Iizuka, Mana



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


Project Assistant Professor (Non-tenured)/Project Research Associate (Non-tenured)/Project Instructor (Non-tenured)


Papers 【 Display / hide

  • Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications

    Iizuka-Koga, M., Nakatsukasa, H., Ito, M., Akanuma, T., Lu, Q. and Yoshimura, A.

    J Autoimmun 83   113 - 121 2017.09

    ISSN  0896-8411

     View Summary

    Regulatory T cells (Tregs) are an essential cell subset for the maintenance of immune homeostasis. Foxp3 (Forkhead box P3) is the Treg master gene which is essential for immune suppressing activity. In addition, Tregs are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory genes. The molecular mechanisms of Treg development and maintenance have been intensively investigated. Tregs are characterized by expression of the transcription factor Foxp3. Several intronic enhancers and a promoter at the Foxp3 gene locus were shown to play important roles in Treg differentiation. The enhancers have been designated as conserved non-coding sequences (CNSs) 0, 1, 2, and 3. We showed that the transcription factors Nr4a and Smad2/3 are essential for the development of thymic Tregs and induced Tregs, respectively. Recently, Treg-specific DNA demethylation has been shown to play an important role in Treg stability. DNA demethylation of CNS2 has been implicated in Treg stability, and recent reports have revealed that the ten-eleven translocation (Tet) family of demethylation factor plays an important role in CpG demethylation at CNS2. This article reviews the recent progress on the roles of transcription factors and epigenetic modifications in the differentiation, maintenance, and function of Tregs.

  • Functional Analysis of Dendritic Cells Generated from T-iPSCs from CD4+ T Cell Clones of Sjogren's Syndrome

    Iizuka-Koga, M., Asashima, H., Ando, M., Lai, C. Y., Mochizuki, S., Nakanishi, M., Nishimura, T., Tsuboi, H., Hirota, T., Takahashi, H., Matsumoto, I., Otsu, M. and Sumida, T.

    Stem Cell Reports 8 ( 5 ) 1155 - 1163 2017.05

    ISSN  2213-6711

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    Although it is important to clarify the pathogenic functions of T cells in human samples, their examination is often limited due to difficulty in obtaining sufficient numbers of dendritic cells (DCs), used as antigen-presenting cells, especially in autoimmune diseases. We describe the generation of DCs from induced pluripotent stem cells derived from T cells (T-iPSCs). We reprogrammed CD4+ T cell clones from a patient with Sjogren's syndrome (SS) into iPSCs, which were differentiated into DCs (T-iPS-DCs). T-iPS-DCs had dendritic cell-like morphology, and expressed CD11c, HLA-DR, CD80, CD86, and also BDCA-3. Compared with monocyte-derived DCs, the capacity for antigen processing was similar, and T-iPS-DCs induced the proliferative response of autoreactive CD4+ T cells. Moreover, we could evaluate T cell functions of the patient with SS. In conclusion, we obtained adequate numbers of DCs from T-iPSCs, which could be used to characterize pathogenic T cells in autoimmune diseases such as SS.

  • A crucial role of RORgammat in the development of spontaneous Sialadenitis-like Sjogren's syndrome

    Iizuka, M., Tsuboi, H., Matsuo, N., Asashima, H., Hirota, T., Kondo, Y., Iwakura, Y., Takahashi, S., Matsumoto, I. and Sumida, T.

    J Immunol 194 ( 1 ) 56 - 67 2015.01

    ISSN  0022-1767

     View Summary

    The nuclear receptor retinoic acid-related orphan receptor (ROR)gammat is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjogren's syndrome (SS). However, the pathological role of RORgammat in SS remains to be elucidated. The present study was designed to clarify the role of RORgammat in the pathogenesis of sialadenitis-like SS. Histological analysis of RORgammat transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4(+) T cells. RORgammat-overexpressing CD4(+) T cells induced sialadenitis as a result of transferred CD4(+) T cells from Tg mice into Rag2(-/-) mice. The examination of IL-17-deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2(-/-) mice transferred with effector cells from Tg mice. These results suggest that both RORgammat-overexpressed CD4(+) T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis.

  • Prophylactic effect of the oral administration of transgenic rice seeds containing altered peptide ligands of type II collagen on rheumatoid arthritis

    Iizuka, M., Wakasa, Y., Tsuboi, H., Asashima, H., Hirota, T., Kondo, Y., Matsumoto, I., Sumida, T. and Takaiwa, F.

    Biosci Biotechnol Biochem 78 ( 10 ) 1662 - 8 2014.10

    ISSN  0916-8451

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    Rheumatoid arthritis is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We generated transgenic rice seeds expressing three types of altered peptide ligands (APL) and the T cell epitope of type II collagen (CII256-271). When these transgenic rice and non-transgenic rice seeds were orally administrated to DBA/1 J mice once a day for 14 days, followed by immunization with CII, the clinical score of collagen-induced arthritis (CIA) was reduced and inflammation and erosion in the joints were prevented in mice fed APL7 transgenic rice only. IL-10 production against the CII antigen significantly increased in the splenocytes and iLN of CIA mice immunized with the CII antigen, whereas IFN-gamma, IL-17, and IL-2 levels were not altered. These results suggest that IL-10-mediated immune suppression is involved in the prophylactic effects caused by transgenic rice expressing APL7.

  • Suppression of collagen-induced arthritis by oral administration of transgenic rice seeds expressing altered peptide ligands of type II collagen

    Iizuka, M., Wakasa, Y., Tsuboi, H., Asashima, H., Hirota, T., Kondo, Y., Matsumoto, I., Takaiwa, F. and Sumida, T.

    Plant Biotechnol J  2014.07

    ISSN  1467-7644

     View Summary

    Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We previously reported that altered peptide ligands (APLs) of type II collagen (CII256-271) suppress the development of collagen-induced arthritis (CIA). In this study, we generated transgenic rice expressing CII256-271 and APL6 contained in fusion proteins with the rice storage protein glutelin in the seed endosperm. These transgene products successfully and stably accumulated at high levels (7-24 mg/g seeds) in protein storage vacuoles (PB-II) of mature seeds. We examined the efficacy of these transgenic rice seeds by performing oral administration of the seeds to CIA model mice that had been immunized with CII. Treatment with APL6 transgenic rice for 14 days significantly inhibited the development of arthritis (based on clinical score) and delayed disease onset during the early phase of arthritis. These effects were mediated by the induction of IL-10 from CD4+ CD25- T cells against CII antigen in splenocytes and inguinal lymph nodes (iLNs), and treatment of APL had no effect on the production of IFN-gamma, IL-17, IL-2 or Foxp3+ Treg cells. These findings suggest that abnormal immune suppressive mechanisms are involved in the therapeutic effect of rice-based oral vaccine expressing high levels of APLs of type II collagen on the autoimmune disease CIA, suggesting that the seed-based mucosal vaccine against CIA functions via a unique mechanism.

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

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

  • シェーグレン症候群における自己反応性T細胞の活性化因子の解明


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 基盤研究(C), Principal investigator

  • シェーグレン症候群における病因T細胞と腸内細菌叢との関連の解析


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Awards 【 Display / hide

  • 第九回日本シェーグレン症候群学会奨励賞



Courses Taught 【 Display / hide