研究者データベース

高田 健介(タカダ ケンスケ)
獣医学研究院 獣医学部門 臨床獣医科学分野
准教授

基本情報

所属

  • 獣医学研究院 獣医学部門 臨床獣医科学分野

職名

  • 准教授

学位

  • 博士(獣医学)(北海道大学)

ホームページURL

科研費研究者番号

  • 40570073

J-Global ID

研究キーワード

  • 免疫記憶   獲得免疫   T細胞   免疫学   胸腺   ストローマ細胞   正の選択   リンパ節   二次リンパ組織   Tリンパ球レパトア形成   レパトア形成   Tリンパ球   

研究分野

  • ライフサイエンス / 免疫学

職歴

  • 2017年04月 - 現在 北海道大学 大学大学院獣医学研究院 准教授
  • 2016年10月 - 2017年03月 北海道大学 大学院獣医学研究科 准教授
  • 2015年08月 - 2016年09月 徳島大学 疾患プロテオゲノム研究センター 准教授
  • 2010年09月 - 2014年07月 徳島大学 講師
  • 2005年06月 - 2009年08月 ミネソタ大学 免疫学センター 博士研究員

学歴

  • 2001年04月 - 2005年03月   北海道大学   大学院獣医学研究科
  • 1995年04月 - 2001年03月   北海道大学   獣医学部

所属学協会

  • 日本獣医学会   日本免疫学会   

研究活動情報

論文

  • Zimeng Cai, Taishin Ishibashi, Mina Kozai, Hironobu Mita, Shangyi Wang, Kensuke Takada, Mutsumi Inaba
    Immunology & Cell Biology 2020年09月17日 [査読有り][通常論文]
  • Benjaporn Kiatpakdee, Kota Sato, Yayoi Otsuka, Nobuto Arashiki, Yuqi Chen, Takuya Tsumita, Wataru Otsu, Akito Yamamoto, Reo Kawata, Jumpei Yamazaki, Yoshikazu Sugimoto, Kensuke Takada, Narla Mohandas, Mutsumi Inaba
    The Journal of biological chemistry 295 23 8048 - 8063 2020年06月05日 [査読有り][通常論文]
     
    TSPO2 (translocator protein 2) is a transmembrane protein specifically expressed in late erythroblasts and has been postulated to mediate intracellular redistribution of cholesterol. We identified TSPO2 as the causative gene for the HK (high-K+) trait with immature red cell phenotypes in dogs and investigated the effects of the TSPO2 defects on erythropoiesis in HK dogs with the TSPO2 mutation and Tspo2 knockout (Tspo2-/-) mouse models. Bone marrow-derived erythroblasts from HK dogs showed increased binucleated and apoptotic cells at various stages of maturation and shed large nuclei with incomplete condensation when cultured in the presence of erythropoietin, indicating impaired maturation and cytokinesis. The canine TSPO2 induces cholesterol accumulation in the endoplasmic reticulum and could thereby regulate cholesterol availability by changing intracellular cholesterol distribution in erythroblasts. Tspo2-/- mice consistently showed impaired cytokinesis with increased binucleated erythroblasts, resulting in compensated anemia, and their red cell membranes had increased Na,K-ATPase, resembling the HK phenotype in dogs. Tspo2-deficient mouse embryonic stem cell-derived erythroid progenitor (MEDEP) cells exhibited similar morphological defects associated with a cell-cycle arrest at the G2/M phase, resulting in decreased cell proliferation and had a depletion in intracellular unesterified and esterified cholesterol. When the terminal maturation was induced, Tspo2-/- MEDEP cells showed delays in hemoglobinization; maturation-associated phenotypic changes in CD44, CD71, and TER119 expression; and cell-cycle progression. Taken together, these findings imply that TSPO2 is essential for coordination of maturation and proliferation of erythroblasts during normal erythropoiesis.
  • Umme Shahina Khanom, Izumi Ohigashi, Sayumi Fujimori, Kenta Kondo, Kensuke Takada, Yousuke Takahama
    Journal of immunology (Baltimore, Md. : 1950) 203 4 881 - 887 2019年08月15日 [査読有り][通常論文]
     
    The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4+CD8+ thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8+ T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8+ T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells.
  • Yaser Hosny Ali Elewa, Osamu Ichii, Kensuke Takada, Teppei Nakamura, Md. Abdul Masum, Yasuhiro Kon
    Frontiers in Immunology 9 271  2018年02月15日 [査読有り][通常論文]
     
    Bleomycin (BLM) has been reported to induce lung inflammation and fibrosis in human and mice and showed genetic susceptibility. Interestingly, the C57BL/6 (B6) mice had prominent mediastinal fat-associated lymphoid cluster (MFALCs) under healthy condition, and showed susceptibility to development of lung fibrosis following BLM administration. However, the pathogenesis of lung lesion progression, and their correlation with MFALC morphologies, remain to be clarified. To investigate the correlations between MFALC structures and lung injuries in B6 mice, histopathological examination of mediastinal fat tissues and lungs was examined at 7 and 21 days (d) following a single 50 μL intranasal (i.n.) instillation of either BLM sulfate (5 mg/kg) (BLM group) or phosphate-buffered saline (control group). The lung fibrosis was examined by Masson's trichrome (MT) stain of paraffin sections and mRNA expression levels of Col1a1, Col3a1, and Acta2 in different frozen lung samples. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1, BrdU, LYVE-1, and peripheral node addressin (PNAd) was performed to detect T- and B-cells, macrophages, granulocytes, proliferating cells, lymph vessels (LVs), and high endothelial venules (HEVs). We found that MFALCs were more abundant in the BLM group as compared to the control group. The lung of BLM group developed pneumonitis with severe cellular infiltrations at 7 days and significant collagen deposition (MT) and higher expression of Col1a1, and Col3a1 at 21 days post-administration. Numerous immune cells, proliferating cells, HEVs, and LVs were observed in both MFALCs and lungs of the BLM group. Interestingly, PNAd + HEVs were observed in the lungs of the BLM group, but not the control group. Moreover, numerous Gr1 + polymorphonuclear and mononuclear-like ring cells were found in the MFALCs and lungs of the BLM group. Interestingly, flow cytometric analysis revealed a significant increase of B-cell populations within the MFALCs of BLM group suggesting a potential proliferative induction of B-cells following inflammation. Furthermore, significant positive correlations were observed between quantitative parameters of these immune cells in both the lungs and MFALCs. Thus, we suggest a potentially important role for MFALCs and HEVs in the progression of lung disease, especially in inflammatory lung disease.
  • Kenta Kondo, Kensuke Takada, Yousuke Takahama
    CURRENT OPINION IN IMMUNOLOGY 46 53 - 57 2017年06月 [査読有り][通常論文]
     
    The processing and presentation of major histocompatibility complex (MHC)-associated antigens depend on the intracellular digestion of self- and nonself-proteins, the loading of digested peptides onto MHC molecules, and the traffic of peptide MHC complexes to plasma membrane surface for display to interacting T cells. Recent studies have revealed unique machineries for antigen Processing and presentation in thymic antigen-presenting cells that display self-antigens to developing thymocytes for the formation of functionally competent yet self-tolerant T cell repertoire. Here, we briefly summarize those machineries, focusing on the biology of cortical and medullary thymic epithelial cells.
  • Kensuke Takada, Kenta Kondo, Yousuke Takahama
    JOURNAL OF IMMUNOLOGY 198 6 2215 - 2222 2017年03月 [査読有り][通常論文]
     
    To establish an immunocompetent TCR repertoire that is useful yet harmless to the body, a de novo thymocyte repertoire generated through the rearrangement of genes that encode TCR is shaped in the thymus through positive and negative selection. The affinity between TCRs and self-peptides associated with MHC molecules determines the fate of developing thymocytes. Low-affinity TCR engagement with self-peptide-MHC complexes mediates positive selection, a process that primarily occurs in the thymic cortex. Massive efforts exerted by many laboratories have led to the characterization of peptides that can induce positive selection. Moreover, it is now evident that protein degradation machineries unique to cortical thymic epithelial cells play a crucial role in the production of MHC-associated self-peptides for inducing positive selection. This review summarizes current knowledge on positive selection-inducing self-peptides and Ag processing machineries in cortical thymic epithelial cells. Recent studies on the role of positive selection in the functional tuning of T cells are also discussed.
  • 胸腺プロテアソームを介したCD8+ T細胞の正の選択
    髙田健介, 髙濵洋介
    臨床免疫・アレルギー科 65 506 - 512 2016年 [査読無し][招待有り]
  • 胸腺プロテアソーム依存的な正の選択はCD8+T細胞の抗原応答性を至適化する
    高田健介, 高浜洋介
    実験医学 34 446 - 449 2016年 [査読無し][招待有り]
  • Kensuke Takada, Francois Van Laethem, Yan Xing, Kazuyuki Akane, Haruhiko Suzuki, Shigeo Murata, Keiji Tanaka, Stephen C. Jameson, Alfred Singer, Yousuke Takahama
    NATURE IMMUNOLOGY 16 10 1069 - + 2015年10月 [査読有り][通常論文]
     
    In the thymus, low-affinity T cell antigen receptor (TCR) engagement facilitates positive selection of a useful T cell repertoire. Here we report that TCR responsiveness of mature CD8(+) T cells is fine tuned by their affinity for positively selecting peptides in the thymus and that optimal TCR responsiveness requires positive selection on major histocompatibility complex class I-associated peptides produced by the thymoproteasome, which is specifically expressed in the thymic cortical epithelium. Thymoproteasome-independent positive selection of monoclonal CD8(+) T cells results in aberrant TCR responsiveness, homeostatic maintenance and immune responses to infection. These results demonstrate a novel aspect of positive selection, in which TCR affinity for positively selecting peptides produced by thymic epithelium determines the subsequent antigen responsiveness of mature CD8(+) T cells in the periphery.
  • Katsuhiro Sasaki, Kensuke Takada, Yuki Ohte, Hiroyuki Kondo, Hiroyuki Sorimachi, Keiji Tanaka, Yousuke Takahama, Shigeo Murata
    NATURE COMMUNICATIONS 6 7484  2015年06月 [査読有り][通常論文]
     
    Positive selection in the thymus provides low-affinity T-cell receptor (TCR) engagement to support the development of potentially useful self-major histocompatibility complex class I (MHC-I)-restricted T cells. Optimal positive selection of CD8(+) T cells requires cortical thymic epithelial cells that express beta 5t-containing thymoproteasomes (tCPs). However, how tCPs govern positive selection is unclear. Here we show that the tCPs produce unique cleavage motifs in digested peptides and in MHC-I-associated peptides. Interestingly, MHC-I-associated peptides carrying these tCP-dependent motifs are enriched with low-affinity TCR ligands that efficiently induce the positive selection of functionally competent CD8(+) T cells in antigen-specific TCR-transgenic models. These results suggest that tCPs contribute to the positive selection of CD8(+) T cells by preferentially producing low-affinity TCR ligand peptides.
  • T細胞のレパトア形成における胸腺皮質上皮の役割
    高田健介, 高浜洋介
    臨床免疫・アレルギー科 63 507 - 513 2015年 [査読無し][招待有り]
  • T細胞分化のチェックポイント
    高田健介, 高浜洋介
    炎症と免疫 12 3 - 9 2015年 [査読無し][招待有り]
  • Kensuke Takada, Yousuke Takahama
    ADVANCES IN IMMUNOLOGY, VOL 125 125 87 - 110 2015年 [査読有り][通常論文]
     
    A repertoire of antigen recognition specificities in mature T cell pool is formed by the selection during T cell development in the thymus. Positive selection is an essential process for the development of functionally competent T cells and is dependent on the interaction between T cell antigen receptors (TCRs) that newly generated thymocytes express and self-peptide-associated major histocompatibility complex (pMHC) molecules that cortical thymic epithelial cells (cTECs) express. Characterization of positive-selection-inducing peptides has revealed that the low-affinity TCR engagement by the positive-selection-inducing pMHC complexes initiates intracellular signals that induce the survival of immature thymocytes and their differentiation into mature T cells. Recent studies suggest unique mechanisms of antigen processing in cTECs for the production of positively selecting MHC-bound self-peptides.
  • Khongorzul Togoo, Yousuke Takahama, Kensuke Takada
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 449 2 241 - 247 2014年06月 [査読有り][通常論文]
     
    Significant attention has been given to the role played by non-hematopoietic cells in the immune organs, including the lymph nodes, in hopes of understanding the development, maintenance, and regulation of the immune system. However, the molecular and cellular characterization of non-hematopoietic cells is still in its infancy. Here we show that non-hematopoietic cells in mouse lymph nodes can be fractionated into previously unidentified subpopulations according to the transgenic reporter expression of alpha-smooth muscle actin (alpha SMA). alpha SMA(+) non-hematopoietic cells were predominantly detected in gp38(+)CD31(-) and gp38(-)CD31(-) cells. Molecular expression profiles suggest similarities between alpha SMA(+)gp38(+)CD31(-) and alpha SMA(-)gp38(+)CD31(-) subpopulations and dissimilarities between alpha SMA(+)gp38(-)CD31(-) and alpha SMA(-)gp38(-)CD31(-) subpopulations. The results indicate that alpha SMA is a useful marker for further understanding the molecular and cellular characteristics of non-hematopoietic cells in the lymph nodes. (C) 2014 Elsevier Inc. All rights reserved.
  • Kouta Yano, Christine Carter, Naofumi Yoshida, Takaya Abe, Akiko Yamada, Takeshi Nitta, Naozumi Ishimaru, Kensuke Takada, Geoffrey W. Butcher, Yousuke Takahama
    EUROPEAN JOURNAL OF IMMUNOLOGY 44 2 561 - 572 2014年02月 [査読有り][通常論文]
     
    Gimap3 (IAN4) and Gimap5 (IAN5) are highly homologous GTP-binding proteins of the Gimap family. Gimap3 and Gimap5, whose transcripts are abundant in mature lymphocytes, can associate with antiapoptotic Bcl-2 family proteins. While it is established that Gimap5 regulates T-cell survival, the in vivo role of Gimap3 is unclear. Here we report the preparation and characteristics of mouse strains lacking Gimap3 and/or Gimap5. We found that the number of T cells was markedly reduced in mice deficient in both Gimap3 and Gimap5. The defects in T-cell cellularity were more severe in mice lacking both Gimap3 and Gimap5 than in mice lacking only Gimap5. No defects in the cellularity of T cells were detected in mice lacking only Gimap3, whereas bone marrow cells from Gimap3-deficient mice showed reduced T-cell production in a competitive hematopoietic environment. Moreover, retroviral overexpression and short hairpin RNAs-mediated silencing of Gimap3 in bone marrow cells elevated and reduced, respectively, the number of T cells produced in irradiated mice. These results suggest that Gimap3 is a regulator of T-cell numbers in the mouse and that multiple Gimap family proteins cooperate to maintain T-cell survival.
  • Kensuke Takada, Izumi Ohigashi, Michiyuki Kasai, Hiroshi Nakase, Yousuke Takahama
    THYMIC DEVELOPMENT AND SELECTION OF T LYMPHOCYTES 373 1 - 17 2014年 [査読有り][通常論文]
     
    The thymic cortex provides a microenvironment that supports the generation and T cell antigen receptor (TCR)-mediated selection of CD4(+)CD8(+)TCR alpha beta(+) thymocytes. Cortical thymic epithelial cells (cTECs) are the essential component that forms the architecture of the thymic cortex and induces the generation as well as the selection of newly generated T cells. Here we summarize current knowledge on the development, function, and heterogeneity of cTECs, focusing on the expression and function of beta 5t, a cTEC-specific subunit of the thymoproteasome.
  • Takahama Y, Takada K, Murata S, Tanaka K
    Current opinion in immunology 24 1 92 - 98 2012年02月 [査読有り][通常論文]
     
    Proteasomes are multisubunit proteolytic complexes that degrade cytoplasmic and nuclear proteins in eukaryotes. Proteasome-dependent proteolysis contributes to various cellular processes, including misfolded protein degradation, signal transduction, and antigen presentation. The thymoproteasome is a form of proteasome that contains the vertebrate-specific catalytic subunit beta 5t specifically expressed by cortical epithelial cells in the thymus. The thymoproteasome is essential for the positive selection of CD8+ T cells that carry an immunocompetent repertoire of antigen recognition specificity. Here we summarize the structure and expression of the thymoproteasome and discuss how it regulates the positive selection of CD8+T cells.
  • Kensuke Takada, Xiaodan Wang, Geoffrey T. Hart, Oludare A. Odumade, Michael A. Weinreich, Kristin A. Hogquist, Stephen C. Jameson
    JOURNAL OF IMMUNOLOGY 186 2 775 - 783 2011年01月 [査読有り][通常論文]
     
    The transcription factor Kruppel-like factor 2 (KLF2) was proposed to regulate genes involved in cell cycle entry and T cell trafficking; however, the physiological role of its expression in postactivated T cells is not well defined. Previous studies suggested that the cytokines IL-2 and IL-15 differentially regulate KLF2 re-expression in postactivation T cells and that these cytokines also influence effector versus memory T cell differentiation. Using conditional and inducible KLF2-knockout model systems, we tested the specific role of KLF2 expression in activated CD8(+) T cells cultured with these cytokines. KLF2 was required for effective transcription of sphingosine-1-phosphate receptor-1 (S1P(1)) and CD62L in postactivation T cells. However, although different cytokines dramatically altered the expression of cell-cycle-related genes, endogenous KLF2 had a minimal impact. Correspondingly, KLF2-deficient T cells showed dysregulated trafficking but not altered proliferative characteristics following in vivo responses to Ag. Thus, our data help to define KLF2-dependent and -independent aspects of activatedCD8(+) T cell differentiation and argue against a physiological role in cell cycle regulation. The Journal of Immunology, 2011, 186: 775-783.
  • Kensuke Takada, Yousuke Takahama
    NATURE IMMUNOLOGY 11 5 370 - 371 2010年05月 [査読有り][通常論文]
  • Kensuke Takada, Stephen C. Jameson
    NATURE REVIEWS IMMUNOLOGY 9 12 823 - 832 2009年12月 [査読有り][通常論文]
     
    The peripheral naive T cell pool is fairly stable in number, diversity and functional competence in the absence of vigorous immune responses. However, this apparent tranquillity is not an intrinsic property of T cells but involves continuous tuning of the T cell pool composition by homeostatic signals. In the past decade, studies have revealed that naive T cells rely on combinatorial signals from self-peptide-MHC complexes and interleukin-7 for their physical and functional maintenance. Competition for these factors dictates T cell 'space'. In addition, recent studies show that these and other homeostatic factors are offered to T cells on stromal cell networks, which also serve to guide T cell trafficking in secondary lymphoid organs. Such findings suggest the importance of 'place' in the perception and integration of homeostatic cues for the maintenance and functional tuning of the naive T cell pool.
  • Kensuke Takada, Stephen C. Jameson
    JOURNAL OF EXPERIMENTAL MEDICINE 206 10 2253 - 2269 2009年09月 [査読有り][通常論文]
     
    Previous studies have suggested that naive CD8 T cells require self-peptide-major histocompatability complex (MHC) complexes for maintenance. However, interpretation of such studies is complicated because of the involvement of lymphopenic animals, as lymphopenia drastically alters naive T cell homeostasis and function. In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide-MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was mediated through a transcriptional mechanism. Hence, our data suggest that, in a nonlymphopenic setting, self-class I MHC molecules support CD8 T cell survival, but that these interactions also attenuate naive T cell sensitivity by dynamic tuning of CD8 levels.
  • H. Hamlet Chu, James J. Moon, Kensuke Takada, Marion Pepper, Jerry A. Molitor, Timothy W. Schacker, Kristin A. Hogquist, Stephen C. Jameson, Marc K. Jenkins
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 27 11241 - 11245 2009年07月 [査読有り][通常論文]
     
    T cell receptors (TCRs) on T lymphocytes in an individual bind foreign peptides bound to major histocompatibility complex (MHC) molecules expressed in that individual (designated MHCA). Results from radiation bone marrow chimeras and TCR transgenic mice indicate that this complex form of antigen recognition is the result of positive selection of clones with low affinity for self peptide: MHCA complexes during development. Here we used a sensitive peptide: MHC tetramer enrichment method to quantify the role of positive selection in the generation of the preimmune polyclonal T cell repertoire in normal individuals. We made the surprising observation that mouse and human naive T cells capable of binding to foreign peptide: MHCA were present at the same frequency in hosts that expressed MHCA or a different MHC isoform (MHCB). However, most of the clones in MHCB hosts also recognized self peptide: MHCA complexes. When these "alloreactive'' T cells were removed from the MHCB repertoire via negative selection in an MHCA host, the number of foreign peptide: MHCA-binding T cells was reduced to one fifth and many of the remaining cells did not respond to the peptide. Therefore, although positive selection on MHCA was not required to produce foreign peptide: MHCA-binding clones, it had a large effect on selecting responsive clones.
  • Michael A. Weinreich, Kensuke Takada, Cara Skon, Steven L. Reiner, Stephen C. Jameson, Kristin A. Hogquist
    IMMUNITY 31 1 122 - 130 2009年07月 [査読有り][通常論文]
     
    The transcription factor KLF2 regulates T cell trafficking by promoting expression of the lipid-binding receptor S1P(1) and the selectin CD62L. Recently, it was proposed that KLF2 also represses the expression of chemokine receptors. We confirmed the up-regulation of the chemokine receptor CXCR3 on KLF2-deficient T cells. However, we showed that this was a cell-nonautonomous effect, as revealed by CXCR3 upregulation on wild-type bystander cells in mixed bone-marrow chimeras with KLF2-deficient cells. Furthermore, KLF2-deficient T cells overproduced IL-4, leading to the upregulation of CXCR3 through an IL-4-receptor- and eomesodermin-dependent pathway. Consistent with the increased IL-4 production, we found high concentrations of serum IgE in mice with T cell-specific KLF2 deficiency. Our findings support a model where KLF2 regulates T cell trafficking by direct regulation of S1P(1) and CD62L and restrains spontaneous cytokine production in naive T cells.
  • Kensuke Takada, Kristin A. Hogquist, Stephen C. Jameson
    BIOLOGY OF KRUPPEL-LIKE FACTORS 95 - 106 2009年 [査読有り][通常論文]
     
    Several family members of Kruppel-like factors (KLFs) are found in lymphocytes, and their expression is tightly regulated during development and differentiation. The related factors KLF2 and KLF4 have been suggested to promote lymphocyte "quiescence" by inducing withdrawal of cells from the cell cycle. Although the physiological role of KLF2 in cell cycle control in lymphocytes is currently unclear, it is potentially due to redundancy between related KLFs. On the other hand, there is growing evidence that individual KLFs regulate migration of lymphocytes (and other cells) during normal homeostasis of the immune system and in inflammatory situations. In addition to KLF2 and KLF4, the roles of KLF10 and KL13 in lymphocytes are briefly discussed.
  • Konno A, Takiguchi M, Takada K, Usami T, Azumi K, Kubota H, Inaba M, Saegusa J, Kon Y
    Immunogenetics 59 11 853 - 859 2007年11月 [査読有り][通常論文]
     
    Sjogren's syndrome (SS) is caused by an autoimmune sialodacryoadenitis, and up to 5% of patients with SS develop malignant B cell growth. The IQI mouse is a spontaneous model of primary SS in which B cells are the dominant cellular subpopulation among mononuclear infiltrates in sialitis lesions. Understanding the genetic control of aberrant B cell growth in IQI mice may help elucidate the genetic mechanisms involved in B-lineage hyperplasia leading to malignant transformation in human SS. B cell-dominant infiltration in the submandibular glands of 6-month-old IQI and C57BL/6 (B6) mice and their F1 and F2 progenies was quantified as B-lymphocytic sialitis score, and a genome-wide scan of 179 (IQI x B6) F2 females was performed to identify a quantitative trait locus (QTL) controlling this phenotype. A QTL significantly associated with variance in B-lymphocytic sialitis score was mapped to the D6Mit138 marker (position of 0.68cM) on proximal chromosome 6, with a logarithm of odds score of 4.3 (p=0.00005). This QTL, named autoimmune sialitis in IQI mice, associated locus 1 (Asq1), colocalized with Islet cell autoantigen 1 (Ica1), which encodes a target protein of the immune processes that define the pathogenesis of primary SS in humans and in the nonobese diabetic mouse model.
  • Takada K, Takiguchi M, Inaba M
    The Journal of veterinary medical science / the Japanese Society of Veterinary Science 67 9 955 - 957 2005年09月 [査読有り][通常論文]
     
    Thymectomy on day 3 after birth (D3Tx) is understood to eliminate CD4(+)CD25(+) regulatory T cells (T-reg) from the peripheral T cell repertoire in rodents, leading to the activation of autoreactive T cells. Herein, D3Tx was performed in IQI/Jic mice, a model for Sjogren's syndrome characterized by autoimmune infiltrations into the lacrimal and salivary glands. At the age of 16 weeks, very severe lesions were observed in lacrimal tissues from thymectornized mice, suggesting that T-reg preserve their immunoregulatory function in young IQI/Jic mice. In contrast, salivary lesions were comparable in the D3Tx and control groups, raising the possibility that either salivary-specific T-reg escaped elimination in thymectornized mice or spontaneous lesions in IQI/Jic mice developed independently of the tolerance through T-reg.
  • K Takada, M Takiguchi, A Konno, A Inaba
    JOURNAL OF BIOLOGICAL CHEMISTRY 280 5 3982 - 3988 2005年02月 [査読有り][通常論文]
     
    We have recently characterized IQI/Jic mice as a model for Sjogren's syndrome (SS), a chronic autoimmune disease in humans. In SS, local lymphocytic infiltrations into salivary and lacrimal glands frequently develop to the involvement of systemic exocrine and nonexocrine organs, and the mechanism for progression of this disease remains obscure. Herein, we report identification of an autoantigen shared by various target organs in IQI/Jic mice. Polypeptides identified based on immunorecognition by autoantibodies in sera from IQI/ Jic mice affected with autoimmune disease (> 12 weeks of age) were tissue kallikrein (Klk)-1 and -13 and were cross-reactive to the autoantibodies. Interestingly, Klk-13, but not Klk-1, caused a proliferative response of splenic T cells from IQI/Jic mice from the age of 4 weeks onward. In addition, remarkably enhanced expression of Klk-13 was observed in the salivary glands of the mice in accordance with the development of inflammatory lesions. These results indicate that Klk-13 acts as an autoantigen and may increase T cells responsive to organs commonly expressing Klk-13, playing a pivotal role in the etiology of progression of disease in IQI/Jic mice. Our findings provide insights into the contributions of autoantigens shared by multiple organs in the progress of SS from an organ-specific to a systemic disorder.
  • K Takada, M Takiguchi, A Konno, M Inaba
    RHEUMATOLOGY 43 7 858 - 862 2004年07月 [査読無し][通常論文]
     
    Objective. In primary Sjogren's syndrome (SS), systemic exocrine and non-exocrine organs are frequently affected, in addition to the major target tissues of the lacrimal and salivary glands. This study aimed to examine whether the IQI/Jic mouse, an animal model of SS whose autoimmune dacryoadenitis and sialoadenitis have been documented, develops inflammatory lesions in multiple organs as in primary SS. Methods. Systemic histopathological analysis was performed on IQI/Jic mice at various ages. Phenotypes of infiltrated lymphocytes were determined using immunohistochemical techniques. Results. Inflammatory lesions were observed not only in the lacrimal and salivary glands, but also in multiple organs, including the lung, pancreas and kidney at advanced ages, and were mainly composed of CD4(+) T cells and B cells. The incidence and severity of the inflammatory lesions increased with age in all these organs. The histological appearance and spreading of lesions were similar to those in human primary SS. Conclusions. IQI/Jic mice spontaneously develop inflammatory cellular infiltrates in multiple exocrine and non-exocrine organs. This characteristic distinguishes IQI/Jic mice from other murine models, making them favourable for studies on the pathogenesis of systemic involvement in primary SS.
  • Konno A, Takada K, Saegusa J, Takiguchi M
    Autoimmunity 36 4 247 - 254 2003年06月 [査読有り][通常論文]
     
    Subpopulations of infiltrating lymphocytes, professional antigen-presenting cells (APCs), and Th1/Th2 cytokines that could initiate an autoimmune sialodacryoadenitis were studied in the IQI/Jic mouse model of primary Sjogren's syndrome. Although lymphocytic infiltrations were first seen in submandibular glands (SMGs) of females and in lacrimal glands (LGs) of males at 8 weeks of age, clusters of MHC class II+, GD11c+, B7-2+ dendritic cells (DCs) were already localized in these tissues at 4 weeks. At 8 weeks, the infiltrating lymphocytes consisted of almost equal numbers of B cells and CD4+ T cells. In the inflammatory foci, MHC class II+, CD11c+, B7-2+ DCs formed network-like structures. Duct cells in the lesions showed immunoreactivities for MHC class II and ALCAM (a costimulatory adhesion molecule). IL-12 and IFN-γ transcripts were detected by RT-PCR in SMGs of females and in LGs of males at 8-12 weeks. These results suggest that the clustered DCs might play an important role in the initiation of the adenitis, and further suggest that the DCs and epithelial cells may participate in the activation of CD4+ T cells. It is also likely that Th1 cytokines mediate the functional interactions between the APCs and CD4+ T cells in the early lesions.

講演・口頭発表等

  • マウスのエフェクターおよびメモリーT細胞の分化における核内受容体REV-ERBの役割  [通常講演]
    Zimeng Cai, 香西美奈, 三田泰誠, Shangyi Wang, 高田健介, 稲葉睦
    第163回日本獣医学会学術集会 2020年09月
  • 核内受容体間の競合がCD8+ T細胞の活性化と記憶形成に及ぼす影響  [通常講演]
    石橋 太心, Zimeng Cai, 香西 美奈, 高田 健介, 稲葉 睦
    2019年09月 口頭発表(一般)
  • Functional education of CD8 T cells in the thymus  [招待講演]
    高田健介
    The 20th Seoul National University – Hokkaido University Joint Symposium 2017年11月 口頭発表(招待・特別)
  • CD8+T細胞の記憶形成における核内受容体の役割  [通常講演]
    高田健介
    第160回日本獣医学会学術集会 2017年09月 口頭発表(一般)
  • 胸腺における正の選択を介したT細胞の機能的教育  [招待講演]
    高田健介
    第54回日本生化学会北海道支部会 2017年07月 口頭発表(招待・特別)

受賞

  • 2015年11月 徳島大学 学長表彰
     
    受賞者: 高田健介
  • 2015年11月 日本免疫学会 研究奨励賞
     
    受賞者: 高田健介

共同研究・競争的資金等の研究課題

  • 再感染リスクに対応した免疫記憶維持の分子機構
    日本学術振興会:科学研究費助成事業 挑戦的研究(萌芽)
    研究期間 : 2020年07月 -2022年03月 
    代表者 : 高田 健介
  • 核内受容体間を介した免疫記憶形成機構の解明とワクチン療法への応用
    日本学術振興会:科学研究費補助金 基盤研究(B)
    研究期間 : 2017年04月 -2021年03月 
    代表者 : 高田健介
  • 免疫と脳の記憶をつなぐシナプス形成制御の分子機構
    日本学術振興会:挑戦的研究(萌芽)
    研究期間 : 2018年04月 -2020年03月 
    代表者 : 高田健介
  • 核内受容体を介した免疫記憶機構に基づく免疫力強化戦略と癌免疫療法への応用
    小柳財団:平成30年度 研究助成金
    研究期間 : 2018年04月 -2019年03月 
    代表者 : 高田健介
  • 核内受容体を介した免疫記憶形成機構の解明とワクチン療法への応用
    先進医薬研究振興財団:平成29年度血液医学分野研究助成
    研究期間 : 2017年12月 -2018年11月 
    代表者 : 高田健介
  • 免疫と脳の記憶をつなぐシナプス形成制御の分子メカニズム
    持田記念医学薬学振興財団:平成29年度 研究助成金
    研究期間 : 2017年12月 -2018年11月 
    代表者 : 高田健介
  • 免疫と脳の記憶をつなぐシナプス形成の分子基盤
    住友財団:2017年度 基礎科学研究助成
    研究期間 : 2017年11月 -2018年11月 
    代表者 : 高田健介
  • 免疫と脳をつなぐ記憶メカニズムの解明と新規ワクチン戦略の創出
    ひと・健康・未来研究財団:2017年度研究助成
    研究期間 : 2017年11月 -2018年11月 
    代表者 : 高田健介
  • 核内受容体間の競合を介した免疫記憶形成機構の解明とワクチン療法への応用
    住友電工グループ社会貢献基金:2017年度 学術・研究助成
    研究期間 : 2017年10月 -2018年09月 
    代表者 : 高田健介
  • 核内受容体を介した細胞性免疫記憶形成機構の解明とワクチン療法への応用
    薬理研究会:平成29年度 研究助成
    研究期間 : 2017年10月 -2018年09月 
    代表者 : 高田健介
  • 免疫と脳の記憶をつなぐ分子機構の解明
    秋山記念生命科学振興財団:2017年度研究助成
    研究期間 : 2017年08月 -2018年07月 
    代表者 : 高田健介
  • 核内受容体間の競合を介した細胞性免疫記憶形成機構の解明とワクチン療法への応用
    大山健康財団:第43回学術研究助成金
    研究期間 : 2017年03月 -2018年03月 
    代表者 : 高田健介
  • 正の選択を介したT細胞の機能的教育が生体内免疫応答に果たす役割
    ノバルティス科学振興財団:第29回研究奨励金
    研究期間 : 2016年12月 -2017年11月 
    代表者 : 高田健介
  • 正の選択を介したT 細胞免疫応答制御機構
    上原記念生命科学財団:平成27年度研究奨励金
    研究期間 : 2016年03月 -2017年04月 
    代表者 : 高田健介
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2014年 -2016年 
    代表者 : 高田 健介
  • 文部科学省:科学研究費補助金(新学術領域研究(研究領域提案型))
    研究期間 : 2013年 -2014年 
    代表者 : 高田 健介
     
    リンパ節の内部構造は、各領域に存在するストローマ細胞の独自の機能に基づいて区画化されている。複雑なリンパ節の内部構造が多様なストローマ細胞によって形成されるという認識が広まる一方、リンパ節ストローマ細胞の詳細な分類は進んでおらず、未知の機能を持った亜集団が数多く残されている可能性が高い。本研究では、未だ理解の進んでいないリンパ節血管周囲細胞の亜集団、およびこれらの細胞によって特徴づけられるリンパ節T細胞領域辺縁部の微小環境に詳細な解析を加えることを第一義的な目的とする。また、定常状態においてT細胞領域辺縁部に局在することが最近報告されたメモリーCD8T細胞の維持における役割を検証することを次の目的とする。平成25年度には、血管周囲細胞の分子マーカーであるsmooth muscle actin alpha (alphaSMA)-GFPレポーターマウスを用いて、alphaSMA-GFPを発現するリンパ節ストローマ細胞の特性を解析した。まず、リンパ節組織の免疫蛍光染色解析により、alphaSMA-GFPの発現は、血管周囲細胞および網状ストローマ細胞の一部に認められ、とくに、T細胞領域辺縁部に高密度で認められた。一方、リンパ節の皮質を構成するB細胞領域にはほとんど検出されなかった。さらに、FACS解析において、リンパ節ストローマ細胞の分類に用いられているgp38およびCD31による細胞分画のうち、gp38+CD31-網状線維芽細胞およびgp38-CD31-細胞の一部にalphaSMA-GFPの高い発現が認められ、リンパ節ストローマ細胞はalphaSMAの発現によってさらなる亜集団に分けられることが明らかとなった。とくにgp38-CD31-細胞では、alphaSMA発現の有無によって、様々な分子の発現が大きく異なっていた。このことは、ソーティングによる細胞分離後の定量的PCRでも確認された。
  • T細胞の機能形成における正の選択の役割とその分子機構の解明
    中島記念国際交流財団:平成24年度 日本人若手研究者研究助成金
    研究期間 : 2012年04月 -2013年03月 
    代表者 : 高田健介
  • 正の選択を介したT細胞の中枢性トレランス機構
    かなえ医薬振興財団:第40回 研究助成金
    研究期間 : 2012年02月 -2013年03月 
    代表者 : 高田健介
  • 正の選択に依存するT細胞の自己寛容機構
    武田科学振興財団:2011年度医学系研究奨励
    研究期間 : 2011年11月 -2013年03月 
    代表者 : 高田健介
  • 文部科学省:科学研究費補助金(若手研究(B))
    研究期間 : 2012年 -2013年 
    代表者 : 高田 健介
     
    beta5tを構成鎖とする胸腺プロテアソームは胸腺皮質上皮細胞に発現されCD8T細胞の正の選択を司る。beta5t欠損マウスにおけるOT-I CD8T細胞はSIINFEKL抗原およびそのバリアントに過剰応答を示した。また、beta5t欠損マウスの末梢リンパ組織ではメモリー様細胞が増加していた。この異常はIL-2/15受容体シグナルに依存し、T細胞の恒常性維持への関与が示唆された。さらにbeta5t欠損マウス由来のOT-I 細胞はリステリア菌の感染に伴って短期生存エフェクター細胞に分化する傾向があった。これらの結果は正の選択がT細胞の抗原特異性のみならず抗原応答性をも決定していることを示唆する。
  • 正の選択に依存したT細胞の自己寛容成立機構
    内藤記念科学振興財団:第43回研究助成金
    研究期間 : 2011年12月 -2012年12月 
    代表者 : 高田健介
  • 正の選択を介したT細胞の中枢性トレランス成立機構
    アステラス病態代謝研究会:平成23年度研究助成金
    研究期間 : 2011年12月 -2012年11月 
    代表者 : 高田健介
  • T細胞の恒常性維持を制御する自己認識の分子メカニズム
    上原記念生命科学財団:平成22年度研究奨励金
    研究期間 : 2011年03月 -2012年04月 
    代表者 : 高田健介
  • 末梢T細胞の恒常性を制御する自己認識のメカニズム
    ノバルティス科学振興財団:第24回研究奨励金
    研究期間 : 2011年04月 -2012年03月 
    代表者 : 高田健介
  • 末梢T細胞による自己認識のペプチド特異性
    住友財団:2010年度研究助成
    研究期間 : 2010年11月 -2011年11月 
    代表者 : 高田健介
  • 末梢リンパ組織および胸腺における微小環境の機能的関連性
    金原一郎記念医学医療振興財団:第25回基礎医学医療研究助成金
    研究期間 : 2010年10月 -2011年10月 
    代表者 : 高田健介
  • 成熟T細胞の維持を制御する末梢ストローマ細胞の同定とその分子機構
    持田記念医学薬学振興財団:平成22年度研究助成金
    研究期間 : 2010年10月 -2011年10月 
    代表者 : 高田健介
  • 文部科学省:科学研究費補助金(若手研究(B))
    研究期間 : 2010年 -2011年 
    代表者 : 高田 健介, 高浜 洋介
     
    T細胞ホメオスタシスの場の実体解明を目指した長期計画の基盤として、末梢リンパ組織を構成するストローマ細胞の詳細な分類、およびT細胞ホメオスタシスに関与するストローマ細胞サブセットの同定を目的とした。リンパ節および胸腺におけるストローマ細胞について、上皮細胞、血管内皮細胞、間葉系細胞、間葉系幹細胞の分類に用いられる一般的な分子マーカーの発現を網羅的に検討した結果、T細胞ホメオスタシスに重要な線維芽網状細胞および血管周囲細胞の分類におけるalpha smooth muscle actinの有用性を見出した。

教育活動情報

主要な担当授業

  • 先端獣医科学特論A 動物分子医学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学研究科
  • 内科学実習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 獣医内科学, 診断法,処置法,予防法,治療法
  • 獣医科学基礎科目 臨床疾病学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院
  • 臨床診断学実習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 問診、身体検査、臨床検査、病態生理、鑑別診断
  • 先端獣医科学科目 動物分子医学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院


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