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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 | Fujimoto A.,Center for Integrative Medical science | Furuta M.,Center for Integrative Medical science | And 28 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.

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