Updated on 2025/10/19

写真a

 
KATAKAI Tomoya
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Professor
Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine Professor
Title
Professor
Homepage
https://www.med.niigata-u.ac.jp/zoo/welcome.html
External link

Degree

  • 博士（理学） ( 1999.3   新潟大学 )

Research Interests

  • Stromal cell

  • Lymphocyte

  • T cell

  • CXCL13

  • cell-cell interaction

  • integrin

  • Peyer's patch

  • T-cell area

  • NF-kappaB

  • CCL21

  • Spleen

  • Imaging

  • Live imaging

  • 間質細胞

  • Chemokine

  • Cell adhesion

  • Secondary lymphoid tissue

  • Secondary lymphoid organ

  • Immune cell trafficking

  • Cell migration

  • Tissue microenvironment

  • dendritic cell

  • Lymph node

Research Areas

  • Life Science / Cell biology

  • Life Science / Anatomy

  • Life Science / Immunology

Research History (researchmap)

  • -   Professor

    2014.9

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  • Kansai Medical University   Institute of Biomedical Science, Department of Molecular Genetics   Lecturer

    2007.7 - 2014.8

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  • Kyoto University   Translational Research Center, Hospital   Assistant Professor

    2007.3 - 2007.6

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  • Kyoto University   Graduate School of Medicine, Center for Genomic Medicine   Research Assistant

    2004.4 - 2007.2

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  • Kyoto University   Research Assistant

    2000.4 - 2004.3

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Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Community Disease Control Infectious Disease Control and International Medicine   Professor

    2014.9

 

Papers

  • A battle between two biological singularities: Immune response vs. cancer

    Tomoya Katakai, Taku Okazaki

    Biophysics and Physicobiology   21 ( Supplemental )   e211006 - n/a   2024

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    Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Biophysical Society of Japan  

    DOI： 10.2142/biophysico.bppb-v21.s006

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  • 免疫・炎症のリンパ学 獲得免疫応答におけるリンパ節ストローマ細胞サブセットの機能的役割

    片貝 智哉, 小澤 まどか, 中島 汐梨

    リンパ学   46 ( 2 )   82 - 84   2023.12

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    Language：Japanese   Publisher：日本リンパ学会  

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  • Endogenous CCL21-Ser deficiency reduces B16–F10 melanoma growth by enhanced antitumor immunity

    Ryonosuke Fujie, Kaoru Kurowarabe, Yuki Yamada, Kakeru Fujiwara, Hayato Nakatani, Kenta Tsutsumi, Ryota Hayashi, Hinami Kawahata, Megumi Miyamoto, Madoka Ozawa, Tomoya Katakai, Yousuke Takahama, Izumi Ohigashi, Haruko Hayasaka

    Heliyon   9 ( 8 )   e19215 - e19215   2023.8

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.heliyon.2023.e19215

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  • Yin and yang roles of B lymphocytes in solid tumors: Balance between antitumor immunity and immune tolerance/immunosuppression in tumor-draining lymph nodes. International journal

    Tomoya Katakai

    Frontiers in oncology   13   1088129 - 1088129   2023

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    Language：English   Publishing type：Research paper (scientific journal)  

    The role of B cells in antitumor immunity has been reported to be either promotive or suppressive, but the specific mechanism remains to be comprehensively understood. However, this complicated situation likely depends on the temporal and spatial relationship between the developing tumor and B cells that recognize tumor antigens. Unlike responses against microbial or pathogenic infections, tumor cells are derived from autologous cells that have mutated and become aberrant; thus, elimination by the adaptive immune system is essentially inefficient. If tumor cells can evade immune attack at an early stage, non-destructive responses, such as tolerance and immunosuppression, are established over time. In tumor-draining lymph nodes (TDLNs), tumor antigen-reactive B cells potentially acquire immunoregulatory phenotypes and contribute to an immunosuppressive microenvironment. Therefore, triggering and enhancing antitumor responses by immunotherapies require selective control of these regulatory B cell subsets in TDLNs. In contrast, B cell infiltration and formation of tertiary lymphoid structures in tumors are positively correlated with therapeutic prognosis, suggesting that tumor antigen-specific activation of B cells and antibody production are advantageous for antitumor immunity in mid- to late-stage tumors. Given that the presence of B cells in tumor tissues may reflect the ongoing antitumor response in TDLNs, therapeutic induction and enhancement of these lymphocytes are expected to increase the overall effectiveness of immunotherapy. Therefore, B cells are promising targets, but the spatiotemporal balance of the subsets that exhibit opposite characteristics, that is, the protumor or antitumor state in TDLNs, should be understood, and strategies to separately control their functions should be developed to maximize the clinical outcome.

    DOI： 10.3389/fonc.2023.1088129

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  • 免疫・アレルギー・炎症 リンパ節鎖システムによるリンパ液中異物の段階的な濾過と血液への漏出阻止

    片貝 智哉, 小澤 まどか, 中島 汐梨

    リンパ学   45 ( 2 )   93 - 95   2022.12

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    Language：Japanese   Publisher：日本リンパ学会  

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  • Tas2R signaling enhances mouse neutrophil migration via a ROCK-dependent pathway

    Daichi Kobayashi, Tomoya Watarai, Madoka Ozawa, Yasuhiro Kanda, Fumihiro Saika, Norikazu Kiguchi, Arata Takeuchi, Masahito Ikawa, Shinsuke Matsuzaki, Tomoya Katakai

    Frontiers in Immunology   13   2022.8

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    Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    Type-2 bitter taste receptors (Tas2Rs) are a large family of G protein-coupled receptors that are expressed in the oral cavity and serve to detect substances with bitter tastes in foods and medicines. Recent evidence suggests that Tas2Rs are also expressed extraorally, including in immune cells. However, the role of Tas2Rs in immune cells remains controversial. Here, we demonstrate that Tas2R126, Tas2R135, and Tas2R143 are expressed in mouse neutrophils, but not in other immune cells such as macrophages or T and B lymphocytes. Treatment of bone marrow-derived neutrophils from wild-type mice with the Tas2R126/143 agonists arbutin and d-salicin led to enhanced C-X-C motif chemokine ligand 2 (CXCL2)-stimulated migration in vitro, but this response was not observed in neutrophils from Tas2r126/135/143-deficient mice. Enhancement of CXCL2-stimulated migration by Tas2R agonists was accompanied by increased phosphorylation of myosin light chain 2 (MLC2) and was blocked by pretreatment of neutrophils with inhibitors of Rho-associated coiled-coil-containing protein kinase (ROCK), but not by inhibitors of the small GTPase RhoA. Taken together, these results demonstrate that mouse neutrophils express functional Tas2R126/143 and suggest a role for Tas2R126/143–ROCK–MLC2-dependent signaling in the regulation of neutrophil migration.

    DOI： 10.3389/fimmu.2022.973880

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  • Micro- and Macro-Anatomical Frameworks of Lymph Nodes Indispensable for the Lymphatic System Filtering Function. International journal

    Madoka Ozawa, Shihori Nakajima, Daichi Kobayashi, Koichi Tomii, Nan-Jun Li, Tomoya Watarai, Ryo Suzuki, Satoshi Watanabe, Yasuhiro Kanda, Arata Takeuchi, Tomoya Katakai

    Frontiers in cell and developmental biology   10   902601 - 902601   2022

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    Language：English   Publishing type：Research paper (scientific journal)  

    In the lymphatic vascular system, lymph nodes (LNs) play a pivotal role in filtering and removing lymph-borne substances. The filtering function of LNs involves resident macrophages tightly associated with unique lymphatic sinus structures. Moreover, an intermittently arranged LN in the lymphatic pathway is considered to cooperatively prevent lymph-borne substances from entering blood circulation. However, the functional significance of tissue microarchitecture, cellular composition, and individual LNs in the "LN chain" system is not fully understood. To explore the mechanistic and histo-anatomical significance of LNs as lymph fluid filters, we subcutaneously injected fluorescent tracers into mice and examined the details of lymphatic transport to the LNs qualitatively and quantitatively. Lymph-borne tracers were selectively accumulated in the MARCO+ subcapsular-medullary sinus border (SMB) region of the LN, in which reticular lymphatic endothelial cells and CD169+F4/80+ medullary sinus macrophages construct a dense meshwork of the physical barrier, forming the main body to capture the tracers. We also demonstrated stepwise filtration via the LN chain in the lymphatic basin, which prevented tracer leakage into the blood. Furthermore, inflammatory responses that induce the remodeling of LN tissue as well as the lymphatic pathway reinforce the overall filtering capacity of the lymphatic basin. Taken together, specialized tissue infrastructure in the LNs and their systematic orchestration constitute an integrated filtering system for lymphatic recirculation.

    DOI： 10.3389/fcell.2022.902601

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  • Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade International journal

    Yasuhiro Kanda, Taku Okazaki, Tomoya Katakai

    Cancers   13 ( 18 )   4616 - 4616   2021.9

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

    The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.

    DOI： 10.3390/cancers13184616

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  • Arf1 and Arf6 Synergistically Maintain Survival of T Cells during Activation. Reviewed International journal

    Mami Sumiyoshi, Yui Kotani, Yuki Ikuta, Kazutomo Suzue, Madoka Ozawa, Tomoya Katakai, Taketo Yamada, Takaya Abe, Kana Bando, Shigeo Koyasu, Yasunori Kanaho, Toshio Watanabe, Satoshi Matsuda

    Journal of immunology (Baltimore, Md. : 1950)   206 ( 2 )   366 - 375   2021.1

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    ADP-ribosylation factor (Arf) family consisting of six family members, Arf1-Arf6, belongs to Ras superfamily and orchestrates vesicle trafficking under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins. It is well established that brefeldin A, a potent inhibitor of ArfGEFs, blocks cytokine secretion from activated T cells, suggesting that the Arf pathway plays important roles in T cell functions. In this study, because Arf1 and Arf6 are the best-characterized members among Arf family, we established T lineage-specific Arf1-deficient, Arf6-deficient, and Arf1/6 double-deficient mice to understand physiological roles of the Arf pathway in the immune system. Contrary to our expectation, Arf deficiency had little or no impact on cytokine secretion from the activated T cells. In contrast, the lack of both Arf1 and Arf6, but neither Arf1 nor Arf6 deficiency alone, rendered naive T cells susceptible to apoptosis upon TCR stimulation because of imbalanced expression of Bcl-2 family members. We further demonstrate that Arf1/6 deficiency in T cells alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis, whereas Ab response under Th2-polarizing conditions is seemingly normal. Our findings reveal an unexpected role for the Arf pathway in the survival of T cells during TCR-induced activation and its potential as a therapeutic target in the autoimmune diseases.

    DOI： 10.4049/jimmunol.2000971

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  • Extracellular ATP Limits Homeostatic T Cell Migration Within Lymph Nodes. Reviewed International journal

    Daichi Kobayashi, Yuki Sugiura, Eiji Umemoto, Akira Takeda, Hisashi Ueta, Haruko Hayasaka, Shinsuke Matsuzaki, Tomoya Katakai, Makoto Suematsu, Itaru Hamachi, Gennady G Yegutkin, Marko Salmi, Sirpa Jalkanen, Masayuki Miyasaka

    Frontiers in immunology   12   786595 - 786595   2021

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    Whereas adenosine 5'-triphosphate (ATP) is the major energy source in cells, extracellular ATP (eATP) released from activated/damaged cells is widely thought to represent a potent damage-associated molecular pattern that promotes inflammatory responses. Here, we provide suggestive evidence that eATP is constitutively produced in the uninflamed lymph node (LN) paracortex by naïve T cells responding to C-C chemokine receptor type 7 (CCR7) ligand chemokines. Consistently, eATP was markedly reduced in naïve T cell-depleted LNs, including those of nude mice, CCR7-deficient mice, and mice subjected to the interruption of the afferent lymphatics in local LNs. Stimulation with a CCR7 ligand chemokine, CCL19, induced ATP release from LN cells, which inhibited CCR7-dependent lymphocyte migration in vitro by a mechanism dependent on the purinoreceptor P2X7 (P2X7R), and P2X7R inhibition enhanced T cell retention in LNs in vivo. These results collectively indicate that paracortical eATP is produced by naïve T cells in response to constitutively expressed chemokines, and that eATP negatively regulates CCR7-mediated lymphocyte migration within LNs via a specific subtype of ATP receptor, demonstrating its fine-tuning role in homeostatic cell migration within LNs.

    DOI： 10.3389/fimmu.2021.786595

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  • Lymph Node Stromal Cells: Diverse Meshwork Structures Weave Functionally Subdivided Niches. International journal

    Arata Takeuchi, Madoka Ozawa, Guangwei Cui, Koichi Ikuta, Tomoya Katakai

    Current topics in microbiology and immunology   434   103 - 121   2021

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    Lymph nodes (LNs) are secondary lymphoid organs that function as the first line of defense against invasive foreign substances. Within the LNs, different types of immune cells are strategically localized to induce immune responses efficiently. Such a sophisticated tissue structure is a complex of functionally specialized niches, constructed by a variety of fibroblastic stromal cells. Elucidating the characteristics and functions of the niches and stromal cells will facilitate comprehension of the immune response induced in the LNs. Three recent studies offered novel insights into specialized stromal cells. In our discussion of these surprisingly diverse stromal cells, we will integrate information from these studies to improve knowledge about the structure and niches of LN.

    DOI： 10.1007/978-3-030-86016-5_5

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  • Bitter taste receptor signaling facilitates neutrophil migration

    Kobayashi Daichi, Tohda Atsumasa, Ozawa Madoka, Kanda Yasuhiro, Takeuchi Arata, Saika Fumihiro, Kiguchi Norikazu, Matsuzaki Shinsuke, Katakai Tomoya

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   94   2-Y-G3-3   2021

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    Language：Japanese   Publisher：Japanese Pharmacological Society  

    For a long time ago, people have believed that good medicine tastes bitter to the mouth; however, whether the bitter taste itself has therapeutic effects is less studied. Generally, bitter taste is recognized by Type-2 bitter-taste receptors (TAS2Rs) belonging to G-protein coupled receptors and TAS2Rs are localized on taste bud cells of the tongue. Growing evidence suggests that TAS2Rs are expressed not only in the taste bud cells but also in other cells including airway smooth muscle cells, intestinal tuft cells and immune cells. In this study, we show that bitter taste substance-TAS2R axis regulates neutrophil migration. By gene expression analysis, we found that neutrophils express TAS2R126, TAS2R135 and TAS2R143. Next, we observed the effect of TAS2R126/135/143 agonists on neutrophil migration. Although TAS2R135 agonists did not affect neutrophil migration, TAS2R126/143 agonists significantly enhanced CXCL2-induced neutrophil migration. The enhancing effects were not observed in a TAS2R126/143 deficient neutrophil-like cell line. In addition, TAS2R126/143 agonist also promotes neutrophil infiltration into zymosan-injected abdominal cavity. These results suggest that TAS2R126/143 signaling facilitates neutrophil-mediated immune responses and may be targets to promote host defense against infection.

    DOI： 10.1254/jpssuppl.94.0_2-y-g3-3

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  • Transdermal entry of yeast components elicits transient B cell-associated responses in skin-draining lymph nodes. Reviewed International journal

    Md Azizur Rahman, Yasuhiro Kanda, Madoka Ozawa, Toshihiko Kawamura, Arata Takeuchi, Tomoya Katakai

    Cellular immunology   355   104159 - 104159   2020.9

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    Immune responses to non-pathogenic yeasts induced within the draining lymph node remain to be understood. In this study, we have investigated the changes in lymphocytes and their activity in skin-draining lymph nodes in response to transdermally injected zymosan (component of the yeast cell wall). Zymosan elicited the transient increase of B cell number and activation status without affecting the capacity for proliferation. The increased B cell content in the regional lymph nodes was likely due to the reduction of B cell egress from the tissue and in part the increase of homing from the circulation. Zymosan also upregulated the inflammatory cytokines, such as IL-1β, IL-6, IL-12, and IFNγ, regulatory cytokines IL-10 and TGFβ, and lymphoid chemokine CXCL13. Among these, the expression of IL-12 and IL-10 was markedly high in B cells. Altogether, these findings demonstrate a unique B cell-associated response to non-pathogenic yeast component in the draining lymph nodes. This will provide insights into the clinical and healthcare applications of non-pathogenic beneficial microbes.

    DOI： 10.1016/j.cellimm.2020.104159

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  • S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer's Patches. Reviewed International journal

    Kazufumi Kunimura, Daiji Sakata, Xin Tun, Takehito Uruno, Miho Ushijima, Tomoya Katakai, Akira Shiraishi, Ryosuke Aihara, Yasuhisa Kamikaseda, Keisuke Matsubara, Hirokazu Kanegane, Shinichiro Sawa, Gérard Eberl, Shouichi Ohga, Yasunobu Yoshikai, Yoshinori Fukui

    Cell reports   29 ( 9 )   2823 - 2834   2019.11

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    Intestinal microfold cells (M cells) in Peyer's patches are a special subset of epithelial cells that initiate mucosal immune responses through uptake of luminal antigens. Although the cytokine receptor activator of nuclear factor-κB ligand (RANKL) expressed on mesenchymal cells triggers differentiation into M cells, other environmental cues remain unknown. Here, we show that the metastasis-promoting protein S100A4 is required for development of mature M cells. S100A4-producing cells are a heterogenous cell population including lysozyme-expressing dendritic cells and group 3 innate lymphoid cells. We found that in the absence of DOCK8, a Cdc42 activator critical for interstitial leukocyte migration, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells. While S100A4 promotes differentiation into mature M cells in organoid culture, genetic inactivation of S100a4 prevents the development of mature M cells in mice. Thus, S100A4 is a key environmental cue that regulates M cell differentiation in collaboration with RANKL.

    DOI： 10.1016/j.celrep.2019.10.091

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  • Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses. Reviewed International journal

    Motoyoshi Nagai, Ryotaro Noguchi, Daisuke Takahashi, Takayuki Morikawa, Kouhei Koshida, Seiga Komiyama, Narumi Ishihara, Takahiro Yamada, Yuki I Kawamura, Kisara Muroi, Kouya Hattori, Nobuhide Kobayashi, Yumiko Fujimura, Masato Hirota, Ryohtaroh Matsumoto, Ryo Aoki, Miwa Tamura-Nakano, Machiko Sugiyama, Tomoya Katakai, Shintaro Sato, Keiyo Takubo, Taeko Dohi, Koji Hase

    Cell   178 ( 5 )   1072 - 1087   2019.8

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    Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.

    DOI： 10.1016/j.cell.2019.07.047

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  • Novel Targeting to XCR1+ Dendritic Cells Using Allogeneic T Cells for Polytopical Antibody Responses in the Lymph Nodes. Reviewed International journal

    Yusuke Kitazawa, Hisashi Ueta, Yasushi Sawanobori, Tomoya Katakai, Hiroyuki Yoneyama, Satoshi Ueha, Kouji Matsushima, Nobuko Tokuda, Kenjiro Matsuno

    Frontiers in immunology   10   1195 - 1195   2019

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    Vaccination strategy that induce efficient antibody responses polytopically in most lymph nodes (LNs) against infections has not been established yet. Because donor-specific blood transfusion induces anti-donor class I MHC antibody production in splenectomized rats, we examined the mechanism and significance of this response. Among the donor blood components, T cells were the most efficient immunogens, inducing recipient T cell and B cell proliferative responses not only in the spleen, but also in the peripheral and gut LNs. Donor T cells soon migrated to the splenic T cell area and the LNs, with a temporary significant increase in recipient NK cells. XCR1+ resident dendritic cells (DCs), but not XCR1- DCs, selectively phagocytosed donor class I MHC+ fragments after 1 day. After 1.5 days, both DC subsets formed clusters with recipient CD4+ T cells, which proliferated within these clusters. Inhibition of donor T cell migration or depletion of NK cells by pretreatment with pertussis toxin or anti-asialoGM1 antibody, respectively, significantly suppressed DC phagocytosis and subsequent immune responses. Three allogeneic strains with different NK activities had the same response but with different intensity. Donor T cell proliferation was not required, indicating that the graft vs. host reaction is dispensable. Intravenous transfer of antigen-labeled and mitotic inhibitor-treated allogeneic, but not syngeneic, T cells induced a polytopical antibody response to labeled antigens in the LNs of splenectomized rats. These results demonstrate a novel mechanism of alloresponses polytopically in the secondary lymphoid organs (SLOs) induced by allogeneic T cells. Donor T cells behave as self-migratory antigen ferries to be delivered to resident XCR1+ DCs with negligible commitment of migratory DCs. Allogeneic T cells may be clinically applicable as vaccine vectors for polytopical prophylactic antibody production even in asplenic or hyposplenic individuals.

    DOI： 10.3389/fimmu.2019.01195

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  • Essential Role of Canonical NF-κB Activity in the Development of Stromal Cell Subsets in Secondary Lymphoid Organs. Reviewed International journal

    Dana Bogdanova, Arata Takeuchi, Madoka Ozawa, Yasuhiro Kanda, M Azizur Rahman, Burkhard Ludewig, Tatsuo Kinashi, Tomoya Katakai

    Journal of immunology (Baltimore, Md. : 1950)   201 ( 12 )   3580 - 3586   2018.12

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    Organized tissue structure in the secondary lymphoid organs (SLOs) tightly depends on the development of fibroblastic stromal cells (FSCs) of mesenchymal origin; however, the mechanisms of this relationship are poorly understood. In this study, we specifically inactivated the canonical NF-κB pathway in FSCs in vivo by conditionally inducing IκBα mutant in a Ccl19-IκBSR mouse system in which NF-κB activity is likely to be suppressed in fetal FSC progenitors. Given that NF-κB activation in fetal FSCs is essential for SLO development, the animals were expected to lack SLOs. However, all SLOs were preserved in Ccl19-IκBSR mice. Instead, the T cell area was severely disturbed by the lack of CCL21-expressing FSCs, whereas the follicles and associated FSC networks were formed. Fate mapping revealed that IκBSR-expressing cells constituted only a small fraction of stromal compartment outside the follicles. Taken together, our findings indicate an essential role of the canonical NF-κB pathway activity in the development of three FSC subsets common to SLOs and suggest transient or stochastic CCL19 expression in FSC progenitors and a compensatory differentiation program of follicular FSCs.

    DOI： 10.4049/jimmunol.1800539

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  • Visualizing the Rapid and Dynamic Elimination of Allogeneic T Cells in Secondary Lymphoid Organs. Reviewed International journal

    Yasuhiro Kanda, Arata Takeuchi, Madoka Ozawa, Yoichi Kurosawa, Toshihiko Kawamura, Dana Bogdanova, Hidekazu Iioka, Eisaku Kondo, Yusuke Kitazawa, Hisashi Ueta, Kenjiro Matsuno, Tatsuo Kinashi, Tomoya Katakai

    Journal of immunology (Baltimore, Md. : 1950)   201 ( 3 )   1062 - 1072   2018.8

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    DOI： 10.4049/jimmunol.1700219

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    Other Link： http://orcid.org/0000-0002-4290-7028

  • Live Imaging of Interstitial T Cell Migration Using Lymph Node Slices. Reviewed International journal

    Tomoya Katakai

    Methods in molecular biology (Clifton, N.J.)   1763   29 - 42   2018

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Humana Press Inc.  

    DOI： 10.1007/978-1-4939-7762-8_4

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  • A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node. Reviewed International journal

    Arata Takeuchi, Madoka Ozawa, Yasuhiro Kanda, Mina Kozai, Izumi Ohigashi, Yoichi Kurosawa, Md Azizur Rahman, Toshihiko Kawamura, Yuto Shichida, Eiji Umemoto, Masayuki Miyasaka, Burkhard Ludewig, Yousuke Takahama, Takashi Nagasawa, Tomoya Katakai

    Frontiers in immunology   9   2196 - 2196   2018

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.3389/fimmu.2018.02196

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  • Extensively re-organized systemic lymph nodes provide a feasible environment for self-reactivity in lupus-prone NZB × NZW F1 mice. Reviewed International journal

    Yoichi Kurosawa, Madoka Ozawa, Yasuhiro Kanda, Arata Takeuchi, Toshihiko Kawamura, Ichiei Narita, Tomoya Katakai

    International immunology   29 ( 12 )   567 - 579   2017.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/intimm/dxx066

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  • Essential role of CCL21 in establishment of central self-tolerance in T cells. Reviewed International journal

    Mina Kozai, Yuki Kubo, Tomoya Katakai, Hiroyuki Kondo, Hiroshi Kiyonari, Karin Schaeuble, Sanjiv A Luther, Naozumi Ishimaru, Izumi Ohigashi, Yousuke Takahama

    The Journal of experimental medicine   214 ( 7 )   1925 - 1935   2017.7

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    DOI： 10.1084/jem.20161864

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    Other Link： http://orcid.org/0000-0002-4290-7028

  • [Lymph node microenvironment controls high-speed T cell migration]. Reviewed

    Tomoya Katakai

    Seikagaku. The Journal of Japanese Biochemical Society   88 ( 5 )   615 - 20   2016.10

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    Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Biochemical Society  

    DOI： 10.14952/SEIKAGAKU.2016.880615

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  • CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. Reviewed International journal

    Arata Takeuchi, Mohamed El Sherif Gadelhaq Badr, Kosuke Miyauchi, Chitose Ishihara, Reiko Onishi, Zijin Guo, Yoshiteru Sasaki, Hiroshi Ike, Akiko Takumi, Noriko M Tsuji, Yoshinori Murakami, Tomoya Katakai, Masato Kubo, Takashi Saito

    The Journal of experimental medicine   213 ( 1 )   123 - 38   2016.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1084/jem.20150519

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    Other Link： http://orcid.org/0000-0002-4290-7028

  • Microenvironmental Control of High-Speed Interstitial T Cell Migration in the Lymph Node. Reviewed International journal

    Tomoya Katakai, Tatsuo Kinashi

    Frontiers in immunology   7   194 - 194   2016

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    DOI： 10.3389/fimmu.2016.00194

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  • Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells. Reviewed International journal

    Keiki Sugimoto, Fumihiko Hayakawa, Satoko Shimada, Takanobu Morishita, Kazuyuki Shimada, Tomoya Katakai, Akihiro Tomita, Hitoshi Kiyoi, Tomoki Naoe

    Scientific reports   5   13054 - 13054   2015.8

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    DOI： 10.1038/srep13054

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  • 免疫細胞輸送 SEMA3E/Plexin D1軸はRap1シグナル伝達経路を調節することにより胸腺細胞の接着と分極を制御する(Immune cell trafficking SEMA3E/Plexin D1 axis controls thymocyte adhesion and polarization by modulating the Rap1 signaling pathway)

    Ueda Yoshihiro, Kondo Naoyuki, Ozawa Madoka, Katakai Tomoya, Kinashi Tatsuo

    日本免疫学会総会・学術集会記録   43 ( Proceedings )   56 - 56   2014.11

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  • Autotaxin produced by stromal cells promotes LFA-1-independent and Rho-dependent interstitial T cell motility in the lymph node paracortex. Reviewed International journal

    Tomoya Katakai, Naoyuki Kondo, Yoshihiro Ueda, Tatsuo Kinashi

    Journal of immunology (Baltimore, Md. : 1950)   193 ( 2 )   617 - 26   2014.7

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    DOI： 10.4049/jimmunol.1400565

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  • LFA-1/ICAM-1のライブイメージング解析と初代Tリンパ球を用いた免疫シナプス形成におけるMst1の役割(Live-imaging analysis of LFA-1/ICAM-1 and roles of Mst1 in immunological synapse formation using primary T lymphocytes)

    Kondo Naoyuki, Ueda Yoshihiro, Katakai Tomoya, Kinashi Tatsuo

    日本免疫学会総会・学術集会記録   42 ( Proceedings )   174 - 174   2013.11

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  • Dendritic cells regulate high-speed interstitial T cell migration in the lymph node via LFA-1/ICAM-1. Reviewed International journal

    Tomoya Katakai, Katsuyoshi Habiro, Tatsuo Kinashi

    Journal of immunology (Baltimore, Md. : 1950)   191 ( 3 )   1188 - 99   2013.8

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    DOI： 10.4049/jimmunol.1300739

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  • Antigen-specific suppression and immunological synapse formation by regulatory T cells require the Mst1 kinase. Reviewed International journal

    Takashi Tomiyama, Yoshihiro Ueda, Tomoya Katakai, Naoyuki Kondo, Kazuichi Okazaki, Tatsuo Kinashi

    PloS one   8 ( 9 )   e73874   2013

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    DOI： 10.1371/journal.pone.0073874

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  • 2SEP-03 Regulation of Lymphocyte "Stop and Go" via LFA-1 and ICAM-1 : Lymphocyte Trafficking Analysis using Live Imaging Techniques(2SEP Exploring mechanisms of emerging order in multicellular systems : Cross-talk between moving cells and microenvironment,Symposium,The 51th Annual Meeting of the Biophysical Society of Japan)

    Kinashi Tatsuo, Katakai Tomoya, Ueda Yoshihiro, Kondo Naoyuki

    Seibutsu Butsuri   53 ( 1 )   S100   2013

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    DOI： 10.2142/biophys.53.S100_2

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  • DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses Reviewed

    Yosuke Harada, Yoshihiko Tanaka, Masao Terasawa, Markus Pieczyk, Katsuyoshi Habiro, Tomoya Katakai, Kyoko Hanawa-Suetsugu, Mutsuko Kukimoto-Niino, Tomoko Nishizaki, Mikako Shirouzu, Xuefeng Duan, Takehito Uruno, Akihiko Nishikimi, Fumiyuki Sanematsu, Shigeyuki Yokoyama, Jens V. Stein, Tatsuo Kinashi, Yoshinori Fukui

    BLOOD   119 ( 19 )   4451 - 4461   2012.5

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    DOI： 10.1182/blood-2012-01-407098

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  • [Lymph node stromal cells: architecture and functions]. Reviewed

    Tomoya Katakai

    Seikagaku. The Journal of Japanese Biochemical Society   84 ( 3 )   183 - 8   2012.3

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  • Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms Reviewed

    Kyoko Hanawa-Suetsugu, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Ryogo Akasaka, Noboru Ohsawa, Shun-ichi Sekine, Takuhiro Ito, Naoya Tochio, Seizo Koshiba, Takanori Kigawa, Takaho Terada, Mikako Shirouzu, Akihiko Nishikimi, Takehito Uruno, Tomoya Katakai, Tatsuo Kinashi, Daisuke Kohda, Yoshinori Fukui, Shigeyuki Yokoyama

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   109 ( 9 )   3305 - 3310   2012.2

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    DOI： 10.1073/pnas.1113512109

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  • Marginal reticular cells: a stromal subset directly descended from the lymphoid tissue organizer. Reviewed International journal

    Tomoya Katakai

    Frontiers in immunology   3   200 - 200   2012

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    DOI： 10.3389/fimmu.2012.00200

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  • Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. Reviewed International journal

    Yoshihiro Ueda, Koko Katagiri, Takashi Tomiyama, Kaneki Yasuda, Katsuyoshi Habiro, Tomoya Katakai, Susumu Ikehara, Mitsuru Matsumoto, Tatsuo Kinashi

    Nature communications   3   1098 - 1098   2012

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    DOI： 10.1038/ncomms2105

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  • Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function Reviewed

    Satoshi Tanaka, Shinji Maeda, Motomu Hashimoto, Chihiro Fujimori, Yoshinaga Ito, Shin Teradaira, Keiji Hirota, Hiroyuki Yoshitomi, Tomoya Katakai, Akira Shimizu, Takashi Nomura, Noriko Sakaguchi, Shimon Sakaguchi

    JOURNAL OF IMMUNOLOGY   185 ( 4 )   2295 - 2305   2010.8

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    DOI： 10.4049/jimmunol.1000848

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  • Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and -independent manners Reviewed

    Yukihiko Ebisuno, Koko Katagiri, Tomoya Katakai, Yoshihiro Ueda, Tomomi Nemoto, Hiroyuki Inada, Junichi Nabekura, Takaharu Okada, Reiji Kannagi, Toshiyuki Tanaka, Masayuki Miyasaka, Nancy Hogg, Tatsuo Kinashi

    BLOOD   115 ( 4 )   804 - 814   2010.1

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    DOI： 10.1182/blood-2009-03-211979

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  • Mst1 controls lymphocyte trafficking and interstitial motility within lymph nodes Reviewed

    Koko Katagiri, Tomoya Katakai, Yukihiko Ebisuno, Yoshihiro Ueda, Takaharu Okada, Tatsuo Kinashi

    EMBO JOURNAL   28 ( 9 )   1319 - 1331   2009.5

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    DOI： 10.1038/emboj.2009.82

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  • CXCL13 production by an established lymph node stromal cell line via lymphotoxin-beta receptor engagement involves the cooperation of multiple signaling pathways Reviewed

    Hidenori Suto, Tomoya Katakai, Manabu Sugai, Tatsuo Kinashi, Akira Shimizu

    INTERNATIONAL IMMUNOLOGY   21 ( 4 )   467 - 476   2009.4

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    DOI： 10.1093/intimm/dxp014

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  • Organizer-Like Reticular Stromal Cell Layer Common to Adult Secondary Lymphoid Organs Reviewed

    Tomoya Katakai, Hidenori Suto, Manabu Sugai, Hiroyuki Gonda, Atsushi Togawa, Sachiko Suematsu, Yukihiko Ebisuno, Koko Katagiri, Tatsuo Kinashi, Akira Shinlfizu

    JOURNAL OF IMMUNOLOGY   181 ( 9 )   6189 - 6200   2008.11

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    DOI： 10.4049/jimmunol.181.9.6189

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  • Undesired meeting of lymphocytes: Organ-specific infiltration and the organization of ectopic lymphoid tissue in a murine experimental autoimmune gastritis Reviewed

    Tomoya Katakai, Akira Shimizu

    IMMUNOLOGY LETTERS   118 ( 2 )   103 - 109   2008.6

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  • The network of fibroblastic reticular cells in the lymph node: Functional framework for immune surveillance Reviewed

    T. Katakai, A. Shimizu

    Current Immunology Reviews   3 ( 4 )   251 - 257   2007

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    DOI： 10.2174/157339507783334228

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  • Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H+/K+-ATPase-Reactive TCR transgenic mouse Reviewed

    Tomoya Katakai, Takashi Nomura, Hiroyuki Gonda, Manabu Sugai, Yasutoshi Agata, Akiyoshi Nishio, Tohru Masuda, Shimon Sakaguchi, Akira Shimizu

    JOURNAL OF IMMUNOLOGY   177 ( 11 )   7858 - 7867   2006.12

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    DOI： 10.4049/jimmunol.177.11.7858

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  • A transmembrane chemokine, CXC chemokine ligand 16, expressed by lymph node fibroblastic reticular cells has the potential to regulate T cell migration and adhesion Reviewed

    T Hara, T Katakai, JH Lee, Y Nambu, N Nakajima-Nagata, H Gonda, M Sugai, A Shimizu

    INTERNATIONAL IMMUNOLOGY   18 ( 2 )   301 - 311   2006.2

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    DOI： 10.1093/intimm/dxh369

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  • CpG inhibits IgE class switch recombination through suppression of NF kappa B activity, but not through Id2 or Bcl6 Reviewed

    T Kusunoki, M Sugai, H Gonda, Y Nambu, N Nagata-Nakajima, T Katakai, M Kusunoki, A Sakamoto, TD Takeshisa, T Nakahata, Y Yokota, A Shimizu

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   328 ( 2 )   499 - 506   2005.3

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    DOI： 10.1016/j.bbrc.2004.12.192

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  • Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation Reviewed

    JH Lee, T Katakai, T Hara, H Gonda, M Sugai, A Shimizu

    JOURNAL OF CELL BIOLOGY   167 ( 2 )   327 - 337   2004.10

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    DOI： 10.1083/jcb.200403091

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  • Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes Reviewed

    T Katakai, T Hara, M Sugai, H Gonda, A Shimuzu

    JOURNAL OF EXPERIMENTAL MEDICINE   200 ( 6 )   783 - 795   2004.9

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    DOI： 10.1084/jem.20040254

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  • A novel reticular stromal structure in lymph node cortex: an immuno-platform for interactions among dendritic cells, T cells and B cells Reviewed

    T Katakai, T Hara, JH Lee, H Gonda, M Sugai, A Shimizu

    INTERNATIONAL IMMUNOLOGY   16 ( 8 )   1133 - 1142   2004.8

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    DOI： 10.1093/intimm/dxh113

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  • In vitro induction of adult hepatic progenitor cells into insulin-producing cells Reviewed

    N Nakajima-Nagata, T Sakurai, T Mitaka, T Katakai, E Yamato, J Miyazaki, Y Tabata, M Sugai, A Shimizu

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   318 ( 3 )   625 - 630   2004.6

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    DOI： 10.1016/j.bbrc.2004.04.059

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  • Chemokines and autoimmune diseases Reviewed

    T. Katakai, A. Shimizu

    Current Medicinal Chemistry: Anti-Inflammatory and Anti-Allergy Agents   3 ( 4 )   341 - 350   2004

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    DOI： 10.2174/1568014043355221

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  • Transcription-coupled events associating with immunoglobulin switch region chromatin Reviewed

    Y Nambu, M Sugai, H Gonda, CG Lee, T Katakai, Y Agata, Y Yokota, A Shimizu

    SCIENCE   302 ( 5653 )   2137 - 2140   2003.12

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    DOI： 10.1126/science.1092481

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  • The balance between Pax5 and Id2 activities is the key to AID gene expression Reviewed

    H Gonda, M Sugai, Y Nambu, T Katakai, Y Agata, KJ Mori, Y Yokota, A Shimizu

    JOURNAL OF EXPERIMENTAL MEDICINE   198 ( 9 )   1427 - 1437   2003.11

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    DOI： 10.1084/jem.20030802

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  • Th1-biased tertiary lymphoid tissue supported by CXC chemokine ligand 13-producing stromal network in chronic lesions of autoimmune gastritis Reviewed

    T Katakai, T Hara, M Sugai, H Gonda, A Shimizu

    JOURNAL OF IMMUNOLOGY   171 ( 8 )   4359 - 4368   2003.10

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  • T(H)2 dominance and defective development of a CD8(+) dendritic cell subset in Id2-deficient mice Reviewed

    T Kusunoki, M Sugai, T Katakai, Y Omatsu, T Iyoda, K Inaba, T Nakahata, A Shimizu, Y Yokota

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   111 ( 1 )   136 - 142   2003.1

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    DOI： 10.1067/mai.2003.29

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  • Essential role of Id2 in negative regulation of IgE class switching Reviewed

    M Sugai, H Gonda, T Kusunoki, T Katakai, Y Yokota, A Shimizu

    NATURE IMMUNOLOGY   4 ( 1 )   25 - 30   2003.1

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    DOI： 10.1038/ni874

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  • Chemokine-independent preference for T-helper-1 cells in transendothelial migration Reviewed

    T Katakai, T Hara, M Sugai, H Gonda, Y Nambu, E Matsuda, Y Agata, A Shimizu

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 52 )   50948 - 50958   2002.12

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    DOI： 10.1074/jbc.M204133200

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  • Selective accumulation of type 1 effector cells expressing P-selectin ligand and/or alpha(4)beta(7)-integrin at the lesions of autoimmune gastritis Reviewed

    T Katakai, KJ Mori, T Masuda, A Shimizu

    INTERNATIONAL IMMUNOLOGY   14 ( 2 )   167 - 175   2002.2

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  • Histone acetylation determines the developmentally regulated accessibility for T cell receptor γ gene recombination Reviewed

    Y. Agata, T. Katakai, S.-K. Ye, M. Sugai, H. Gonda, T. Honjo, K. Ikuta, A. Shimizu

    Journal of Experimental Medicine   193 ( 7 )   873 - 879   2001.4

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    DOI： 10.1084/jem.193.7.873

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  • Targeting of Krüppel-associated box-containing zinc finger proteins to centromeric heterochromatin. Implication for the gene silencing mechanisms Reviewed

    E. Matsuda, Y. Agata, M. Sugai, T. Katakai, H. Gonda, A. Shimizu

    Journal of Biological Chemistry   276 ( 17 )   14222 - 14229   2001.4

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    DOI： 10.1074/jbc.M010663200

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  • DNA polymerase β is not essential for the formation of palindromic (P) region of T cell receptor gene Reviewed

    H. Gonda, M. Sugai, T. Katakai, N. Sugo, Y. Aratani, H. Koyama, K.J. Mori, A. Shimizu

    Immunology Letters   78 ( 1 )   45 - 49   2001

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  • The helix-loop-helix inhibitor Id2 and cell differentiation control Reviewed

    Y. Yokota, S. Mori, S.-I. Nishikawa, A. Mansouri, P. Gruss, T. Kusunoki, T. Katakai, A. Shimizu

    Current Topics in Microbiology and Immunology   251   35 - 41   2000

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  • Differential localization of T(h)1 and T(h)2 cells in autoimmune gastritis Reviewed

    T Katakai, KJ Mori, T Masuda, A Shimizu

    INTERNATIONAL IMMUNOLOGY   10 ( 9 )   1325 - 1334   1998.9

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  • Structure of the TCR expressed on a gastritogenic T cell clone, IL-6, and frequent appearance of similar clonotypes in mice bearing autoimmune gastritis Reviewed

    T. Katakai, Y. Agata, A. Shimizu, C. Ohshima, A. Nishio, M. Inaba, S. Kasakura, K.J. Mori, T. Masuda

    International Immunology   9 ( 12 )   1849 - 1855   1997.12

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    DOI： 10.1093/intimm/9.12.1849

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  • Destruction of hematopoietic microenvironment by cytotoxic T cells Reviewed

    E Takashita, K Sugimoto, Y Adachi, Y Aihara, H Inoue, HJ Jiang, T Katakai, KJ Mori

    EXPERIMENTAL HEMATOLOGY   25 ( 10 )   1034 - 1041   1997.9

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  • A possible involvement of Fas-Fas ligand signaling in the pathogenesis of murine autoimmune gastritis. Reviewed

    Nishio A, Katakai T, Oshima C, Kasakura S, Sakai M, Yonehara S, Suda T, Nagata S, Masuda T

    Gastroenterology   111 ( 4 )   959 - 967   1996.10

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  • BREAKDOWN OF SELF-TOLERANCE BY INTRATHYMIC INJECTION OF A T-CELL LINE INDUCING AUTOIMMUNE GASTRITIS IN MICE Reviewed

    A NISHIO, T KATAKAI, M HOSONO, M INABA, M SAKAI, M OKUMA, S KASAKURA, T MASUDA

    IMMUNOLOGY   85 ( 2 )   270 - 275   1995.6

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  • 自然免疫刺激によって誘導されるサイトカイン産生B細胞の機能多様性の理解と炎症制御

    Grant number：24K09283

    2024.4 - 2027.3

    System name：科学研究費助成事業

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    藤間 真紀, 片貝 智哉

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • リンパ節におけるリンパ洞フィルターの分子・細胞基盤と免疫応答制御

    Grant number：21H02653

    2021.4 - 2024.3

    System name：科学研究費助成事業

    Research category：基盤研究(B)

    Awarding organization：日本学術振興会

    片貝 智哉, 奥田 修二郎, 平島 正則

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    Grant amount：\17420000 （ Direct Cost: \13400000 、 Indirect Cost：\4020000 ）

    リンパ節において、リンパ管を介して到達した抗原や液性因子に対する素早い応答は、リンパ洞の独特な組織構造と濾過機能に依存し、免疫・生理学的にも極めて重要な過程であると考えられる。しかし、このリンパ洞フィルターの構造や機能の詳細については未だ不明な点が多い。本研究は、リンパ節の特定領域に局在する特殊なリンパ管内皮細胞、間質ストローマ細胞、組織マクロファージにより構成されるリンパ洞フィルターの組織・細胞構造の分子基盤と構築原理、および免疫・生理学的意義の究明を目的とする。
    初年度は、野生型マウスや各種遺伝子発現レポーターマウスを用いて、リンパ節の洞内皮細胞、ストローマ細胞、マクロファージを含む免疫細胞の各種マーカーについて、共焦点および多光子励起レーザー顕微鏡による高解像度顕微観察を行い、リンパ洞フィルターの分子細胞構成・微細構造の詳細を明らかにした。また、蛍光標識デキストラン(分子量可変)、ポリスチレンビーズ(粒径可変)、黄色ブドウ球菌、酵母菌、LPS、卵白アルブミン(OVA)をマウス皮下に投与し、浸出リンパ節のリンパ洞フィルターによる捕捉・移送の経時的観察を行うとともに、フローサイトメトリーによりマクロファージサブセットへの取り込みを定量的に評価した。さらに、クロドロン酸内包リポソーム投与によるマクロファージ除去の影響を検討した。これらの解析により、髄洞の一部が網目状のリンパ管内皮細胞ネットワークと髄質マクロファージにより特殊な物理フィルター構造を形成し、リンパ節におけるリンパ液フィルターの本体であることを明確にした。我々は、この領域を辺縁髄洞接続帯（SMB）領域と名付けた。

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  • 自然免疫型制御性B細胞の分化機序と炎症制御機構の解明

    Grant number：21K05970

    2021.4 - 2024.3

    System name：科学研究費助成事業

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    藤間 真紀, 片貝 智哉

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    生体内で分化する自然免疫型制御性B細胞（自然型Breg)の局在や性状を明らかにするために、炎症性物質のひとつであるリポ多糖(LPS)をマウスの腹腔に投与することで誘導される腹膜炎モデルを用いた。まず、 低容量のLPSを頻回投与することで、腹腔と脾臓で抗炎症性サイトカインであるIL-10を産生するB細胞が顕著に増加することが確認された。また、以前から炎症誘発時にはIL-10と同時に炎症性サイトカインであるIL-6を産生するB細胞も増加することがわかっていたが、今回、LPS投与で誘導されたIL-10産生B細胞の多くがIL-6を同時に産生していることが明らかになった。また、これらのIL-10, IL-6共産生B細胞が、Breg亜集団として報告されている脾臓のB10細胞や腹腔のB-1a細胞に由来することが、ex vivo実験で明らかになった。マウスへのLPS投与回数を変えて、IL-10単独産生B細胞とIL-10, IL-6共産生B細胞の発生のタイミングを比較したが、両者ともほぼ同じタイミングで生体で発生、増加した。IL-10とIL-6は炎症応答において拮抗する作用もあるため、IL-10とIL-6を同時に産生するB細胞が炎症抑制作用を持つ制御性B細胞として機能するのかは不明であり、現在はその機能をin vivo, ex vivoの両方で解析中である。また、IL-10, IL-6共産生B細胞の生体内での機能や発生のタイミング、局在解析も進行中である。

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  • Live cell recovery and wide area analysis of dynamic lymphoid tissue subcompartments

    Grant number：19K22528

    2019.6 - 2023.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Challenging Research (Exploratory)

    Awarding organization：Japan Society for the Promotion of Science

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    Grant amount：\6500000 （ Direct Cost: \5000000 、 Indirect Cost：\1500000 ）

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  • 皮膚所属リンパ節における抗原捕捉部位の違いがアレルゲン性に及ぼす影響の解明

    Grant number：19K07603

    2019.4 - 2023.3

    System name：科学研究費助成事業

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    竹内 新, 片貝 智哉

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    経皮的に侵入した抗原が予想以上にアレルギーの発症と深く関わっていることが明らかとなってきているが、発症に至るメカニズムは依然として不明な点が多い。本研究では皮膚所属リンパ節の内部に注目し、流入する抗原がリンパ節内に取り込まれる場所やリンパ球の活性化が誘導される場所とアレルギー発症との関係を明らかにすることを目的としている。特に免疫原性の高い抗原はリンパ節の髄質域に蓄積し易く、その近傍にはB細胞の集積を認める固有の微小環境（深皮質辺縁部：DCP）が形成されていることに注目している。この領域独自の免疫監視システムとアレルギー発症との関わりを解明しようと試みている。
    本年度は、初年度に解析を行ったリンパ節内でのB細胞の循環経路と、昨年度確認にしたリンパ節内への抗原の取り込みの結果を元に、DCP領域で実際にB細胞による抗原の認識が行われているのかを確認した。一連の実験において抗原として使用しているオボアルブミン－卵白リゾチーム複合体は、卵白リゾチーム特異的B細胞受容体を持つトランスジェニックマウス(MD4)由来のB細胞によって認識することができる。MD4由来のB細胞を移植後、オボアルブミン－卵白リゾチーム複合体を皮下に投与すると、所属リンパ節においてB細胞の活性化が認められた。この活性化がDCP領域で誘導されているのかを調べたところ、抗原特異的B細胞が抗原と接触する頻度は濾胞領域よりもDCP領域で優位に高いことが判った。これらの結果から、DCP領域はリンパ節に流れ着いて濃縮された抗原の一部を樹状細胞依存的にリンパ節内部に取り込む場所であると同時に、新たに血流から進入してきたB細胞を呼び寄せ、効率的に免疫監視を行う場所を提供している可能性が示唆された。

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  • Singularity cells in immunity and cancer development

    Grant number：18H05417

    2018.6 - 2023.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Awarding organization：Japan Society for the Promotion of Science

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    Grant amount：\129350000 （ Direct Cost: \99500000 、 Indirect Cost：\29850000 ）

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  • Spatio-temporal regulation and tissue basis of functional innate-adaptive immune cooperation in the lymph node

    Grant number：16H05204

    2016.4 - 2019.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    Katakai Tomoya, TAKEUCHI Arata, KANDA Yasuhiro, OZAWA Madoka

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    Grant amount：\17160000 （ Direct Cost: \13200000 、 Indirect Cost：\3960000 ）

    Lymph node is an important organ for immune responses. In this study, we focused on a tissue area, medulla-cortex transitional region (MCT), in which innate and adoptive immune cells are co-localized and unique stromal cells support the tissue. Three dimensional tissue structure, cell composition, molecular expression, and the motility/interaction of immune cells were investigated in detail. Consequently, we found previously less understood tissue subcompartments and unique stromal cell subsets, showing that at least 6 stromal cell subtypes are present in lymph node. These findings also suggest an innate-adoptive immune activation pathway through the medullary side. Moreover, transcription factor NFkB plays crucial role in the differentiation of multiple stromal cell types in the lymph node.

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  • Fetastasis-supportive microenvironment induced by the interaction between metastatic tumor cells and stromal cells in the lymph node

    Grant number：16K15287

    2016.4 - 2018.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Challenging Exploratory Research

    Awarding organization：Japan Society for the Promotion of Science

    Katakai Tomoya, KANDA Yasuhiro, TAKEUCHI Arata

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    Grant amount：\3510000 （ Direct Cost: \2700000 、 Indirect Cost：\810000 ）

    Cancer metastasis to the lymph node is crucial issue in disease pathophysiology, although the underlying mechanisms are largely unclear. This study aimed to reveal the cellular and molecular processes in lymph node metastasis through the detailed examinations focusing on the behavior of metastatic tumor cells within lymph node tissue structures and interactions between tumor cells and immune cells or stromal cells.
    Subcutaneously injected mouse mammary tumor cells metastasized to draining lymph node until around 4 weeks and first settled in the subcapsular lymphatic sinus followed by expanding into tissue parenchyma. Inside the growing tumor, stromal network and blood vessels with unique features seemed to be formed and the infiltration of macrophages and T cells was also observed. In a coculture system, tumor cells selectively adhered to stromal cells, suggesting that metastatic tumor cells are likely to use stromal cells as scaffold for further invasion into the tissue in vivo.

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  • Artificial induction of the property of FRC in lymph node paracortex

    Grant number：25670101

    2013.4 - 2016.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Challenging Exploratory Research

    Awarding organization：Japan Society for the Promotion of Science

    Katakai Tomoya

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    The paracortical region of lymph node (LN) is a prime site where antigen-specific interactions between T cells and dendritic cells takes place, therefore it plays a crucial role in the induction of adoptive immunity. Tissue structure of the paracortex is supported by fibroblastic reticular cells (FRCs) that produce CCL21, an important chemokine for attracting T cells and dendritic cells. However, mechanism for the selective expression of CCL21 in FRCs remains to be elucidated. The purpose of this study is to clarifying the molecular process. To identify the regulatory factors critical for the expression of CCL21, candidate genes highly expressing in mouse LN stromal cells were stably transfected to FRC cell lines established from LN using retroviral vectors. Although some transfectants showed alterations in responsibility to inflammatory cytokines, we unfortunately could not found the settings that induce CCL21 expression in FRC cell lines.

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  • Characteristics and functions of stromal cells in secondary lymphoid tissues

    Grant number：24111005

    2012.6 - 2017.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Awarding organization：Japan Society for the Promotion of Science

    MIYASAKA Masayuki, Takeda Akira, Sirpa Jalkanen, Malko Salmi

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    Grant amount：\171210000 （ Direct Cost: \131700000 、 Indirect Cost：\39510000 ）

    In collaboration with Drs. A. Takeda, S. Jalkanen, and M. Salmi of University of Turku, Finland, the principal investigator, M. Miyasaka, and the co-investigator, E. Umemoto, found that a specific stromal subset secretes multiple bioactive molecules that regulate lymphocyte trafficking into and within lymph nodes. They also found that a different stromal subset mediates transport of small-molecular substances from the lymphatic sinus into the lymph node parenchyma. A co-investigator, H. Hayasaka, identified a mechanism whereby a chemokine induces homo- and hetero-oligomerization of chemokine receptors. A co-investigator, T. Katakai, analyzed stromal cells in lymph nodes in detail and identified a novel stromal subset.

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  • Ｔ細胞のリンパ節間質高速遊走における細胞内動態と組織微小環境

    Grant number：23113517

    2011.4 - 2013.3

    System name：科学研究費助成事業

    Research category：新学術領域研究(研究領域提案型)

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\11830000 （ Direct Cost: \9100000 、 Indirect Cost：\2730000 ）

    免疫系細胞は全身を循環しながら感染部位や病変組織へと素早く移行する必要性から、活発に移動すること自体が重要な機能のひとつであるといえる。本研究では二光子励起レーザー顕微鏡を用いた組織内生体イメージングにより、リンパ節間質を高速移動するT細胞の動態観察および隣接する組織細胞の同時可視化を試み、３次元的組織微小環境内における遊走機構の解明を目指した。
    二光子励起レーザー顕微鏡を用いたマウスのリンパ節イメージングの方法として、個体を用いたIntravital法やリンパ節Explant法に加え、組織Slice法を用いたT細胞遊走観察系を確立した。特に組織Slice法は抗体や薬剤を用いた阻害実験が容易で、遊走メカニズムの詳細な検討に非常に有効である。T細胞はリンパ節組織中で概ね10μm/min以上の速度で活発に移動した。また、CAG-ECFPマウス、CD11c-Venusマウスやそれらの骨髄キメラマウスを用いて、ストローマ細胞および樹状細胞のネットワーク構造を可視化し、遊走中のT細胞との関係を詳細に観察したところ、T細胞は両ネットワーク細胞に頻繁に接触しながら組織中を移動した。
    インテグリンLFA-1およびそのリガンドであるICAM-1の阻害はT細胞遊走を部分的に抑制し、野生型およびICAM-1欠損マウス骨髄キメラ由来のリンパ節を用いた解析から、樹状細胞が発現するICAM-1がLFA-1依存的な高速遊走に必要であることが明らかになった。また、ストローマ細胞が産生するAutotaxinとそれにより産生されるリゾフォスファチジン酸（LPA）がT細胞遊走に部分的に関与していることが示唆され、LFA-1非依存的な遊走活性に寄与していると推測される。
    以上のことから、リンパ節内のT細胞高速遊走は複数の組織細胞に支持された、いくつかの分子機構の協調作用により制御されていると考えられる。

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  • Regulatory mechanisms of immune cell trafficking by spatiotemporal control of cell adhesion

    Grant number：22111003

    2010.4 - 2015.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Awarding organization：Japan Society for the Promotion of Science

    KINASHI Tatsuo, KATAKAI Tomoya, UEDA Yoshihiro, KONDO Naoyuki, KITA Toshiyuki

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    Grant amount：\138060000 （ Direct Cost: \106200000 、 Indirect Cost：\31860000 ）

    We examined lymphocyte intranodal migration and antigen recognition to clarify the the functions and regulations of LFA-1 mainly using two-photon imaging techniques. We demonstrate: (1) there are two migration modes in peripheral lymph nodes; chemokine-independent random migration and chemokine-dependent directional migration, the latter of which depends on LFA-1 binding to dendritic ICAM-1, (2) thymocytes exhibit fast migration within the medulla of the thymus, and recognize self-antigen, which require LFA-1/ICAM-1 dependent adhesion regulated by Mst1, (3) regulatory T cells show migratory immune synapses in vitro and in lymph nodes , which regulated by Mst1. We further establish single-molecule analysis of LFA-1/ICAM-1 bindings in immune synapse in which Rap1/Mst-1 regulate high-affinity bindings.

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  • Construction of the basis oflymph node tissue microenvironment by stromal cell derived factors

    Grant number：22790194

    2010 - 2011

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Young Scientists (B)

    Awarding organization：Japan Society for the Promotion of Science

    KATAKAI Tomoya

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    Lymph node is a crucial site for the induction of immune responses, in which stromal cells constructing elaborate network support the activity of immune cells. However, the molecular basis of stromal cell function is still unclear. In this study, we tried to identify factors expressed in stromal cells and addressed their roles in the regulation of immune cell function. As a consequence, we found that stromal cells produce a lysophosphatidic acid(LPA) synthetic enzyme, autotaxin(ATX), and ATX-LPA axis is involved in the interstitial migration of lymphocytes. Therefore, stromal cells are suggested to control the activity of lymphocytes via producing various molecular mediators.

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  • 二次リンパ器官ストローマ細胞による免疫支持場の構築メカニズム

    Grant number：20057029

    2008 - 2009

    System name：科学研究費助成事業

    Research category：特定領域研究

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\4000000 （ Direct Cost: \4000000 ）

    免疫応答誘導の場として重要な役割を担う二次リンパ器官では、ネットワークを形成するストローマ細胞が組織構造や免疫細胞の活動のための足場を提供している。しかし、ネットワークの構築原理やリンパ球動態を制御するするメカニズムの詳細は明らかになっていない。
    本研究ではいくつかの新たな研究手法を開発し、ストローマ細胞の免疫支持能を発揮する原理の探求を試みた。まず、マウスリンパ節からストローマ細胞を単離・培養する手法を確立し、これにより形成させた単層上においてマウスT細胞を効率よく遊走させることに成功した。この系を用いてT細胞がケモカインやインテグリンに依存してストローマ細胞上を移動することを明らかにした。一方、繊維径や網目サイズが適したスポンジ素材を選定し、リンパ節由来ストローマ細胞を播種し三次元的なネットワーク構造の再現を試みた。それにより、生体内に見られる組織構造の状況を良く反映した細胞ネットワーク構造を形成させることが可能となった。さらに、マイクロアレイ解析によりリンパ節ストローマ細胞分画とマウス胎仔線維芽細胞を比較し、ストローマ細胞に特異的に発現する多数の遺伝子を同定した。
    そのほか、生体内の組織においてストローマ細胞の役割を直接的に調べるため、ストローマ細胞特異的に誘導性遺伝子改変が可能なモデル動物を作製した。すなわち、ストローマ細胞を含む間葉系細胞においてエストロゲン受容体のリガンド結合ドメインにCreリコンビナーゼを融合させたCreERT2やGFP遺伝子を発現させたトランスジェニックマウス作製した。これによりストローマ細胞の特異的機能を検討することが可能となった。

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  • Immunological and physiological analysis of the function and construction of stromal cell network in secondary lymphoid organ

    Grant number：20689005

    2008 - 2009

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Young Scientists (A)

    Awarding organization：Japan Society for the Promotion of Science

    KATAKAI Tomoya

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    Grant amount：\22360000 （ Direct Cost: \17200000 、 Indirect Cost：\5160000 ）

    In the secondary lymphoid organs in which immune responses are efficiently induced, the network of mesenchymal stromal cells support tissue architecture and immune cells behaviors. However, the detailed functions of stromal cells are still largely unclear. Technical advances to investigate lymphoid stromal cells are also required.
    We established a method to efficiently isolate stromal cell fraction from mouse lymph node and for the culture of the stromal cells to make a confluent monolayer. Using this technique, we observed that isolated primary lymphocytes efficiently migrated on the stromal monolayer. Moreover, We constructed three-dimensional network of primary stromal cells using supportive meshwork substrates in vitro. We also tried to develop an animal model for genetically modifying stromal cells in vivo.

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  • リンパ組織間質ストローマ細胞におけるセルピン遺伝子発現と免疫制御機構

    Grant number：18790197

    2006 - 2007

    System name：科学研究費助成事業

    Research category：若手研究(B)

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\3400000 （ Direct Cost: \3400000 ）

    二次リンパ組織の発生や維持にはリンフォトキシンβ受容体(LTβR)シグナルによるストローマ細胞の特殊化が重要である。LTβRの下流ではセリン・スレオニンキナーゼNIKを介し転写因子RelB/p52複合体の活性化に至る、いわゆるNF-kB NC経路が様々な遺伝子発現を制御していると考えられるが、リンパ組織ストローマ細胞内における各分子個々の機能や相互の連携に関しては未解明の問題が多く残されている。我々はマウスリンパ節ストローマ細胞株BLSを用いて種々のプロテアーゼ阻害因子の発現を網羅的に検討した結果、LTβRシグナル特異的に強く応答する標的遺伝子としてSerpin-A1bを同定した。また、NC経路の構成分子の野生型や変異型の強制発現系においてSerpinの発現誘導や阻害を確認するとともに、様々な薬剤による発現誘導阻害を検討した結果、プロテインキナーゼCがこの経路の活性化に極めて重要であることが判明し、その作用起点は複数存在することも明らかになった。Serpinファミリー因子群は数多くの種類が存在するが、データベース上ではヒト、マウスともにゲノム中に遺伝子重複の結果、複数のA1タイプSerpin(A1a-e)遺伝子が連なったクラスター領域が存在していることが知られている。興味深いことに、各サブタイプの遺伝子構造およびプロモーター領域の配列は高度に保存されているにもかかわらず、A1b以外のサブタイプについてはLTβRシグナルによる発現誘導が全く認められない。詳細な解析の結果、A1bにのみ数十kb上流に代替プロモーター領域/Exon1bが存在し、この領域がLTβRシグナルの制御下にあった。したがって、Serpin-A1bがNC経路の標的遺伝子のひとつとして特別な制御を受け、ストローマ細胞の機能に直接関与している可能性が想定される。

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  • リンパ球とストローマ細胞の相互作用によるリンパ節細網ネットワーク構築機構

    Grant number：17047018

    2005 - 2006

    System name：科学研究費助成事業

    Research category：特定領域研究

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\9500000 （ Direct Cost: \9500000 ）

    リンパ節ストローマ細胞株BLS12をTNF、LTbRアゴニスト抗体(LTbR-AAb)により刺激すると、TNFではCXCL13の産生はほとんど認められないが、LTbR-AAbでは顕著な産生がみられ、さらにTNFaとLTbR-AAbを同時に処理することによりCXCL13産生が増強された。したがって、BLS12細胞においてLTbRの架橋はCXCL13発現を誘導するためパに充分なシグナルを入力すると考えられる。TNF受容体(TNFR)架橋ではその活性がみられないが、LTbRのよる効果を増幅するシグナルを入力すると考えられる。TNFR架橋はRelA/p50複合体(C経路)のみを活性化し、LTbR架橋はCおよびRelB/p52複合体(NC経路)両経路を活性化することが知られており、C経路の活性化にはRelA/p50複合体の阻害タンパク質であるIkBがシグナル依存的にリン酸化され、それにより分解されることが必要である。一方で、NC経路の活性化にはIkB同様に阻害的な働きを担うp52の前駆体p100が、シグナル依存的にリン酸化/分解され活性型RelB/p52複合体となる過程を要する。BLS12細胞にC経路の活性化を遮断するIkB変異体を強制発現すると、LTbR-AAbやTNFとの共刺激によるCXCL13産生がほぼ完全に阻害された。また、非分解型p100変異体の強制発現においてもCXCL13産生が強く阻害された。すなわちCXCL13発現にはCおよびNC両経路が必要であると考えられる。BLS12細胞においてもTNFa刺激などに伴うC経路の活性化によりRelB、p100の発現亢進が認められるが、IkB変異体を強制発現により刺激依存的なRelB、p100発現亢進が全く誘導されないばかりか、定常状態における発現量も激減していた。したがって、C経路は少なくともRelB、p100発現を誘導することによりCXCL13発現に寄与していると考えられる。

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  • T細胞の細胞極性とユーロポット形成におけるERMタンパク質Ezrinの役割

    Grant number：16770147

    2004 - 2005

    System name：科学研究費助成事業

    Research category：若手研究(B)

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\3500000 （ Direct Cost: \3500000 ）

    遊走中のリンパ球においては前後軸に沿って非常に明確な細胞極性が形成されるが、その極性形成の分子メカニズムは明らかにされていない。特に細胞後方にユーロポッドという特徴的な半球状の構造体が一つだけ形成され、細胞極性の成立に深く関わっている可能性が高いが、その構造の分子基盤についてもこれまで詳しくは解析されていなかった。ユーロポッドにはEzrinと呼ばれる細胞膜-骨格架橋タンパクとそれに結合するCD44といった膜タンパクが集積し、ユーロポッド分子複合体の一部を成していることから、これらの分子が解析の手掛かりになるとと考えられる。
    恒常的にユーロポッドを形成するEL4.G8リンパ腫細胞を用いて、Ezrinの細胞内局在とユーロポッド形成との関わりを検討した。EzrinはC末端のスレオニン残基のリン酸化により不活性型/活性型が制御され特にリン酸化型が膜-骨格架橋機能を有するが、擬似リン酸化型変異T567DEzrinはユーロポッドに限局して存在し、発現細胞はユーロポッドが肥大したほか細胞遊走能が増加した。一方、効果的な細胞遊走が起るためには、細胞体の後方が連続的に収縮する必要がある。一般的に、細胞収縮にはRhoGTPaseとその下流のキナーゼROCKが重要であることが知られているが、ドミナントネガティブT19NRhoの過剰発現やROCKの阻害剤Y27632処理はEL4.G8細胞のユーロポッドを破壊し、細胞遊走を阻害した。また、Rho活性化因子Dblはリン酸化型Ezrinに選択的に結合し、Rho活性可能を示した。以上のことから、Ezrinのリン酸化による膜-骨格架橋機能およびRho-ROCKシグナル伝達経路との連携がリンパ球の細胞極性とユーロポッド形成に重要な役割を担っていることが示唆された。

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  • リンパ球とストローマ細胞の相互作用によるリンパ節細網ネットワーク構築機構

    Grant number：16043226

    2004

    System name：科学研究費助成事業

    Research category：特定領域研究

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\5700000 （ Direct Cost: \5700000 ）

    リンパ節は効果的な獲得免疫応答のための「場」を与える二次リンパ器官であり、各種免疫細胞が区画化された機能的な組織構造がみられる。この特徴的な組織構造はストローマ細胞が構築する緻密なネットワークによって裏打ちされ支えられている。特に細網線維芽細胞(FRC)とそれらが産生する細胞外マトリクス(ECM)繊維からなる細網ネットワーク(RN)はリンパ節組織全体を幅広く支持しており、免疫細胞の活動のために必要な足場と空間を提供していると考えられる。しかし、どのようにしてこの洗練された微細構造が構築されるのかはこれまで明らかにされていなかった。我々がマウスのリンパ節より樹立したストローマ細胞株BLS4は線維芽細胞状の形態を示し、定常状態において細胞質内にER-TR7抗原を認めるほか、いくつかのFRCマーカーを発現することからFRC細胞株であると考えられる。興味深いことに、この細胞はリンパ球との共培養によりER-TR7抗原を細胞外に放出し緻密な網目構造を構築する。また、TNFやLTα3により断片的な繊維の産生が見られ、部分的にTNF受容体を介したシグナル経路が関与することが示唆された。さらに、TNFやLTα存在下においてLTβ受容体からのシグナルを模倣する抗LTβ受容体アゴニスト抗体を添加すると劇的なメッシュワーク形成が誘導されたことから、TNF受容体とLTβ受容体の同時刺激が重要な役割を果たすことが明らかになった。BLS4にNFκB/RelA複合体の活性化を抑制するIκB変異体を強制発現させるとメッシュワーク形成を完全に抑制することから、TNF受容体により活性化されるこの経路が必須であることも確認された。リンパ組織の形成・維持にはとりわけTNF/LT系シグナルが重要であるが、BLS4を用いた解析から得られた知見はこうした事実と合致する。LTβ受容体のリガンドであるLTα1β2はリンパ球の細胞膜上タンパク複合体であり、シグナルの伝達には受容体発現細胞との直接的な接触が必要である。

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  • リンパ節ストローマ細胞が産生する膜型ケモカインによる初期免疫応答の制御

    Grant number：15019047

    2003

    System name：科学研究費助成事業

    Research category：特定領域研究

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\3300000 （ Direct Cost: \3300000 ）

    マウスリンパ節付着性細胞の長期間培養により、ER-TR7、gp38、VCAM-1といった細網線維芽細胞の分子マーカーをいくつか発現する間質系細胞株を複数樹立した(BLS細胞)。これらの細胞は、リンパ球との共培養によりin vitroにおいて細網ネットワーク様構造を形成することを見い出し、リンパ節細網線維芽細胞、ストローマ細胞の性質や機能を調べる上で有用な材料になり得ると考えられる。この細胞の培養上清はT細胞に対して細胞遊走を誘導し、TNF-α等の炎症性サイトカイン刺激によりその活性は増強された。また、この活性はケモカインシグナルを阻害する百日咳毒素により顕著に減弱することから、BLS細胞が産生するケモカインの関与が示唆された。そこで、様々なケモカインの発現を検討したところ、いくつかの興味深いケモカインの発現が認められた。その一つに膜型ケモカインCXCL16があり,TNF-α刺激により顕著に発現が増加した。培養上清中には可溶型CXCL16が検出され、マトリクス・メタロプロテアーゼ阻害剤により抑制されることから、メタロプロテアーゼによる細胞外の切断による産生機構が示唆された。また、CD8陽性T細胞をIL-12存在下で抗原刺激を行うと、CXCL16の特異的受容体CXCR6が劇的に発現誘導されることを見い出した。IL-12刺激CD8陽性T細胞は組み換え型CXCL16に対して遊走能を示し、TNF-α刺激BLS細胞に対する接着は抗CXCL16抗体により顕著に抑制された。したがって、実際のリンパ節内においても細網線維芽細胞が産生するCXCL16免疫応答制御に関与していることが示唆される。

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  • Tヘルパー1細胞の血管内皮透過におけるCD44-PKCζシグナル経路の解明

    Grant number：14770045

    2002 - 2003

    System name：科学研究費助成事業

    Research category：若手研究(B)

    Awarding organization：日本学術振興会

    片貝 智哉

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    Grant amount：\3000000 （ Direct Cost: \3000000 ）

    種々の慢性炎症に重要な役割を果たすTh1細胞の組織遊走過程、血管内皮透過過程を詳細に解析するために、試験管内において均一な抗原特異性を有するマウス由来のTh1細胞株を樹立し、マウス血管内皮細胞株F-2を用いた再現性のある経内皮透過実験系を確立した。この実験系を用いた解析により、Th1細胞にはケモカインに依存した経内皮透過能と依存しない経内皮透過能があり、両活性がTh1細胞優位な組織浸潤の悪循環を引き起している可能性を示した。また、Th1細胞細胞が発現するLFA-1やCD44といった接着分子を介した血管内皮細胞への接着が重要であり、特に細胞表面のCD44分子架橋刺激がTh1細胞形態を大きく変化させ、細胞遊走を誘導していることが明らかになった。Th1細胞に対する種々の薬剤処理により、この過程にはPI3K、PLC、SrcPTK等のシグナル伝達分子が関与し、アクチン細胞骨格の再編を引き起すことが示唆された。さらに、CD44分子架橋刺激は、特に細胞極性が際立った特有の細胞伸長変化をもたらし、実際の血管内皮透過におけるTh1細胞の遊走にも細胞極性の形成が極めて重要な過程であることがはっきりした。したがって、ケモカイン非依存的かつ接着依存的なシグナルがTh1細胞の経内皮透過過程に重要な役割を担っていることが示唆された。一方で、実験的に扱い易いリンフォーマ細胞株に対して安定遺伝子導入を行い、シグナル伝達経路に関係する分子の様々な変異体について、細胞遊走や形態変化への影響をを観察する系を確立するした。

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Teaching Experience

  • 先端医科学研究概説

    2022
    -
    2023
    Institution name：新潟大学

  • 医学論文を読む(ジャーナルクラブ)B

    2021
    -
    2023
    Institution name：新潟大学

  • 生体防御と感染(医動物学)

    2017
    Institution name：新潟大学

  • 生体防御と感染(免疫学)

    2017
    Institution name：新潟大学