Curriculum Vitaes
Profile Information
- Affiliation
- Faculty of Applied Life ScienceSchool of Animal Science, Nippon Veterinary and Life Science University
- J-GLOBAL ID
- 201601013591655505
- researchmap Member ID
- B000250522
- External link
Research Areas
1Research History
7-
Feb, 2009 - Mar, 2014
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Mar, 2006 - Jan, 2009
Education
2-
Apr, 2000 - Mar, 2004
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Apr, 1998 - Mar, 2000
Papers
31-
PLoS pathogens, 16(12) e1009177, Dec, 2020 Peer-reviewedHIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128-135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.
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Immunological investigations, 1-19, Dec 13, 2019 Peer-reviewedLead authorBackground: Psychological stress affects the immune system. Upon stress occurrence, glucocorticoid is released that binds to the glucocorticoid receptor and regulates gene expression. Thus, we aimed to examine the stress-induced immunomodulatory mechanisms by investigating the expression patterns of stress-inducible genes in murine immune cells.Methods: BALB/c, C57BL/6, glucocorticoid-receptor congenic mice, and corticotropin-releasing hormone (CRH)-deficient mice were exposed to synthetic glucocorticoid, dexamethasone, or placed under a restraint condition. The expression level of stress-related genes, such as Rtp801, Gilz, Mkp-1, Bnip3, and Trp53inp1 was measured in the immune cells in these mice.Results: Short restraint stress induced Rtp801 and Gilz expressions that were higher in the spleen of BALB/c mice than those in C57BL/6 mice. Mkp-1 expression increased equally in these two strains, despite the difference in the glucocorticoid level. These three genes induced by short restraint stress were not induced in the CRH-deficient mice. In contrast, Bnip3 and Trp53inp1 were only upregulated upon longer restraint events. In the thymus, Trp53inp1 expression was induced upon short restraint stress, whereas Gilz expression constantly increased upon short and repetitive restraint stresses.Conclusion: These results suggest that singular and repetitive bouts of stress lead to differential gene expression in mice and stress-induced gene expression in thymocytes is distinct from that observed in splenocytes. Gilz, Rtp801, and Mkp-1 genes induced by short restraint stress are dependent on CRH in the spleen.
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Immunological investigations, 1-18, Oct, 2018 Peer-reviewed
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EBioMedicine, 36 103-112, Sep, 2018 Peer-reviewedBackground: HLA-B*35 is an HLA allele associated with rapid progression to AIDS. However, a mechanism underlying the detrimental effect of HLA-B*35 on disease outcome remains unknown. Recent studies demonstrated that most prevalent subtype HLA-B*35:01 is a detrimental allele in HIV-1 Glade B-infected individuals. We here investigated the effect of mutations within the epitopes on HLA-B*35:01-restricted CD8(+) T cells having abilities to suppress HIV-1 replication.Methods: We analyzed 16 HLA-B*35:01-restricted epitope-specific T cells in 63 HIV-1 Glade B-infected Japanese B*35:01(+) individuals and identified HLA-B*35:01-restricted CD8(+) T cells having abilities to suppress HIV-1 replication. We further analyzed the effect of HLA-associated mutations on the ability of these T cells.Findings: The breadth of T cell responses to 4 epitopes was inversely associated with plasma viral load (pVL). However, the accumulation of an Y135F mutation in NelYF9 out of the 4 epitopes, which is selected by HLA-A*24:02-restricted T cells, affected the ability of YF9-specific T cells to suppress HIV-1 replication. HLA-B*35:01(+) individuals harboring this mutation had much higher pVL than those without it. YF9-specific T cells failed to suppress replication of the Y135F mutant in vitro. These results indicate that this mutation impairs suppression of HIV-1 replication by YF9-specific T cells.Interpretation: These findings indicate that the Y135F mutation is a key factor underlying the detrimental effect of HIA-B*35:01 on disease outcomes in HIV-1 Glade B-infected individuals. (C) 2018 The Authors. Published by Elsevier B.V.
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Immunity Inflammation and Disease, 6(1) 58-71, Mar 1, 2018 Peer-reviewedIntroduction: Mina is a JmjC family 2-oxoglutarate oxygenase with pleiotropic roles in cell proliferation, cancer, T cell differentiation, pulmonary inflammation, and intestinal parasite expulsion. Although Mina expression varies according to cell-type, developmental stage and activation state, its transcriptional regulation is poorly understood. Across inbred mouse strains, Mina protein level exhibits a bimodal distribution, correlating with inheritance of a biallelic haplotype block comprising 21 promoter/intron 1-region SNPs. We previously showed that heritable differences in Mina protein level are transcriptionally regulated. Methods: Accordingly, we decided to test the hypothesis that at least one of the promoter/intron 1-region SNPs perturbs a Mina cis-regulatory element (CRE). Here, we have comprehensively scanned for CREs across a Mina locus-spanning 26-kilobase genomic interval. Results: We discovered 8 potential CREs and functionally validated 4 of these, the strongest of which (E2), residing in intron 1, contained a SNP whose BALB/c - but not C57Bl/6 allele - abolished both Smad3 binding and transforming growth factor beta (TGFβ) responsiveness. Conclusions: Our results demonstrate the TGFβ signaling pathway plays a critical role in regulating Mina expression and SNP rs4191790 controls heritable variation in Mina expression level, raising important questions regarding the evolution of an allele that uncouples Mina expression from the TGFβ signaling pathway.
Misc.
72-
東京女子医科大学雑誌, 70(10) 663-663, Nov 25, 2000
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東京女子医科大学総合研究所紀要, 21 29-30, 2000
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東京女子医科大学雑誌, 69(12) 730-730, Dec 25, 1999
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Journal of Tokyo Women's Medical College, 69(11) 659-668, Nov 25, 1999We examined the immunologic behaviors of a superantigen Staphylococcal enterotoxin A (SEA)-reactive four distinct T cell populations (Vβ3^+CD4^+, Vβ3^+CD8^+, Vβ11^+CD4^+ and Vβ11^+CD8^+ T cells) in mice injected with SEA twice in a 2-day interval. The four T cell populations increased equally at 2 days after the first injection and thereafter decreased equally to the control level. However, these four T cell populations expanded by the first SEA injection exhibited different behaviors upon the second SEA injection, depending on the T cell receptor Vβ elements expressed and the T cell subsets. Vβ3^+CD4^+ T cells expanded exhibited further expansion, and Vβ11^+CD8^+ T cells expanded decreased rapidly. Vβ3^+CD8^+ and Vβ11^+CD4^+ T cells expanded were sustained in similar levels for 2 days after the second injection. Peak of serum IL-2 activity was seen in a higher level and at earlier hours after the second SEA injection than the first injection. Levels of IL-2 receptor a chain expression were more than 90% in Vβ3^+CD4^+ T cells and Vβ11^+CD4^+ T cells, about 80% in Vβ3^+CD8^+ T cells, and about 70% in Vβ11^+CD8^+ T cells, suggesting that large parts of these T cell populations can recognized SEA. These results suggest that Vβ3^+CD4^+ T cells are low and Vβ11^+CD8^+ T cells are high in the susceptibility to anergic induction with SEA. Vβ3^+CD8^+ and Vβ11^+CD4^+ T cells may be sustained at intermediate level.
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日本免疫学会総会・学術集会記録, 29 168, Oct 30, 1999
Professional Memberships
1Research Projects
2-
科学研究費 基盤研究C, 科学研究助成事業 日本学術振興会, Apr, 2017 - Mar, 2020
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科学研究費 若手研究B, 科学研究費助成事業 日本学術振興会, Apr, 2013 - Mar, 2015