Role of novel regulatory T cells in malaria

• Project/Area Number: 25293101
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Parasitology (including sanitary zoology)
• Research Institution: Nagasaki University
• Principal Investigator: YUI Katsuyuki 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90274638)
• Co-Investigator(Kenkyū-buntansha): KIMURA Daisuke 長崎大学, 医歯薬学総合研究科(医学系), 助教 (50423637) ; SHITASHIGE Miki 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (00392340)
• Co-Investigator(Renkei-kenkyūsha): YOSHIDA Hiroki 佐賀大学, 医学部, 教授 (40260715)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: T細胞 / マラリア / サイトカイン / 赤血球 / 免疫抑制 / 制御 / マウス / Ｔ細胞 / 免疫制御 / 感染

Outline of Final Research Achievements

We reported unique regulatory CD4+ T cells that produce IL-27, dimeric regulatory cytokine of IL-12 family, in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-27-dependent manner. IL-27-producing CD4+ T cells were malaria antigen-specific CD4+ T cells, and were distinct from Foxp3+ regulatory T cells, interferon (IFN)-γ producing Th1, or IL-10 producing Tr1 cells. In mice lacking IL-27 in T cells, IL-2 production was restored and clonal expansion and IFN-γ production by specific CD4+ T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-27 producing regulatory CD4+ T cells and their critical role in the regulation of the protective immune response against malaria parasites.

Research Products

• [Journal Article] Interleukin-27-Producing CD4(+) T Cells Regulate Protective Immunity during Malaria Parasite Infection. (2016)
  • Author(s): Kimura D, Miyakoda M, Kimura K, Honma K, Hara H, Yoshida H, Yui K
  • Journal Title: Immunity Volume: 44 Issue: 3 Pages: 672-682
  • DOI: 10.1016/j.immuni.2016.02.011
  • Peer Reviewed
• [Journal Article] Expression of PD-1/LAG-3 and cytokine production by CD4+ T cells during infection with Plasmodium parasites (2016)
  • Author(s): Henrietta, T D, Kimura, D, Miyakoda, M., Kimura K., Akbari, M, Yui, K.
  • Journal Title: Microbiol. Immunol Volume: 60 Issue: 2 Pages: 121-131
  • DOI: 10.1111/1348-0421.12354
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Proteomic Approach Identifies Candidate Early Biomarkers to Predict Severe Dengue in Children (2016)
  • Author(s): Nhi DM, Huy NT, Ohyama K, Kimura D, Lan NT, Uchida L, Thuong NV, Nhon CT, Phuc le H, Mai NT, Mizukami S, Bao LQ, Doan NN, Binh NV, Quang LC, Karbwang J, Yui K, Morita K, Huong VT, Hirayama K.
  • Journal Title: PLoS Negl Trop Dis. Volume: 10 Issue: 2 Pages: e0004435-e0004435
  • DOI: 10.1371/journal.pntd.0004435
  • NAID: 120006666536
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recruitment of distinct immune cell populations to the lung after intractracheal TLR4 signaling activation by two different stimulations (2016)
  • Author(s): Inamura, Y, Honma, K, Kimura, D, Miyakoda, M, Kimura, K, Fukudome, K, Nanashima, A, Nagayasu, T, and Yui, K,
  • Journal Title: Acta Medica Nagasakientia Volume: 60 Pages: 77-84
  • Peer Reviewed
• [Journal Article] インターロイキン27を産生するCD4陽性T細胞によるマラリア原虫の感染に対する免疫防御の制御 (2016)
  • Author(s): 木村大輔・由井克之
  • Journal Title: First Author's Volume: - Pages: 021
  • DOI: 10.7875/first.author.2016.021
  • Open Access
• [Journal Article] Intravital imaging of the immune responses during liver-stage malaria infection: An improved approach for fixing the liver. (2016)
  • Author(s): Akbari M, Kimura K, Houts JT, Yui K.
  • Journal Title: Parasitol Int. Volume: 印刷中 Issue: 5 Pages: 0-0
  • DOI: 10.1016/j.parint.2016.02.011
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Reduction of conventional dendritic cells during Plasmodium infection is dependent on activation induced cell death by type I and II interferons. (2015)
  • Author(s): Tamura T, Kimura K, Yui K, Yoshida S.
  • Journal Title: Exp Parasitol Volume: 159 Pages: 127-135
  • DOI: 10.1016/j.exppara.2015.09.010
  • Peer Reviewed
• [Journal Article] Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in non-obese diabetic mice. (2015)
  • Author(s): Akazawa S, Kobayashi K, Kuriya G, Horie I, Yu L, Yamasaki H, Okita M, Nagayama Y, Matsuyama T, Akbari M, Yui K, Kawakami A, Abiru N.
  • Journal Title: Diabetologia Volume: 58 (11) Issue: 11 Pages: 2606-2614
  • DOI: 10.1007/s00125-015-3724-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antigen-driven focal inflammatory death of malaria liver stages (2015)
  • Author(s): G. Bayarsaikhan, M. Akbari, K. Yui, R. Amino
  • Journal Title: Front Microbiol Volume: - Pages: 00047-00047
  • NAID: 120006987088
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nanoparticle formulation enhanced protective immunity provoked by PYGPI8p-transamidase related protein (PyTAM) DNA vaccine in Plasmodium yoelii malaria model (2014)
  • Author(s): Cherif, MS, Shuaibu, MN, Kodama, Y, Kurosaki, T, Helegbe, GK, Kikuchi, M, Ichinose, A, Yanagi, T, Sasaki, H, Yui, K, Tien, NH, Karbwang, J, Hirayama, K
  • Journal Title: Vaccine Volume: 32 Pages: 1998-2006
  • Peer Reviewed
• [Journal Article] Daily feeding of fructooligosaccharide or glucomannan delays onset of senescence in SAMP8 mice (2014)
  • Author(s): Nakamura, S., Kondo, N., Yamaguchi, Y., Hashiguchi, M., Tanabe, K., Ushiroda, C., Kawahashi-Tokuhisa, M., Yui, K., Miyakoda, M., Oku, T.
  • Journal Title: Gastroenterol. Res. Pract. Volume: - Pages: 303184-303184
  • DOI: 10.1155/2014/303184
  • NAID: 120006986487
  • Peer Reviewed / Open Access
• [Journal Article] Local immune response to injection of Plasmodium sporozoites into the skin. J. Immunol (2014)
  • Author(s): L. Mac-Daniel, M. Buckwalter, M. Berthet, Y. Virk, K. Yui, M. Albert, P. Gueirard, R. Menard
  • Journal Title: J. Immunol Volume: 193 Pages: 1246-1257
  • Peer Reviewed
• [Journal Article] Flt3 ligand treatment modulates parasitemia during infection with rodent malaria parasites via MyD88- and IFN-γ-dependent mechanisms. (2014)
  • Author(s): Takahiko Tamura, Masoud Akbari, Kazumi Kimura, Daisuke Kimura and Katsuyuki Yui
  • Journal Title: Parasite Immunology Volume: 36 Issue: 2 Pages: 87-99
  • DOI: 10.1111/pim.12085
  • Peer Reviewed
• [Journal Article] RF4 in dendritic cells inhibits IL-12 production and controls Th1 immune responses against Leishmania major. (2014)
  • Author(s): Akbari Masoud, Kiri Honma, Daisuke Kimura, Mana Miyakoda, Kazumi Kimura, Toshifumi Matsuyama, Katsuyuki Yui
  • Journal Title: Journal of Immunology Volume: 192 Issue: 5 Pages: 2271-2279
  • DOI: 10.4049/jimmunol.1301914
  • Peer Reviewed
• [Journal Article] Closeup: Cross-presentation of malaria antigen by brain microvessels: why CD8+ T cells are critical for the pathogeneisis of cerebral malaria. (2013)
  • Author(s): Yui,K.
  • Journal Title: EMBO Mol. Med. Volume: 5 Issue: 7 Pages: 899-901
  • DOI: 10.1002/emmm.201302849
• [Journal Article] CD8+ T cells specific for a malaria cytoplasmic antigen form clusters around infected hepatocytes and are protective at the liver stage of infection. (2013)
  • Author(s): Kazumi Kimura, Daisuke Kimura, Yoshifumi Matsushima, Mana Miyakoda, Kiri Honma, Masao Yuda, and Katsuyuki Yui
  • Journal Title: Infection of Immunology Volume: 81 Issue: 10 Pages: 3825-3834
  • DOI: 10.1128/iai.00570-13
  • NAID: 120006986085
  • Peer Reviewed
• [Journal Article] Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. (2013)
  • Author(s): Tamiya T, Ichiyama K, Kotani H, Fukaya T, Sekiya T, et al.
  • Journal Title: J Immunol. Volume: 191 Issue: 5 Pages: 2360-2371
  • DOI: 10.4049/jimmunol.1301276
  • Peer Reviewed
• [Journal Article] Splenic delivery system as DNA vaccination platform using ternary complexes, (2013)
  • Author(s): Kurosaki, T., Kitahara, T., Miyakoda, M., Yui, K., Sasaki, H.,
  • Journal Title: Biol Pharm Bull Volume: 36 Pages: 1800-1806
  • Peer Reviewed
• [Presentation] マラリア原虫感染におけるIL-27依存的な免疫記憶抑制 (2016)
  • Author(s): 木村大輔、都田真奈、Akbari Masoud, 井手宏二、木村一美、原博満、吉田裕樹、由井克之
  • Organizer: 第85回日本寄生虫学会大会
  • Place of Presentation: 宮崎市
  • Year and Date: 2016-03-19
• [Presentation] IL-27-producing CD4+ T cells induced during malaria infection are distinct from Tr1 cells (2015)
  • Author(s): KIMURA Daisuke, MIYAKODA Mana, DOE Henrietta Terko, KIMURA Kazumi, HARA Hiromitsu, YOSHIDA Hiroki, YUI Katsuyuki
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2015-11-18
• [Presentation] Mechanisms underlying the induction of IL-27-producing CD4+ T cells during immune responses against intracellular pathogens (2015)
  • Author(s): DOE Henrietta Terko, KIMURA Kazumi, MIYAKODA Mana, masoud Akbari, Kazumi Kimura, YUI Katsuyuki
  • Organizer: 64th annual meeting of American Society of Tropical Medicine and Hygine
  • Place of Presentation: Philadelphia, U.S.A.
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] Regulation of immune responses by IL-27-producing CD4+ T cells during malaria infection (2015)
  • Author(s): K. Yui
  • Organizer: The 12th NUS-Nagasaki joint symposium
  • Place of Presentation: NUS, Singapore
  • Year and Date: 2015-06-11
  • Int'l Joint Research / Invited
• [Presentation] IL-27-producing CD4+ T cells regulate protective immune responses during malaria infection (2015)
  • Author(s): KIMURA Daisuke, MIYAKODA Mana, DOE Henrietta Terko, KIMURA Kazumi, Hiromitsu Hara, Hiroki Yoshida, YUI Katsuyuki
  • Organizer: 25th Annual molecular parasitology vector biology Symposium
  • Place of Presentation: Athens, GO USA
  • Year and Date: 2015-04-28
  • Int'l Joint Research / Invited
• [Presentation] IL-27-producing malaria-specific CD4+ T cells regulate protective imune responses (2014)
  • Author(s): KIMURA Daisuke, MIYAKODA Mana, KIMURA Kazumi, HONMA Kiri, HARA Hiromitsu, YOSHIDA Hiroki, YUI Katsuyuki
  • Organizer: 第４３回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場（京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] IL-27-producing CD4+ T cells are induced during malaria infection in a manner independent of TLR signaling (2014)
  • Author(s): DOE Henrietta Terko, KIMURA Daisuke, MIYAKODA Mana, Akbari Masoud, KIMURA Kazumi, Bayarsaikhan Ganchimeg, YUI Katsuyuki
  • Organizer: 第４３回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場（京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 原虫感染におけるIL-27の二つの役割；Th1誘導と免疫制御 (2014)
  • Author(s): 吉田裕樹、木村大輔、由井克之、原博満
  • Organizer: 第79回インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 北海道大学（札幌市）
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] T cell responses during infection with malaria parasitets (2014)
  • Author(s): K. Yui
  • Organizer: 4th International Conference on Current Advances in Microbiology and Immunology
  • Place of Presentation: Corporate hotel and convention center及びモンゴル国立医療大学（ウランバートル市、モンゴル国）
  • Year and Date: 2014-06-19 – 2014-06-20
  • Invited
• [Presentation] T cell responses during infection with Plasmodium berghei ANKA (2014)
  • Author(s): 由井克之
  • Organizer: Mini symposium on malaria immunopathology
  • Place of Presentation: 吹田市大阪大学IFrec
  • Invited
• [Presentation] マラリア原虫特異的CD4+ T細胞は、IL-27を介してCD4+ T細胞の防御機能を抑制する (2014)
  • Author(s): 木村大輔、都田真奈、木村一美、本間季里、原博満、堀昌平、吉田裕樹、由井克之
  • Organizer: 第83回日本寄生虫学会大会
  • Place of Presentation: 松山市愛媛大学城北キャンパス
• [Presentation] IL-27 is produced by CD4＋ T cells during infection with malaria parasites and inhibits protective immune responses (2013)
  • Author(s): Kimura D, Miyakoda M, Kimura K, Honma K, Hara H, Hori S, Yoshida H, Yui K
  • Organizer: 第４２回日本免疫学会学術集会
  • Place of Presentation: 千葉市幕張メッセ
• [Presentation] IRF4 is critical for proliferation and effector differentation of CD8＋ T cells (2013)
  • Author(s): Miyakoda M, Honma K, Kimura D, Kimura K, Matsuyama T, YUI K,
  • Organizer: 第４２回日本免疫学会学術集会
  • Place of Presentation: 千葉市幕張メッセ
• [Presentation] CD8＋ T cells form clusters around infected hepatocytes protecting against liver-stage infextion with plasmodium berghei ANKA (2013)
  • Author(s): Kimura K, Kimura D, Miyakoda M, YUI K
  • Organizer: 第４２回日本免疫学会学術集会
  • Place of Presentation: 千葉市幕張メッセ
• [Presentation] Flt3 ligand treatment inhibits parasitemia during infection with rodent malaria parasites via MyD88-and IFN-g-dependent mechanisms (2013)
  • Author(s): Tamura T, Kimura K, Yui K
  • Organizer: 第４２回日本免疫学会学術集会
  • Place of Presentation: 千葉市幕張メッセ
• [Remarks] 長崎大学大学院医歯薬学総合研究科新興感染症病態制御学系専攻免疫学分野
  • URL: http://www.med.nagasaki-u.ac.jp/mmi/im/
• [Remarks] 長崎大学大学院医歯薬学総合研究科 免疫学分野
  • URL: http://www.med.nagasaki-u.ac.jp/mmi/im/