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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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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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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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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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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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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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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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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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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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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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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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Allogeneic organ transplants are rejected by the recipient immune system within several days or weeks. However, the rejection process of allogeneic T (allo-T) cells is poorly understood. In this study, using fluorescence-based monitoring and two-photon live imaging in mouse adoptive transfer system, we visualized the fate of allo-T cells in the in vivo environment and showed rapid elimination in secondary lymphoid organs (SLOs). Although i.v. transferred allo-T cells efficiently entered host SLOs, including lymph nodes and the spleen, ∼70% of the cells had disappeared within 24 h. At early time points, allo-T cells robustly migrated in the T cell area, whereas after 8 h, the numbers of arrested cells and cell fragments were dramatically elevated. Apoptotic breakdown of allo-T cells released a large amount of cell debris, which was efficiently phagocytosed and cleared by CD8+ dendritic cells. Rapid elimination of allo-T cells was also observed in nu/nu recipients. Depletion of NK cells abrogated allo-T cell reduction only in a specific combination of donor and recipient genetic backgrounds. In addition, F1 hybrid transfer experiments showed that allo-T cell killing was independent of the missing-self signature typically recognized by NK cells. These suggest the presence of a unique and previously uncharacterized modality of allorecognition by the host immune system. Taken together, our findings reveal an extremely efficient and dynamic process of allogeneic lymphocyte elimination in SLOs, which could not be recapitulated in vitro and is distinct from the rejection of solid organ and bone marrow transplants.

DOI： 10.4049/jimmunol.1700219

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The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12highLepRhigh FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN.

DOI： 10.3389/fimmu.2018.02196

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

Live imaging using various microscopic technologies is an indispensable tool for investigating the dynamic nature of immune cells. One of the most powerful techniques is the two-photon laser-scanning microscopy (TP-LSM), which has various advantages in observing deep tissues in vivo. Interstitial T cell migration in the lymph node (LN) is a phenomenon intensively examined using TP-LSM in the field of immunology. Intravital and explant methods have been standards for imaging T cell behaviors in the LN, though there are several limitations. Live imaging of LN slices, an LN explant sliced by a vibratome to expose tissue parenchyma, could provide an alternative approach with technical advantages for an in-depth analysis of interstitial T cell migration in vivo.

DOI： 10.1007/978-1-4939-7762-8_4

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Lymphadenopathy is a frequently observed symptom in systemic lupus erythematosus, although the immunological role of lymph nodes (LNs) in systemic autoimmunity remains largely unknown. Here, we performed comprehensive and systematic analyses of LNs in lupus-prone NZB × NZW F1 (BWF1) mice, demonstrating extensive tissue re-organization of the systemic LNs with follicular expansion, hyper germinal center (GC) formation, atrophy of the paracortical T-cell area and expansion of the medulla in aged BWF1 mice bearing glomerulonephritis. The proportion of B cells was significantly increased in these reactive LNs but not in the spleen, and lymphocyte subsets involved in antibody production, i.e. GC B cells, follicular helper T cells and plasma cells, were elevated. Draining LNs of the affected organs, such as the renal and cervical nodes, showed enhanced tissue re-organization and accumulation of effector lymphocytes, suggesting the presence of a positive feedback loop of regional responses. LN cells isolated from disease-bearing animals produced anti-DNA antibody, indicating activation of autoreactive lymphocytes in situ. The substantial development of disease and LN alterations in mice that received a splenectomy at a young age points to the importance of other secondary lymphoid organs, most likely LNs, for the progression of autoimmune responses independent of the spleen. Taken together, our findings highlight the value of taking LN alterations and activities into consideration for understanding the pathogenesis of systemic autoimmunity.

DOI： 10.1093/intimm/dxx066

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo.

DOI： 10.1084/jem.20161864

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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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Naive T cells differentiate into various effector T cells, including CD4(+) helper T cell subsets and CD8(+) cytotoxic T cells (CTL). Although cytotoxic CD4(+) T cells (CD4 +: CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4(+) T cells that express class I-restricted T cell-associated molecule (CRTAM) upon activation possesses the characteristics of both CD4(+) and CD8(+) T cells. CRTAM(+) CD4(+) T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM(+) T cells are the precursor of CD4(+)CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4(+)CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM(+) T cells traffic to mucosal tissues and inflammatory sites and developed into CD4(+)CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4(+)CTL through the induction of Eomes and CTL-related gene.

DOI： 10.1084/jem.20150519

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

T cells are highly concentrated in the lymph node (LN) paracortex, which serves an important role in triggering adoptive immune responses. Live imaging using two-photon laser scanning microscopy revealed vigorous and non-directional T cell migration within this area at average velocity of more than 10 μm/min. Active interstitial T cell movement is considered to be crucial for scanning large numbers of dendritic cells (DCs) to find rare cognate antigens. However, the mechanism by which T cells achieve such high-speed movement in a densely packed, dynamic tissue environment is not fully understood. Several new findings suggest that fibroblastic reticular cells (FRCs) and DCs control T cell movement in a multilateral manner. Chemokines and lysophosphatidic acid produced by FRCs cooperatively promote the migration, while DCs facilitate LFA-1-dependent motility via expression of ICAM-1. Furthermore, the highly dense and confined microenvironment likely plays a key role in anchorage-independent motility. We propose that T cells dynamically switch between two motility modes; anchorage-dependent and -independent manners. Unique tissue microenvironment and characteristic migration modality of T cells cooperatively generate high-speed interstitial movement in the LN.

DOI： 10.3389/fimmu.2016.00194

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development.

DOI： 10.1038/srep13054

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Language：English   Publisher：(NPO)日本免疫学会  

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T cells exhibit high-speed migration within the paracortical T zone of lymph nodes (LNs) as they scan cognate Ags displayed by dendritic cells in the tissue microenvironment supported by the network of stromal cells. Although intranodal T cell migration is controlled in part by chemokines and LFA-1/ICAM-1, the mechanisms underlying their migratory activity independent of these factors remain to be elucidated. In this study, we show that LN stromal cells constitutively express autotaxin (ATX), an ectoenzyme that is important for the generation of lysophosphatidic acid (LPA). Importantly, CCL21(+) stromal cells in the T zone produced and immobilized ATX on their cell surface. Two-photon imaging using LN tissue slices revealed that pharmacological inhibition of ATX or LPA receptors significantly reduced T cell migration, and this was further exacerbated by blockage of Gαi signaling or LFA-1. Therefore, T cell motility mediated by the ATX-LPA axis was independent of Gαi and LFA-1. LPA induced slow intermittent movement of T cells in vitro in a LFA-1-independent manner and enhanced CCL21-induced migration. Moreover, LPA and CCL21 cooperatively augmented RhoA activity in T cells, which was necessary for efficient intranodal T cell migration via the downstream ROCK-myosin II pathway. Taken together, T zone stromal cells control optimal migratory behavior of T cells via multiple signaling cues mediated by chemokines and ATX/LPA.

DOI： 10.4049/jimmunol.1400565

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T lymphocytes vigorously migrate within the paracortex of lymph nodes (LNs) in search of cognate Ags that are presented by dendritic cells (DCs). However, the mechanisms that support T cells to exert the highest motility in a densely packed LN microenvironment are not fully understood. Two-photon microscopy using LN tissue slices revealed that LFA-1 and ICAM-1 were required for high-velocity migration (>10 μm/min) with relatively straight movement. Importantly, ICAM-1 expressed by myeloid lineages, most likely DCs, but not stromal cells or lymphocytes, was sufficient to support the high-velocity migration. Visualizing DCs in the LN from CD11c-EYFP mice showed that T cells traveled over thin dendrites and the body of DCs. Interestingly, DCs supported T cell motility in vitro in chemokine- and ICAM-1-dependent manners. Moreover, an acute lymphopenic environment in the LN significantly increased LFA-1 dependency for T cell migration, indicating that lymphocyte density modulates the use of LFA-1. Therefore, our results indicate that LFA-1/ICAM-1-dependent interactions between T cells and DCs play a crucial role not only in supporting firm arrest during Ag recognition but also in facilitating the Ag scanning processes.

DOI： 10.4049/jimmunol.1300739

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Although the cell-to-cell contact between CD4(+)Foxp3(+) regulatory T (Treg) and their target cells is important for the suppressor function of Treg cells, the regulation of this process is not well understood. Here we show that the Mst1 kinase plays a critical role in the suppressor function of Treg cells through regulation of cell contact dependent processes. Mst1 (-/-) Treg cells failed to prevent the development of experimental colitis and antigen-specific suppression of naïve T cells proliferation in vitro. Mst1 (-/-) Treg cells exhibited defective interactions with antigen-presenting dendritic cells (DCs), resulting in reduced down-regulation of costimulatory molecules. While wild-type CD4(+) Foxp3(+) Treg cells formed mobile immunological synapses on supported planar membrane, Mst1 (-/-) Treg cells did not exhibit ICAM-1 ring or central peptide-MHC clustering. Using two-photon imaging we showed that antigen-specific wild-type Treg cells exhibited dynamic mobile contacts with antigen-pulsed DCs bearing stably associated naïve T cells. In contrast, Mst1 (-/-) Treg had impairments in their interactions with DCs. Thus, Mst1 is required for Treg cells to mediate contact-dependent suppressor functions.

DOI： 10.1371/journal.pone.0073874

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Language：English   Publisher：The Biophysical Society of Japan General Incorporated Association  

DOI： 10.2142/biophys.53.S100_2

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To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially. (Blood. 2012;119(19):4451-4461)

DOI： 10.1182/blood-2012-01-407098

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DOCK2, a hematopoietic cell-specific, atypical guanine nucleotide exchange factor, controls lymphocyte migration through ras-related C3 botulinum toxin substrate (Rac) activation. Dedicator of cytokinesis 2-engulfment and cell motility protein 1 (DOCK2.ELMO1) complex formation is required for DOCK2-mediated Rac signaling. In this study, we identified the N-terminal 177-residue fragment and the C-terminal 196-residue fragment of human DOCK2 and ELMO1, respectively, as the mutual binding regions, and solved the crystal structure of their complex at 2.1-angstrom resolution. The C-terminal Pro-rich tail of ELMO1 winds around the Src-homology 3 domain of DOCK2, and an intermolecular five-helix bundle is formed. Overall, the entire regions of both DOCK2 and ELMO1 assemble to create a rigid structure, which is required for the DOCK2.ELMO1 binding, as revealed by mutagenesis. Intriguingly, the DOCK2.ELMO1 interface hydrophobically buries a residue which, when mutated, reportedly relieves DOCK180 from autoinhibition. We demonstrated that the ELMO-interacting region and the DOCK-homology region 2 guanine nucleotide exchange factor domain of DOCK2 associate with each other for the autoinhibition, and that the assembly with ELMO1 weakens the interaction, relieving DOCK2 from the autoinhibition. The interactions between the N- and C-terminal regions of ELMO1 reportedly cause its autoinhibition, and binding with a DOCK protein relieves the autoinhibition for ras homolog gene family, member G binding and membrane localization. In fact, the DOCK2.ELMO1 interface also buries the ELMO1 residues required for the autoinhibition within the hydrophobic core of the helix bundle. Therefore, the present complex structure reveals the structural basis by which DOCK2 and ELMO1 mutually relieve their autoinhibition for the activation of Rac1 for lymphocyte chemotaxis.

DOI： 10.1073/pnas.1113512109

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Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue Mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAM-1 within the medulla. Using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire(+) ICAM-1(hi) medullary thymic epithelia in a negatively selecting environment. Notably, Mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAM-1 results in inefficient migration and antigen recognition of CD4(+) thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1(-/-) mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. Our results suggest that Mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla.

DOI： 10.1038/ncomms2105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS RESEARCH FOUNDATION  

The architecture of secondary lymphoid organs (SLOs) is supported by several non-hematopoietic stromal cells. Currently it is established that two distinct stromal subsets, follicular dendritic cells and fibroblastic reticular cells, play crucial roles in the formation of tissue compartments within SLOs, i.e., the follicle and T zone, respectively. Although stromal cells in the anlagen are essential for SLO development, the relationship between these primordial cells and the subsets in adulthood remains poorly understood. In addition, the roles of stromal cells in the entry of antigens into the compartments through some tissue structures peculiar to SLOs remain unclear. A recently identified stromal subset, marginal reticular cells (MRCs), covers the margin of SLOs that are primarily located in the outer edge of follicles and construct a unique reticulum. MRCs are closely associated with specialized endothelial or epithelial structures for antigen transport. The similarities in marker expression profiles and successive localization during development suggest that MRCs directly descend from organizer stromal cells in the anlagen. Therefore, MRCs are thought to be a crucial stromal component for the organization and function of SLOs.

DOI： 10.3389/fimmu.2012.00200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Mice with a mutation of the z-associated protein of 70 kDa gene (skg mutation) are genetically prone to develop autoimmune arthritis, depending on the environment. In a set of mice with the mutation, the amount of z-associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg/+, skg/skg, to skg/- mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3(+) natural regulatory T cells (Tregs) and their respective functions. Consequently, skg/- mice spontaneously developed autoimmune arthritis even in a microbially clean environment, whereas skg/skg mice required stimulation through innate immunity for disease manifestation. After Treg depletion, organ-specific autoimmune diseases, especially autoimmune gastritis, predominantly developed in +/+, at a lesser incidence in skg/+, but not in skg/skg BALB/c mice, which suffered from other autoimmune diseases, especially autoimmune arthritis. In correlation with this change, gastritis-mediating TCR transgenic T cells were positively selected in +/+, less in skg/+, but not in skg/skg BALB/c mice. Similarly, on the genetic background of diabetes-prone NOD mice, diabetes spontaneously developed in +/+, at a lesser incidence in skg/+, but not in skg/skg mice, which instead succumbed to arthritis. Thus, the graded attenuation of TCR signaling alters the repertoire and the function of autoimmune T cells and natural Tregs in a progressive manner. It also changes the dependency of disease development on environmental stimuli. These findings collectively provide a model of how genetic anomaly of T cell signaling contributes to the development of autoimmune disease. The Journal of Immunology, 2010, 185: 2295-2305.

DOI： 10.4049/jimmunol.1000848

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The small GTPase Rap1 and its effector RAPL regulate lymphocyte adhesion and motility. However, their precise regulatory roles in the adhesion cascade preceding entry into lymph nodes and during interstitial migration are unclear. Here, we show that Rap1 is indispensably required for the chemokine-triggered initial arrest step of rolling lymphocytes through LFA-1, whereas RAPL is not involved in rapid arrest. RAPL and talin play a critical role in stabilizing lymphocyte arrest to the endothelium of blood vessels under flow or to the high endothelial venules of peripheral lymph nodes in vivo. Further, mutagenesis and peptide studies suggest that release of a trans-acting restraint from the beta 2 cytoplasmic region of LFA-1 is critical for Rap1-dependent initial arrest. Rap1 or RAPL deficiency severely impaired lymphocyte motility over lymph node stromal cells in vitro, and RAPL deficiency impaired high-velocity directional movement within lymph nodes. These findings reveal the several critical steps of Rap1, which are RAPL-dependent and-independent, in lymphocyte trafficking. (Blood. 2010;115:804-814)

DOI： 10.1182/blood-2009-03-211979

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The regulation of lymphocyte adhesion and migration plays crucial roles in lymphocyte trafficking during immunosurveillance. However, our understanding of the intracellular signalling that regulates these processes is still limited. Here, we show that the Ste20-like kinase Mst1 plays crucial roles in lymphocyte trafficking in vivo. Mst1(-/-) lymphocytes exhibited an impairment of firm adhesion to high endothelial venules, resulting in an inefficient homing capacity. In vitro lymphocyte adhesion cascade assays under physiological shear flow revealed that the stopping time of Mst1(-/-) lymphocytes on endothelium was markedly reduced, whereas their L-selectin-dependent rolling/tethering and transition to LFA-1-mediated arrest were not affected. Mst1(-/-) lymphocytes were also defective in the stabilization of adhesion through alpha 4 integrins. Consequently, Mst1(-/-) mice had hypotrophic peripheral lymphoid tissues and reduced marginal zone B cells and dendritic cells in the spleen, and defective emigration of single positive thymocytes. Furthermore, Mst1(-/-) lymphocytes had impaired motility over lymph node-derived stromal cells and within lymph nodes. Thus, our data indicate that Mst1 is a key enzyme involved in lymphocyte entry and interstitial migration. The EMBO Journal (2009) 28, 1319-1331. doi: 10.1038/emboj.2009.82; Published online 2 April 2009

DOI： 10.1038/emboj.2009.82

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Non-hematopoietic mesenchymal stromal cells in secondary lymphoid organs play pivotal roles in tissue organization and immune responses by exhibiting specialized features such as the production of lymphoid homeostatic chemokines. However, the maturational process of stromal cells mediated by lymphotoxin-beta receptor (LT beta R) signaling, a key for stromal maturation, remains unclear. Taking advantage of a stromal cell line established from mouse lymph node, which can produce a homeostatic chemokine, CXC chemokine ligand (CXCL) 13, by the engagement of LT beta R but not by tumor necrosis factor (TNF) receptor (TNFR), we analyzed the details of intracellular signaling events during the maturational process. The activation of both canonical and non-canonical nuclear factor-kappa B (NF-kappa B) pathways was essential for CXCL13 induction; however, an excessive amount of non-canonical RelB-p52 complex was still insufficient for CXCL13 gene expression. Under RelB-p52-over-expressed conditions, TNF alpha could induce a markedly high amount of CXCL13 production, indicating that the downstream of TNFR contains an additional key component of signaling. We also found that protein kinase C activity plays a critical role in this process in addition to the NF-kappa B pathways. Taken together, it is suggested that the maturation of lymphoid stromal cells mediated by LT beta R is accomplished by the cooperation of multiple signaling cascades.

DOI： 10.1093/intimm/dxp014

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Mesenchymal stromal cells are crucial components of secondary lymphoid organs (SLOs). Organogenesis of SLOs involves specialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established a VCAM-1(+)1CAM-1(+)MAdCAM-1(+) reticular cell line that can produce CXCL13 upon LT beta R stimulation and support primary B cell adhesion and migration in vitro. A similar stromal population sharing many characteristics with the LTo, designated marginal reticular cells (MRCs), was found in the outer follicular region immediately underneath the subcapsular sinus of lymph nodes. Moreover, MRCs were commonly observed at particular sites in various SLOs even in Rag2(-/-) mice, but were not found in ectopic lymphoid tissues, suggesting that MRCs are a developmentally determined element. These findings lead to a comprehensive view of the stromal composition and architecture of SLOs. The Journal of Immunology, 2008, 181: 6189-6200.

DOI： 10.4049/jimmunol.181.9.6189

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Autoimmune diseases are caused by the misdirected attack of the immune system against the body's own components. Delicate balance between the activities of several CD4(+) T cell subsets is crucial for determining the initiation of autoimmunity and disease state. In addition, complicated interactions between immune effector cells and tissue resident cells take place in the target organ and construct the inflammatory microenvironment. During the acute,(deterioration phase, autoreactive and cytotoxic effector cells leave blood vessels to infiltrate the target site through a multi-step mechanism involving various molecular processes, and disease pathology progresses though a vicious cycle of accumulation and activation of effector cells. In the chronic phase, long-lasting infiltration of activated lymphocytes in the focal site occasionally results in the formation of ectopic lymphoid tissue that possibly plays important roles in sustaining self-reactivity. The murine experimental model of autoimmune gastritis is one of the most useful systems for studying the complicated cellular events associated with chronic inflammatory disease. (c) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.imlet.2008.03.011

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DOI： 10.2174/157339507783334228

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Autoimmunity is often accompanied by the development of ectopic lymphoid tissues in the target organ, and these tissues have been believed to have close relevance to the severity of the disease. However, the true relationship between the extent of such lymphoid structures and the intensity or type of immune responses mediated by self-reactive T cells has remained unclear. In the present study, we generated transgenic mice expressing TCR from an autoimmune gastritis (AIG)-inducing Th1 cell clone specific for one of the major stomach self-Ags, H+/K+-ATPase alpha subunit. The transgenic mice spontaneously develop massive lymphoid neogenesis with a highly organized tissue structure in the gastric mucosa, demonstrating Ag-specific, T cell-mediated induction of the lymphoid tissues. Nevertheless, the damage of surrounding tissue and autoantibody production were considerably limited compared with those in typical AIG induced by neonatal thymectomy. Such a moderate pathology is likely due to the locally restricted activation and Th2 skewing of self-reactive T cells, as well as the accumulation of naturally occurring regulatory T cells in the target organ. Altogether, the findings suggest that lymphoid neogenesis in chronic autoimmunity does not simply correlate with the destructive response; rather, the overall activation status of the T cell network, i.e., the balance of self-reactivity and tolerance, in the local environment has an impact.

DOI： 10.4049/jimmunol.177.11.7858

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Stromal cells in lymphoid tissues provide microenvironmental fields required for the triggering of efficient immune responses. Fibroblastic reticular cells (FRCs) are one of the integral constituents of such stromal fields; they construct the reticular network and are considered to regulate immune cells' behavior. However, the factors that mediate the interaction between lymphocytes and FRCs are poorly understood. Here we show that a mouse lymph node (LN)-derived FRC cell line, BLS4, expresses a transmembrane chemokine, CXC chemokine ligand (CXCL) 16, in response to tumor necrosis factor alpha (TNF alpha) and IFN gamma. TNF alpha-induced expression of CXCL16 depends on NF kappa B, p38 MAPK and PKA. Matrix metalloproteinase activity is required for producing soluble CXCL16 in the culture supernatant, likely via shedding at the juxtamembrane region of the extracellular domain. IL-12 enhances the expression of CXCR6 in anti-CD3/CD28-stimulated CD8(+) T cells and their adhesion to the BLS4 cell surface in a TNF alpha-dependent fashion. The adherence is significantly inhibited in the presence of both anti-CXCL16 and anti-vascular cell adhesion molecule 1 (VCAM-1) antibodies. CXCL16 expression is also detected in the FRCs in LN sections and in gp38(+)VCAM-1(+) FRCs isolated from LNs. Taken together, these findings suggest that CXCL16 is an important mediator of lymphocyte-stromal interaction within lymphoid tissues.

DOI： 10.1093/intimm/dxh369

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The CpG motif in DNA plays a critical role in immunity via modulating the Th1/Th2 balance. In B cells, CpG-containing oligodcoxynucleotides (CpG ODNs) inhibit IL-4-mediated class switch recombination (CSR) to IgG1 and IgE through inhibition of the germline transcription (GLT) of these isotypes. However, the molecular mechanism of this inhibitory effect remains elusive. We showed here that Id2 and Bc16, both of which inhibit IgE GLT and CSR, are not involved in this inhibitory pathway. We demonstrated that there is reduced activity of NFkappaB binding to the IgE promoter and a reduction of Irf4 protein in CpG ODN-treated B cells. These data indicate the critical role of NFkappaB and Irf4 in the regulation of IgE CSR through actions downstream of CpG signaling. (C) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.12.192

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Front-rear asymmetry in motile cells is crucial for efficient directional movement. The uropod in migrating lymphocytes is a posterior protrusion in which several proteins, including CD44 and ezrin/radixin/moesin (ERM) are concentrated. In Ell T-lymphoma cells, Thr567 phosphorylation in the COOH-terminal domain of ezrin regulates the selective localization of ezrin in the uropod. Overexpression of the phosphorylation-mimetic T567D ezrin enhances uropod size and cell migration. T567D ezrin also induces construction of the CD44-associated polar cap, which covers the posterior cytoplasm in staurosporine-treated, uropod-disrupted Ell cells or in naturally unpolarized X63.653 myeloma cells in an actin cytoskeleton-dependent manner. Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor Y-27632 disrupts the uropod but not the polar cap, indicating that Rho-ROCK signaling is required for posterior protrusion but not for ERM phosphorylation. Phosphorylated ezrin associates with Dbl through its NH2-terminal domain and causes Rho activation. Moreover, constitutively active Q63L RhoA is selectively localized in the rear part of the cells. Thus, phosphorylated ERM has a potential function in establishing plasma membrane "posteriority" in the induction of the uropod in T lymphocytes.

DOI： 10.1083/jcb.200403091

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The sophisticated microarchitecture of the lymph node, which is largely supported by a reticular network of fibroblastic reticular cells (FRCs) and extracellular matrix, is essential for immune function. How FRCs form the elaborate network and remodel it in response to lymphocyte activation is not understood. In this work, we established ERTR7(+)gp38(+)VCAM-l(+) FRC lines and examined the production of the ER-TR7 antigen. Multiple chemokines produced by FRCs induced T cell and dendritic cell chemotaxis and adhesion to the FRC surface. FRCs can secrete the ER-TR7 antigen as an extracellular matrix component to make a reticular meshwork in response to contact with lymphocytes. The formation of the meshwork is induced by stimulation with tumor necrosis factor-alpha or lymphotoxin-alpha in combination with agonistic antibody to lymphotoxin-beta receptor in a nuclear factor-kappaB (RelA)- dependent manner. These findings suggest that signals from lymphocytes induce FRCs to form the network that supports the movement and interactions of immune effectors within the lymph node.

DOI： 10.1084/jem.20040254

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For efficient adaptive immunity, the lymph nodes (LNs) are equipped with a strategically organized microarchitecture, which is largely supported by the reticular network (RN). The RN can be clearly visualized by fluorescence immunohistochemistry coupled with confocal imaging using a monoclonal antibody, EIR-TR7, and can be subdivided into four structurally distinct regions, each of which correlates well with the location of distinct immune cell subsets. In addition, we noticed a characteristic reticular structure designated the 'cortical ridge' at the boundary of the T and B zone, in which dendritic cells are preferentially accumulated. In vitro adhesion assays of frozen sections demonstrated a preference of dendritic cells for the cortical ridge rather than the deeper cortex. Adoptive transfer experiments also demonstrated that antigen-bearing dendritic cells migrated to this region from peripheral tissues, especially in the vicinity of the high endothelial venules, and were anchored on the reticular fibers waiting to interact with the antigen-specific T cells. Taken together, the findings obtained in this study provide new insights into how the LN stromal reticulum works as a specialized 'immuno-platform' for tissue compartmentalization and the immune response.

DOI： 10.1093/intimm/dxh113

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Organ-specific stem cells are the natural progenitors in tissue regeneration and possess plasticity to differentiate into specialized cells in adult tissues. Small hepatocytes (SHCs) identified in the adult liver are one such cell type. Here we show that SHCs, which are capable of self-renewal and differentiation into hepatocytes, can be induced to generate insulin-producing cells under appropriate Culture conditions. These differentiated cells express pancreatic beta cell differentiation-related transcripts and hepatocyte differentiation-related transcripts, as shown by reverse-transcription PCR/nested PCR. In addition, enforced expression of the homeodomain transcription factor Pdx1 in these cells contributes to enhancement Of insulin release in response to insulin secretagogues. These results indicate that the SHCs described here have the ability to differentiate into insulin-producing cells, and further support the idea that engineering to generate insulin-secreting cells could provide a useful resource for future therapies for diabetes mellitus. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.04.059

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DOI： 10.2174/1568014043355221

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Class switch recombination (CSR) at the antibody immunoglobulin locus is regulated by germline transcription (GLT) - coupled modi. cations in the accessibility of the switch region, where CSR takes place. Here we show that histone acetylation of switch regions is linked to CSR but that histone acetylation cannot alone promote CSR or GLT. Activation-induced cytidine deaminase (AID) specifically associates with the CSR target chromatin in a GLT-coupled manner, which may occur potentially by means of physical interaction between AID and the transcription machinery. These data indicate an important role of GLT in the regulation of chromatin accessibility, strongly suggesting that the target of AID is chromatin DNA. Our results give insights on the role of AID and the regulatory mechanism of CSR.

DOI： 10.1126/science.1092481

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Pax5 activity is enhanced in activated B cells and is essential for class switch recombination (CSR). We show that inhibitor of differentiation (Id)2 suppresses CSR by repressing the gene expression of activation-induced cytidine deaminase (AID), which has been shown to be indispensable for CSR. Furthermore, a putative regulatory region of AID contains E2A-and Pax5-binding sites, and the latter site is indispensable for AID gene expression. Moreover, the DNA-binding activity of Pax5 is decreased in Id2-overexpressing B cells and enhanced in Id2(-/-) B cells. The kinetics of Pax5, but not E2A, occupancy to AlD locus is the same as AID expression in primary B cells. Finally, enforced expression of Pax5 induces AID transcription in pro-B cell lines. Our results provide evidence that the balance between Pax5 and Id2 activities has a key role in AID gene expression.

DOI： 10.1084/jem.20030802

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Secondary lymphoid tissue is developmentally programmed and characterized by well-ordered compartmentalization of lymphocyte subsets and specialized stromal cells supporting the tissue architecture. By contrast, tertiary lymphoid tissue is defined as that induced in ectopic sites by inflammation, although its immunological role is largely unknown. In this study, we characterize the lymphoid tissue induced in the chronic lesion of marine autoimmune gastritis (AIG). Within the lymphoid cluster in the gastric mucosa, there is a clear segregation of T and B cells. Follicle-like B cell areas are always located on the luminal side of the mucosa, while T cells are located in the basal part. A typical lymphoid reticular network and follicular dendritic cells support the structure. Importantly, complement receptor 1(+) follicular dendritic cells within the follicle express a B cell homing chemokine, CXC chemokine ligand 13. The number and size of the clusters correlate with the age of the mice and the serum autoantibody titer, suggesting the functional importance of the clusters in local Ab production, although involvement of the autoantibody in the disease progression is still unclear. AIG gastric lesions are known to constitute a Th1-biased, memory T cell-dependent immunomicroenvironment. The expression pattern of cytokines, including lymphotoxin-beta, and chemokines in the AIG stomach is consistent with this observation. Taken together, these facts suggest that, during the chronic phase of autoimmunity, long-lasting lymphocyte infiltration probably induces a unique tertiary lymphoid tissue that has a function distinct from that of regional lymph nodes. These neolymphoid tissues may maintain the local self reactivity supporting the vicious cycle of Th1-type reaction as well as autoantibody production.

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Background: Although the T(H)1/T(H)2 balance is important in many clinical situations, the regulatory mechanisms in vivo have not been well elucidated.
Objective: We sought to characterize the immunologic status of mice lacking Id2, an inhibitor of basic helix-loop-helix transcription factors.
Methods: We analyzed serum immunoglobulin levels, gene-expression profiles in the spleen, T(H)1/T(H)2 balance, and dendritic cell (DC) populations of Id2(-/-) mice.
Results: Serum levels of T(H)2-mediated IgG1 and IgE were increased more than 10-fold in Id2(-/-) mice without antigenic stimulation. Gene-expression analysis in Id2(-/-) splenocytes revealed enhanced expression of T(H)2-related genes, such as IL-4, and reduced expression of T(H)1-related genes, including IFN-gamma and IL-12. Intracellular cytokine staining also confirmed that Id2(-/-) splenic CD4(+) T cells are substantially skewed to T(H)2 cells. However, Id2(-/-) naive CD4(+) T cells differentiated into T(H)1 cells comparably with wild-type T cells under the appropriate culture conditions. Id2(-/-) mice displayed a selective and remarkable reduction of the CD8alpha(+)DC subset,which is known to induce preferential T(H)1 differentiation.
Conclusion: Id2 is an indispensable regulator of the T(H)1/T(H)2 balance, possibly through the proper development of CD8alpha(+) DCs, and could be a novel target to treat allergic diseases.

DOI： 10.1067/mai.2003.29

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Serum concentrations of immunoglobulin E (IgE) in normal circumstances are kept much lower than those of other Ig isotypes to avoid allergic reactions. B cells lacking Id2 have increased E2A activity, which leads to specific enhancement of germline transcription of the immunoglobulin locus. As a consequence, Id2-deficient B cells undergo class switch recombination (CSR) to IgE at a much higher frequency than wild-type B cells. In contrast, Id2 is induced in wild-type B cells by transforming growth factor-beta1 (TGF-beta1) and suppresses IgE CSR. Our results provide evidence for the inhibitory and selective role of Id2 in IgE CSR in response to TGF-beta1. Id2 might act as molecular safeguard to suppress IgE CSR to prevent serious complications such as allergic hypersensitivity during the normal course of immune responses.

DOI： 10.1038/ni874

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

We analyzed differences in the transendothelial migration (TEM) ability of T-helper (Th)-1 and Th2 cells across a murine endothelial cell line (F-2) under static conditions. The TEM abilities of Th1 cells from mice bearing autoimmune diseases and antigen-specific Th1 cell lines were severalfold higher than those of Th2 cells and lines of the same origin. These preferences were observed without exogenous chemoattractant and were insensitive to pertussis toxin, which completely blocks TEM induced by exogenous chemoattractants. Antibodies against LFA-1 and ICAM-1 as well as CD44 markedly blocked the TEM of Th1 cells. TEM ability was also blocked by pharmacological inhibitors of Src family protein-tyrosine kinases (PP2 and herbimycin A), phosphatidylinositol 3-kinase (wortmannin), and phosphatidylinositol-specific phospholipase C (U73122). Crosslinking of CD44 strongly induced highly elongated morphology in Th1 lines, but weakly in Th2 lines. The pharmacological inhibitors that blocked TEM also inhibited this morphological change, whereas pertussis toxin did not. These data indicate that there are signaling pathways for TEM independent of chemokine attraction, but through adhesion molecules including CD44, and that the preferential TEM ability of Th1 over Th2 cells is formed, at least in part, by intrinsic differences in these pathways.

DOI： 10.1074/jbc.M204133200

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T(h)1 cells but not T(h)2 cells accumulate at the inflamed gastric mucosa (GM), while both subsets co-exist in the regional lymph node (RLN) in a murine experimental model for autoimmune gastritis (AIG). To understand the relationship between the immuno-microenvironment and effector localization in GM versus RLN of AIG-bearing mice, cells or tissue sections were stained with several mAb against adhesion molecules. The expression of RNA of various cytokines at these contrasting sites was also assessed. IFN-gamma-producing memory CD4(+) (T(h)1) and CD8(+) T cells as well as IL-12-producing mature macrophages which express P-selectin ligand and/or alpha(4)beta(7)-integrin selectively accumulated in the inflamed GM. Vessel endothelium at the site of infiltration expressed those counter-receptors, P-selectin and mucosal adressin cell adhesion molecule-1. Therefore, the tissue destruction of target tissue in autoimmune diseases might be promoted by a vicious circle between the selective accumulation of type 1 effectors mediated by multiple adhesion molecules and following an unusual type 1-biased microenvironment away from the type 2 response.

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DOI： 10.1084/jem.193.7.873

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DOI： 10.1074/jbc.M010663200

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DOI： 10.1016/S0165-2478(01)00232-2

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The vast majority of CD4(+) T cells infiltrating into gastric mucosa (GM) and in the draining (gastric) lymph node (GLN) shows an activated/memory phenotype, CD45RB(low)-selectin(low)CD44(high), in neonataly thymectomized BALB/c mice bearing autoimmune gastritis (AIG), indicating that these cells are actively involved in this disease. CD4(+) T cells sort-purified from GLN expressed mRNAs encoding for both IFN-gamma and IL-4. However, those infiltrating into GM expressed very low levels of IL-4 mRNA, even though they strongly expressed IFN-gamma mRNA. Among CD4(+) T cells separated from AIG mice expressing detectable levels of either IFN-gamma or IL-4 by intracellular staining, less than one-seventh expressed IL-4 and thus most of them expressed IFN-gamma in GM, whereas roughly half and one-third expressed IL-4 in GLN and spleen respectively. These findings indicate that the T(h)1 cells predominantly infiltrate into autoimmune lesions and T(h)2 cells are mainly resident in the regional LN, We further set up an in vitro model system of transendothelial migration using a murine endothelial cell line, F-2, and found that T(h)1 cells in CD4(+) T cells separated from lymphoid tissues of AIG mice preferentially passed through the monolayer of endothelial cells while only a small portion of T(h)2 cells did so. This differing ability of transendothelial migration and localization might explain the dominance of T(h)1 cells destroying the tissue in focal lesions without inhibition by the T(h)2 cells, in spite of both subsets being simultaneously activated in AIG mice, and the functions of each T cell subset seems to be mutually exclusive.

DOI： 10.1093/intimm/10.9.1325

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DOI： 10.1093/intimm/9.12.1849

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Coculture of cytotoxic T cells (STIL-3 C5) derived from L8313 leukemic mice with hematopoietic supportive stromal cells (MS-5) resulted in the detachment of MS-5 cells from the culture dish, whereas helper T cells (STIL-3 DF) did not induce this detachment. The response of bone marrow (BM) adherent ent cells to the same treatment was similar to that of MS-5 cells. The detached cells were unable to proliferate further, and genomic DNA of these cells showed fragmentation, suggesting that hematopoietic stromal cells died of apoptosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that STIL-3 C5 cells, but not STIL-3 DF cells expressed perforin, granzyme A & B, and Fas ligand. Fas was expressed in MS-5, BM adherent cells, MS-K and NIH/3T3 cells, which do not support hematopoiesis. These data suggest that the aforementioned factors mediate induction of apoptosis in MS-5 cells induced by direct cell-to-cell interaction with STIL-3 C5. This may explain the mechanism responsible for the destruction of the hematopoietic microenvironment by cytotoxic T cells in L8313 leukemia, from which STIL-3 cells are derived; it also suggests that destruction of hematopoietic tissue may be caused by leukemic cytotoxic T cells in some cases of leukemia.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Autoimmune gastritis (AIG) develops spontaneously in BALB/c mice thymectomized 3 days after birth (3d-Tx). We first confirmed our previous observations that CD4(+) splenic T cells in AIG mice induced AIG in nu/nu mice, while those in normal mice suppressed the development of the disease. In addition, we found that a quantitative balance between these effector (Te) and suppressor (Ts) T cells determined either onset or prevention of the disease. Peripheralization of Ts seemed to begin around 3 days after birth, since the incidence of AIG in mice that underwent T x 6 days after birth (6d-Tx) decreased markedly, compared with that of 3d-Tx mice; 12% in the former, while 79% in the latter. Notably, Ts existed in the 6d-Tx mice that escaped AIG. We next examined the target specificity of such Ts using syngeneic parietal cells known as autoantigens and two kinds of T-cell lines established from an AIG mouse; one is gastritis inducible in vivo, termed A-ill while another is not, named AC-II. Intrathymic injection of parietal cells into mice 3 days after birth followed by 6d-Tx completely prevented the development of AIG. In contrast, injection of irradiated A-II, but not AC-II cells resulted in AIG in 67% of the mice. No autoimmune oophoritis (AIO) was induced in female mice, implying that the breakdown of tolerance is organ specific. Taken together, peripheral tolerance for organ-specific autoantigens seems to be maintained by CD4(+) Ts responding to Te, which induces the disease.

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Language：Japanese   Publisher：日本リンパ学会  

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Language：Japanese   Publisher：新潟医学会  

リンパ節は、リンパ管を介して運ばれてきた異物や抗原に対して効果的な免疫応答を誘導するために特化した免疫器官である。活発に移動する多数の免疫細胞が集積し、それらが種類ごとに区画化された複雑な組織構造が見られる。しかし、その微細構造を形成する分子基盤や免疫細胞動態に関しては未だ不明な点が多い。近年、各区画構造が性質の異なる間葉系ストローマ細胞により支えられ、それらが産生する遊走因子が免疫細胞の局在を制御していることが明らかになってきた。我々は、マウスのリンパ節において少なくとも6種類のストローマ細胞サブセットが存在することを確認しており、これらの細胞の分布とケモカインの発現パターンが、免疫細胞の大局的な配置と区画構造を規定していると考えられる。傍皮質ではT細胞が活発に遊走し、樹状細胞が提示する抗原を探索しているが、この過程にはこの領域のストローマ細胞が産生するCCL21とAutotaxin/lysophosphatidic acid経路が協調して働くことが明らかになった。一方、リンパ節内で進行する免疫応答とダイナミックな細胞動態との関連を理解するうえで有用なモデルとして、アロジェニックT細胞移植/排除の生体イメージングを進めており、最近この過程における免疫細胞の活動的な実体が撮らえられた。これらの知見は、リンパ節において免疫細胞の局在・動態を機能的に支えるストローマ細胞と免疫応答の時空間制御の重要性を示している。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00990&link_issn=&doc_id=20200313070001&doc_link_id=%2Fdg3nigta%2F2019%2F013302%2F001%2F0045-0049%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2019%2F013302%2F001%2F0045-0049%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本リンパ学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(公社)日本生化学会  

リンパ節は獲得免疫応答を誘導するための拠点となる免疫器官であり,リンパ球をはじめとした各種の免疫細胞が高密度に集積している.特にT細胞は傍皮質領域に集中し,樹状細胞が提示する異物情報を監視する役割を担う.近年,多光子励起レーザー顕微鏡を用いた生体観察により,T細胞が毎分平均10μm以上の速度で組織内を移動していることが明らかになった.これは末梢組織からリンパ管経由で集められた異物情報を効率よく探索し,免疫応答を効果的に誘導する上で重要であると考えられる.しかし,細胞が密集しダイナミックに動き回る状況下で高速遊走が可能になるメカニズムはこれまで明確にはなっていなかった.最近,その分子基盤に関する解析が進み,細網線維芽細胞や樹状細胞などが産生する複数の因子がT細胞の運動を多面的に制御していることが明らかになった.また,細胞が密集した独特の組織環境も重要な役割を担うと考えられる.本稿では最新の成果を踏まえ,リンパ節内におけるT細胞高速遊走の実態を考察する.(著者抄録)

DOI： 10.14952/SEIKAGAKU.2016.880615

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Language：Japanese   Publisher：新潟医学会  

獲得免疫応答の中枢として機能するリンパ節において、Tリンパ球は傍皮質領域に集積し、毎分平均10μm以上という非常に速い速度で活発に遊走している。この現象は、末梢組織からリンパ管経由で移動してきた樹状細胞が提示する抗原を効率良く探索し、効果的な免疫応答を誘導するために必要であると推測される。近年の多光子励起レーザー顕微鏡を用いた生体イメージングによりそのメカニズムに関する解析が進み、特に樹状細胞やストローマ細胞などの組織微小環境を構成する細胞の役割が重要であることが明らかになりつつある。本稿では、筆者らによる最新の成果を中心にリンパ節内におけるT細胞高速間質遊走の分子機構を概説する。(著者抄録)

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Other Link： http://hdl.handle.net/10191/44391

Language：Japanese   Publisher：新潟県医師会  

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

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Other Link： http://search.jamas.or.jp/link/ui/2014258397

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J-GLOBAL

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Language：Japanese   Publisher：日本リンパ学会  

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Language：English   Publisher：(一社)日本生物物理学会  

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(公社)日本生化学会  

リンパ節は免疫器官の一種で、リンパ管と連結することにより末梢組織における病原体感染などを免疫系がいち早く察知し、免疫応答を効率良く誘導するための巧みな装置である。リンパ節内には特徴的な組織構造がみられ、リンパ球をはじめとするさまざまな免疫細胞が活動するための「場」が整備されている。こうした組織環境を構築・維持しているのはストローマ細胞と呼ばれる間質細胞がつくるネットワークで、リンパ節の領域ごとに機能の異なるストローマ細胞群が分布している。ストローマ細胞は細胞外マトリクスを産生して組織構造を支えるほか、ケモカインやサイトカインなどさまざまな因子を分泌して免疫細胞の移動や分布、機能、恒常性などに深く関わっており、リンパ節内における免疫系の時空間的な挙動を理解するうえで不可欠な存在である。(著者抄録)

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.60.1258_1

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(株)オーム社  

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Other Link： http://search.jamas.or.jp/link/ui/2008305322

Language：Japanese   Publisher：(一社)日本解剖学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：中山書店  

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Language：Japanese   Publisher：医歯薬出版(株)  

免疫系細胞が外来病原体を認識し最大限の効率で獲得免疫反応を誘導するためにはリンパ節のような特殊な"場"が必要である.リンパ節組織内には明瞭な区画構造があり,リンパ球をはじめとする種々の免疫細胞がサブセットごとに効果的に配置されている.こうした特徴的な組織構造は,"諸刃の剣"である免疫細胞が必要以上に活発化するのを抑えつつ,時間的・空間的に秩序のある免疫反応制御のために不可欠であると考えられる.各亜区画内ではそれぞれ機能の異なる非血球系ストローマ細胞(間質支持細胞)群が裏打ちするかのように緻密なネットワークを構築し,免疫細胞の移動や定着を制御している.リンパ節のストローマ細胞についてはいまだに不明な点が多く残されているが,リンフォトキシンを介するシグナル経路や恒常性ケモカインに関する最近の研究から謎の多かったストローマ細胞の実態やその機能的側面が明らかになりつつある(著者抄録)

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Language：Japanese   Publisher：(有)科学評論社  

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Other Link： http://search.jamas.or.jp/link/ui/2005138076

Language：Japanese   Publisher：(一社)日本解剖学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.53.797_1

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：日本小児アレルギー学会  

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Language：Japanese   Publisher：日本小児アレルギー学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：日本小児アレルギー学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MOSBY-YEAR BOOK INC  

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Language：English   Publisher：AMER SOC MICROBIOLOGY  

Helicobacter pylori is the major causative agent of chronic antral gastritis and is thought to be involved in the pathogenesis of mucosa-associated lymphoid tissue lymphoma (MALToma) developing in the human stomach. The aim of this study was to clarify whether corporal autoimmune gastritis (AIG), which is known to decrease acidity due to destruction of parietal cells, predisposes mice to H. pylori infection, thereby leading to MAL-Toma-like pathology, BALB/c mice in which AIG had been induced by thymectomy 3 days after birth (AIG mice) were used. The AIG mice were orally administered mouse-adapted H. pylori at the age of 6 weeks and were examined histologically and serologically after 2 to 12 months. The results were compared with those obtained from uninfected AIG mice and infected normal mice, Germinal centers were induced in the corpus in 57% of the N. pylori-infected AIG mice, which elicited anti-H. pylori antibody responses in association with upregulation of interleukin-4 (IL-4) mRNA. In these mice, parietal cells remained in the corpus mucosa. These findings were in contrast to those with the uninfected AIG mice: fundic gland atrophy due to disappearance of parietal cells associated with upregulation of gamma interferon, but not IL-4, mRNA and no germinal center formation in the corpus. These observations suggest that AIG alters the infectivity of H. pylori, leading to MALToma-like follicular gastritis, at an early stage after H. pylori infection.

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(株)先端医学社  

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Language：Japanese   Publisher：日本臨床免疫学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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