. Histological analyses revealed that the parental cell Line had peritumoral stroma with intrastromal vessels but only a few vessels in tumor parenchyma, whereas the variant cell line showed no stroma but had abundant vasculature in the tumor parenchyma. Most importantly, only stromal vessels in the parental tumors expressed detectable and enhanced levels of vascular cell adhesion molecule 1 (VCAM-1)/ intercellular adhesion molecule 1 (ICAM-1) before and after IL-12 treatment, respectively. In contrast, parenchymal vasculature in the variant cell line failed to express VCAM-1/ICAM-1 even after IL-12 treatment. When transferred into recipient tumor-bearing mice, IL-12-stimulated T cells from the parental CSA1M-bearing or the variant CSA1M-bearing mice migrated into the parental but not into the variant tumor mass. Together with our previous finding that T-cell migration depends on the VCAM-1/ICAM-1 adhesive interactions, the present results indicate a critical role for peritumoral stroma/stromal vasculature in the acceptance of tumor-infiltrating T cells that is a prerequisite for IL-12-induced tumor regression.

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（基調）  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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