Center for Integrative Medical science

Yokohama-shi, Japan

Center for Integrative Medical science

Yokohama-shi, Japan
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Inoue T.,Osaka University | Shinnakasu R.,Osaka University | Shinnakasu R.,Center for Integrative Medical science | Ise W.,Osaka University | And 4 more authors.
Journal of Experimental Medicine | Year: 2017

Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture, which is consistent with recent studies. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch. © 2017 Inoue et al.


Takeuchi A.,CNRS Biotechnology and Cell Signaling Laboratory | Takeuchi A.,Niigata University | Badr M.E.S.G.,CNRS Biotechnology and Cell Signaling Laboratory | Badr M.E.S.G.,Osaka University | And 15 more authors.
Journal of Experimental Medicine | Year: 2016

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 (CRT AM) upon activation possesses the characteristics of both CD4+ and CD8+ T cells. CRT AM+ 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 CRT AM+ T cells are the precursor of CD4+CTL. Indeed, ectopic expression of CRT AM 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 CRT AM-mediated intracellular signaling. CRT AM+ 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 CRT AM is critical to instruct the differentiation of CD4+CTL through the induction of Eomes and CTL-related gene. © 2016 Takeuchi et al.


Shiraishi Y.,Tokyo Medical University | Fujimoto A.,Center for Integrative Medical science | Furuta M.,Center for Integrative Medical science | Tanaka H.,Tokyo Medical University | And 27 more authors.
PLoS ONE | Year: 2014

Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV)- related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive overexpression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome. © 2014 Shiraishi et al.


Hashimoto-Tane A.,Center for Integrative Medical science | Sakuma M.,Center for Integrative Medical science | Ike H.,Center for Integrative Medical science | Ike H.,Osaka University | And 7 more authors.
Journal of Experimental Medicine | Year: 2016

The immunological synapse (IS) formed at the interface between T cells and antigen-presenting cells represents a hallmark of initiation of acquired immunity. T cell activation is initiated at T cell receptor (TCR) microclusters (MCs), in which TCRs and signaling molecules assemble at the interface before IS formation. We found that each TCR-MC was transiently bordered by a ring structure made of integrin and focal adhesion molecules in the early phase of activation, which is similar in structure to the IS in microscale. The micro-adhesion ring is composed of LFA-1, focal adhesion molecules paxillin and Pyk2, and myosin II (MyoII) and is supported by F-actin core and MyoII activity through LFA-1 outside-in signals. The formation of the micro-adhesion ring was transient but especially sustained upon weak TCR stimulation to recruit linker for activation of T cells (LAT) and SLP76. Perturbation of the micro-adhesion ring induced impairment of TCR-MC development and resulted in impaired cellular signaling and cell functions. Thus, the synapse-like structure composed of the core TCR-MC and surrounding micro-adhesion ring is a critical structure for initial T cell activation through integrin outside-in signals. © 2016 Hashimoto-Tane et al.


PubMed | Center for Integrative Medical science and Nanjing University
Type: | Journal: Human genome variation | Year: 2016

Progressive pseudorheumatoid dysplasia (PPD) is a rare disease caused by mutations in the gene for Wnt1-inducible signaling pathway protein 3 (

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