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1-10 of 10
Koichi Ikuta
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Journal Articles
Yuting Ma, Laetitia Aymeric, Clara Locher, Stephen R. Mattarollo, Nicolas F. Delahaye, Pablo Pereira, Laurent Boucontet, Lionel Apetoh, François Ghiringhelli, Noëlia Casares, Juan José Lasarte, Goro Matsuzaki, Koichi Ikuta, Bernard Ryffel, Kamel Benlagha, Antoine Tesnière, Nicolas Ibrahim, Julie Déchanet-Merville, Nathalie Chaput, Mark J. Smyth, Guido Kroemer, Laurence Zitvogel
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2011) 208 (4): 869.
Published: 21 March 2011
Journal Articles
Yuting Ma, Laetitia Aymeric, Clara Locher, Stephen R. Mattarollo, Nicolas F. Delahaye, Pablo Pereira, Laurent Boucontet, Lionel Apetoh, François Ghiringhelli, Noëlia Casares, Juan José Lasarte, Goro Matsuzaki, Koichi Ikuta, Bernard Ryffel, Kamel Benlagha, Antoine Tesnière, Nicolas Ibrahim, Julie Déchanet-Merville, Nathalie Chaput, Mark J. Smyth, Guido Kroemer, Laurence Zitvogel
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2011) 208 (3): 491–503.
Published: 07 March 2011
Abstract
By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ–producing CD8 + αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17–producing γδ (Vγ4 + and Vγ6 + ) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ −/− or Vγ4/6 −/− mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A–IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A −/− hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4 + αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses.
Includes: Supplementary data
Journal Articles
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2002) 196 (1): 141–146.
Published: 24 June 2002
Abstract
The Fas (CD95) gene is among critical genetic factors in some autoimmune diseases, which are characterized by autoantibody (autoAb) productions. In mice, mutations in the Fas gene cause lymphoproliferation ( lpr ) which predominantly develops glomerulonephritis, whereas the mutations in human cause autoimmune lymphoproliferative syndrome (ALPS) characterized by autoimmune hemolytic anemia (AIHA) and thrombocytopenia. Although the mechanism of antinuclear Ab in Fas-deficient background has been well characterized, that of antierythrocyte Ab production in ALPS has been still unclear. To investigate this mechanism, we developed a mouse line by crossing the antierythrocyte antibody transgenic mice (H+L6 mice) and Fas-deficient mice. Although Fas deficiency did not break tolerance of autoreactive B-2 cells in H+L6 mice, autoreactive B-1 cells in Fas-deficient H+L6 homozygous mice became activated and differentiated into autoAb-producing cells in mesenteric lymph nodes and lamina propria of intestine, resulting in severe anemia. In addition, serum levels of interleukin (IL)-10 significantly increased in Fas −/− × H+L6 homozygous mice and administration of anti–IL-10 Ab prevented exacerbation of autoAb production and AIHA. These results suggest that activation of B-1 cells is responsible for induction of AIHA in Fas-deficient condition and that IL-10 plays a critical role in terminal differentiation of B-1 cells in these mice.
Journal Articles
Yasutoshi Agata, Tomoya Katakai, Sang-Kyu Ye, Manabu Sugai, Hiroyuki Gonda, Tasuku Honjo, Koichi Ikuta, Akira Shimizu
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2001) 193 (7): 873–880.
Published: 02 April 2001
Abstract
Variable/diversity/joining (V[D]J) recombination of the T cell receptor (TCR) and immunoglobulin (Ig) genes is regulated by chromatin accessibility of the target locus to the recombinase in a lineage- and stage-specific manner. Histone acetylation has recently been proposed as a molecular mechanism underlying the accessibility control. Here, we investigate the role for histone acetylation in the developmentally regulated rearrangements of the mouse TCR-γ gene, wherein predominant rearrangement is switched from Vγ3 to Vγ2 gene during the fetal to adult thymocyte development. Our results indicate that histone acetylation correlates with accessibility, as histone acetylation at the fetal-type Vγ3 gene in accord with germline transcription is relatively high in fetal thymocytes, but specifically becomes low in adult thymocytes within the entirely hyperacetylated locus. Furthermore, inhibition of histone deacetylation during the development of adult bone marrow–derived thymocytes by a specific histone deacetylase inhibitor, trichostatin A, leads to elevated histone acetylation, germline transcription, cleavage, and rearrangement of the Vγ3 gene. These data demonstrate that histone acetyl- ation functionally determines the chromatin accessibility for V(D)J recombination in vivo and that an epigenetic modification of chromatin plays a direct role in executing a developmental switch in cell fate determination.
Journal Articles
Kenya Honda, Hiroyasu Nakano, Hisahiro Yoshida, Satomi Nishikawa, Paul Rennert, Koichi Ikuta, Masakatsu Tamechika, Kazuhito Yamaguchi, Tetsuo Fukumoto, Tsutomu Chiba, Shin-Ichi Nishikawa
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2001) 193 (5): 621–630.
Published: 05 March 2001
Abstract
Mice deficient in lymphotoxin β receptor (LTβR) or interleukin 7 receptor α (IL-7Rα) lack Peyer's patches (PPs). Deficiency in CXC chemokine receptor 5 (CXCR5) also severely affects the development of PPs. A molecular network involving these three signaling pathways has been implicated in PP organogenesis, but it remains unclear how they are connected during this process. We have shown that PP organogenesis is initiated at sites containing IL-7Rα + lymphoid cells and vascular cell adhesion molecule (VCAM)-1/intercellular adhesion molecule (ICAM)-1 expressing nonlymphoid elements. Here we characterize these lymphoid and nonlymphoid components in terms of chemokine signals. The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC). Importantly, chemokines produced by VCAM-1 + ICAM-1 + nonlymphoid cells mediate the recruitment of lymphoid cells. Furthermore, we show that these VCAM-1 + ICAM-1 + cells are mesenchymal cells that are activated by lymphoid cells through the LTβR to express adhesion molecules and chemokines. Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.
Journal Articles
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2000) 192 (11): 1577–1586.
Published: 27 November 2000
Abstract
Using normal and transgenic (Tg) mice, we have shown that peritoneal B-1 cells are activated by administration of cytokines or lipopolysaccharide and migrate to other lymphoid organs where they differentiate into antibody-secreting cells. However, little is known about the process of B-1 cell migration and differentiation in vivo. We developed a mouse line by crossing the antierythrocyte antibody Tg mice (HL mice) with TCR-γ/δ Tg mice specific for a self-thymus leukemia (TL) antigen in the recombination activating gene (RAG)2 −/− background. In the presence of the self-antigen, Tg γ/δ T cells increased in number and manifested activated phenotypes. Peritoneal B-1 cells in these mice migrated into mesenteric lymph nodes and differentiated into autoantibody-secreting cells, resulting in strong autoimmune hemolytic anemia. Furthermore, transfer of RAG2 −/− × HL bone marrow or peritoneal cells into the peritoneal cavity of RAG2 −/− × TCR-γ/δ Tg mice gave rise to donor-derived B-1 cells in mesenteric lymph nodes, and these cells produced the autoantibody. Thus, this study demonstrates that the migration of B-1 cells and differentiation into the antibody-secreting cells can be induced by noncognate T cell help and implies the possibility that γ/δ T cells may induce B-1 cell differentiation in vivo.
Journal Articles
Sidonia Fagarasan, Reiko Shinkura, Tadashi Kamata, Fumiaki Nogaki, Koichi Ikuta, Kei Tashiro, Tasuku Honjo
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2000) 191 (9): 1477–1486.
Published: 24 April 2000
Abstract
Alymphoplasia ( aly ) mice, which carry a point mutation in the nuclear factor κB–inducing kinase (NIK) gene, are characterized by the systemic absence of lymph nodes and Peyer's patches, disorganized splenic and thymic architectures, and immunodeficiency. Another unique feature of aly/aly mice is that their peritoneal cavity contains more B1 cells than normal and aly/ + mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice into recombination activating gene (RAG)-2 −/− mice revealed that B and T cells fail to migrate to other lymphoid tissues, particularly to the gut-associated lymphatic tissue system. In vivo homing defects of aly/aly peritoneal cells correlated with reduction of their in vitro chemotactic responses to secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC). The migration defect of aly/aly lymphocytes was not due to a lack of expression of chemokines and their receptors, but rather to impaired signal transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G proteins. The results showed that the reduced serum levels of immunoglobulins (Igs) and the absence of class switch to IgA in aly/aly mice are due, at least in part, to a migration defect of lymphocytes to the proper microenvironment where B cells proliferate and differentiate into Ig-producing cells.
Journal Articles
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1999) 190 (4): 461–470.
Published: 16 August 1999
Abstract
Surface-expressed immunoglobulin (Ig) has been shown to have a critical role in allelic exclusion of Ig heavy (H) and light (L) chains. Although various degrees of suppression of endogenous Ig expression are observed in Ig transgenic (Tg) mice, it was not clear whether this difference is due to different onsets of Tg expression or to different levels of Tg expression, which are obviously affected by integration sites of the transgene. In this study we generated antierythrocyte antibody Tg mice that carry tandem joined H and L chain transgenes (H+L) and confirmed that homozygosity of the transgene loci enhances the level of transgene expression as compared with heterozygosity. Suppression of endogenous H and L chain gene expression was stronger in homozygous than in heterozygous Tg mice. Similar results were obtained in control Tg mice carrying the H chain only. These results suggest that there is a threshold of the B cell receptor expression level that induces allelic exclusion. In addition, despite the same B cell receptor specificity, the size of Tg autoreactive B-1 cell compartment in the peritoneal cavity is larger in homozygous than in heterozygous mice, although the number of the Tg B-2 cell subset decreased in the spleen and bone marrow of homozygous Tg mice as compared with heterozygous Tg mice. By contrast, homozygosity of the H chain alone Tg line, which does not recognize self-antigens, did not increase the size of the peritoneal B-1 subset. These results suggest that the size of the B-1 cell subset in the Tg mice may depend on strength of signals through B cell receptors triggered by self-antigens.
Journal Articles
Satoshi Ishii, Tomoyuki Kuwaki, Takahide Nagase, Kazushige Maki, Fumi Tashiro, Shinji Sunaga, Wei-Hua Cao, Kazuhiko Kume, Yoshinosuke Fukuchi, Koichi Ikuta, Jun-ichi Miyazaki, Mamoru Kumada, Takao Shimizu
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1998) 187 (11): 1779–1788.
Published: 01 June 1998
Abstract
Platelet-activating factor (PAF) is a potent phospholipid mediator with diverse biological activities in addition to its well-known ability to stimulate platelet aggregation. Pharmacologic studies had suggested a role for PAF in pregnancy, neuronal cell migration, anaphylaxis, and endotoxic shock. Here we show that disruption of the PAF receptor gene in mice caused a marked reduction in systemic anaphylactic symptoms. Unexpectedly, however, the PAF receptor–deficient mice developed normally, were fertile, and remained sensitive to bacterial endotoxin. These mutant mice clearly show that PAF plays a dominant role in eliciting anaphylaxis, but that it is not essential for reproduction, brain development, or endotoxic shock.
Journal Articles
The V–J Recombination of T Cell Receptor-γ Genes Is Blocked in Interleukin-7 Receptor–deficient Mice
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1996) 184 (6): 2423–2428.
Published: 01 December 1996
Abstract
IL-7R-deficient mice have severely impaired expansion of early lymphocytes and lack γδ T cells. To elucidate the role of IL-7R on γδ T cell development, we analyzed the rearrangements of TCR-α, β, γ, and δ genes in the thymus of the IL-7R-deficient mice. Southern blot analysis with a Jγ1 probe revealed that more than 70% of Jγ1 and Jγ2 alleles are recombined to form distinct Vγ1.2–Jγ2 and Vγ2–Jγ1 fragments in control mice. On the contrary, no such recombination was detected in the mutant mice. The rearrangements in the TCR-α, β, and δ loci were comparably observed in control and mutant mice. PCR analysis indicated that the V–J recombination of all the Vγ genes is severely hampered in the mutant mice. The mRNA of RAG-1 , RAG-2 , Ku-80, and terminal deoxynucleotidyl transferase (TdT) genes was equally detected between control and mutant thymi, suggesting that the expression of common recombination machinery is not affected. These data demonstrated that the V–J recombination of the TCR γ genes is specifically blocked in the IL-7R-deficient mice and suggested the presence of highly specific regulation for TCR γ gene rearrangement.