Nakatsukasa, Hiroko



School of Medicine, Department of Microbiology and Immunology (Shinanomachi)



Career 【 Display / hide

  • 2011.04

    National Institute of Dental and Craniofacial Research, NIH, Visiting Fellow

  • 2012.01

    JSPS Research Fellow in Biomedical and Behavioral Research at NIH

  • 2014.04

    Keio University of Medicine, Department of Microbiology and Immunology, Project Assistant Professor

  • 2015.04

    Japan Society for the Promotion of Science Research Fellow

  • 2017.07

    慶應義塾大学医学部, 微生物学免疫学教室, 助教

Academic Background 【 Display / hide

  • 2011.03

    Tokyo University of Science, Department of Pharmaceutical Science

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(薬学), Tokyo University of Science, Coursework, 2011.03

Licenses and Qualifications 【 Display / hide

  • 薬剤師免許


Research Areas 【 Display / hide

  • Immunology


Papers 【 Display / hide

  • Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis.

    Kasagi S, Wang D, Zhang P, Zanvit P, Chen H, Zhang D, Li J, Che L, Maruyama T, Nakatsukasa H, Wu R, Jin W, Sun L, Chen W

    EBioMedicine 44   50 - 59 2019.06

  • Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression.

    Nakatsukasa H, Oda M, Yin J, Chikuma S, Ito M, Koga-Iizuka M, Someya K, Kitagawa Y, Ohkura N, Sakaguchi S, Koya I, Sanosaka T, Kohyama J, Tsukada YI, Yamanaka S, Takamura-Enya T, Lu Q, Yoshimura A

    International immunology 31 ( 5 ) 335 - 347 2019.04

    ISSN  0953-8178

  • IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse.

    Oike T, Kanagawa H, Sato Y, Kobayashi T, Nakatsukasa H, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Yoshimura A, Iwakura Y, Takeuchi T, Matsumoto M, Nakamura M, Niki Y, Miyamoto T

    Scientific reports 8 ( 1 ) 15783 2018.10

  • Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status.

    Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A

    International immunology 30 ( 8 ) 357 - 373 2018.07

    ISSN  0953-8178

  • Negative Regulation of Cytokine Signaling in Immunity.

    Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H

    Cold Spring Harbor perspectives in biology 10 ( 7 )  2018.07

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

    Ito M., Komai K., Mise-Omata S., Iizuka-Koga M., Noguchi Y., Kondo T., Sakai R., Matsuo K., Nakayama T., Yoshie O., Nakatsukasa H., Chikuma S., Shichita T., Yoshimura A.

    Nature (Nature)  565 ( 7738 ) 246 - 250 2019.01

    ISSN  00280836

     View Summary

    © 2019, Springer Nature Limited. In addition to maintaining immune tolerance, FOXP3 + regulatory T (T reg ) cells perform specialized functions in tissue homeostasis and remodelling 1,2 . However, the characteristics and functions of brain T reg cells are not well understood because there is a low number of T reg cells in the brain under normal conditions. Here we show that there is massive accumulation of T reg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T reg cells are similar to T reg cells in other tissues such as visceral adipose tissue and muscle 3–5 , they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT 7 . The amplification of brain T reg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain T reg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that T reg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.

Research Projects of Competitive Funds, etc. 【 Display / hide

  • The role of DNA demethylase TET in Treg/Th17 differentiation.


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 中司 寛子, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • Association between pathogenic Th17 in periodontal disease and rheumatoid arthritis onsets.


    Akita University, 丸山 貴司, 中司 寛子, 前田 あずさ, Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

  • 腸内細菌叢によるT細胞の老化とがん化促進メカニズムの解明


    日本医療研究開発機構(AMED), 革新的先端研究開発支援事業, 中司 寛子, 微生物叢と宿主の相互作用・共生の理解と、それに基づく疾患発症のメカニズム解明, Principal Investigator

  • The role of DNA demethylase TET in T cell function and differentiation.


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 中司 寛子, Grant-in-Aid for Early-Career Scientists , Principal Investigator

     View Summary

    I. T細胞特異的Tet2/3欠損マウス(CD4DKO)におけるT細胞異常増殖分化メカニズムの解明
    CD4DKOマウスをTh17関連サイトカインシグナルを欠失したマウスと掛け合わせたところ、いずれもT細胞の異常増殖は抑制できなかったが、Il17-/-, Rorgt-/-, Il23-/-マウスとの掛け合わせによりTreg割合は回復し、Il21R-/-マウスとの掛け合わせではTfh細胞分化を抑制できた。この結果より、CD4DKOマウスにおいてはTet2/3の欠損によりTh17関連サイトカインが優位に産生されることが、Th17/Tfh細胞分化に重要であることが明らかとなった。また、異常増殖に関しては、T細胞分化とは独立して引き起こされることが示唆された。
    II. 制御性T細胞特異的Tet2/3欠損マウス(FDKO)を用いたTreg不安定化メカニズムの解明
    Tet2/3欠損によるTregの不安定化メカニズムを解明するため、WTおよびTet2/3欠損TregにおけるDNAメチル化状態をPostt-bisulfite Adaptor Tagging(PBAT)法により、オープンクロマチン状態をAssay for transposase-accessible chromatin using sequencing (ATAC-Seq)を用いて解析した。その結果、Tet2/3欠損TregではFoxp3遺伝子の約5kb上流領域に強いメチル化とATACピークの消失が認められ、本領域におけるFoxp3の安定性への寄与が示唆された。また、遺伝子発現(microarray), DNAメチル化状態(PBAT法, MBD-seq)、オープンクロマチン(ATAC-seq)の統合解析により、TregにおいてTet2/3により制御される遺伝子群を抽出することができた。この内容にて論文発表を行った。
    「I. T細胞特異的Tet2/3欠損マウス(CD4DKO)におけるT細胞異常増殖分化メカニズムの解明」については、各種欠損マウスとの掛け合わせによる解析をほぼ終えることができた。CD4DKOマウスで増殖しているT細胞を用いた原因腸内細菌由来抗原の同定は進行中であり、また発症前後のT細胞を用いたマイクロアレイおよびRNA-seqはサンプルを準備段階で、いずれも次年度中に解析を終える予定である。
    「II. 制御性T細胞特異的Tet2/3欠損マウス(FDKO)を用いたTreg不安定化メカニズムの解明」については、DNAメチル化、遺伝子発現、オープンクロマチン状態の統合解析を終え、論文発表を行った。CRISPR/ Cas9法によるFoxp3遺伝子のCpG領域欠損マウス作製については着手したところである。
    また、FDKOマウスにおいて、TregがTh17細胞に分化するメカニズムの解明を引き続き行う。さらに、CRISPR/ Cas9法によるFoxp3遺伝子のCpG領域欠損マウス作製を行い、Treg不安定化への影響を解析することを計画している。

  • The role of TET proteins in stability and function of regulatory T cells.


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 中司 寛子, Grant-in-Aid for Young Scientists (B), Principal Investigator

     View Summary

    Regulatory T cells (Tregs) play a pivotal role in regulating immune responses and maintaining immunological tolerance. Although DNA demethylation has been proposed to be essential for the stable expression of Foxp3, a master regulator of Treg, actual contribution of DNA demethylating enzymes (Tet family proteins) in Treg stability and function remain to be elucidated. In this study, we analyzed T cell- or Treg-specific Tet2/3-deficient mice and found that Tet2/3 play important roles in the differentiation, stability and function of T cells and Tregs through regulating DNA demethylation. Furthermore, we have successfully induced region-specific demethylation in Foxp3 gene locus.


Courses Taught 【 Display / hide