Identification and analysis of the niches for helper memory T cells

• Project/Area Number: 15H04742
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: ISHII Naoto 東北大学, 医学系研究科, 教授 (60291267)
• Co-Investigator(Kenkyū-buntansha): 宗 孝紀 東北大学, 医学系研究科, 准教授 (60294964)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 記憶T細胞 / ニッチ / 腸管膜リンパ節 / Th17細胞 / 炎症 / 免疫記憶 / ヘルパーT細胞 / リンパ節 / 自己免疫疾患 / 免疫学 / アレルギー / T細胞 / 腸管免疫

Outline of Final Research Achievements

Accumulating evidence suggests that mesenteric lymph nodes (MLNs) play important roles in gut-tropic Th17 cell generation, although it is still unclear if MLNs are involved in the pathogenesis of small intestinal inflammation. To address this issue, we analyzed the roles of both MLNs and Peyer’s patches (PPs) by evaluating MLN- or PP-deficient mice in an experimental model of small intestinal inflammation. MLNs, but not PPs, were essential for the pathogenesis of the intestinal inflammation, in particular the accumulation and infiltration of Th17 cells. Furthermore, MLN removal led to a significantly reduced number of peripheral α4β7+ CD4+ effector memory T (TEM) cells under normal conditions, suggesting that MLNs may play a role in maintaining the number of gut-tropic Th17-TEM cells circulating in the blood. Taken together, the present study highlights the important role of MLNs in contributing to the pathogenesis of small intestinal inflammation.

Research Products

• [Int'l Joint Research] University of Perugia(Italy)
• [Int'l Joint Research] University of Hawaii(U.S.A.)
• [Int'l Joint Research] La Jolla Institute/University of Illinois(米国)
• [Int'l Joint Research] University of Hawaii/Texas Medical Center(米国)
• [Journal Article] TRAF2 and TRAF5 associated with the signal transducing receptor gp130 limit IL-6-driven transphosphorylation of JAK1 through the inhibition of proximal JAK-JAK interaction. (2018)
  • Author(s): Kimura M, Nagashima H, Okuyama Y, Ishii N, and So T
  • Journal Title: Int. Immunol Volume: - Issue: 7 Pages: 219-299
  • DOI: 10.1093/intimm/dxy029
  • Peer Reviewed
• [Journal Article] TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation. (2018)
  • Author(s): Machiyama T, So T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Harigae H, Ishii N.
  • Journal Title: Biochem Biophys Res Commun. Volume: - Issue: 3 Pages: 544-550
  • DOI: 10.1016/j.bbrc.2018.03.186
  • Peer Reviewed
• [Journal Article] GITR cosignal in ILC2s controls allergic lung inflammation. (2018)
  • Author(s): Nagashima H, Okuyama Y, Fujita T, Takeda T, Motomura Y, Moro K, Hidaka T, Omori K, Sakurai T, Machiyama T, Ndhlovu LC, Riccardi C, So T, Ishii N.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 5 Pages: 1939-1943.e8
  • DOI: 10.1016/j.jaci.2018.01.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ES Stress Protein CHOP Mediates Insulin Resistanse by Modulating Adipose Tissue Macrophage Polarity. (2017)
  • Author(s): Suzuki T, Gao J, Ishigaki Y, Kondo K, Sawada S, Izumi T, Uno K, Kaneko K, Tsukita S, Takahashi K, Asao A, Ishii N, Imai J, Yamada T, Oyadomarai S, Katagiri H
  • Journal Title: Cell Rep Volume: 18 Issue: 8 Pages: 2045-2057
  • DOI: 10.1016/j.celrep.2017.01.076
  • Peer Reviewed / Open Access
• [Journal Article] TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury (2017)
  • Author(s): Lan P, Fan Y, Zhao Y, Lou X, Monsour HP, Zhang X, Choi Y, Dou Y, Ishii N, Ghobrial RM, Xiao X, Li XC
  • Journal Title: J Clin Invest. Volume: 127 Issue: 6 Pages: 2222-2234
  • DOI: 10.1172/jci91075
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD103+ CD11b- salivary gland dendritic cells have antigen cross-presenting capacity. (2017)
  • Author(s): Lu L, Tanaka Y, Ishii N, Sasano T, Sugawara S
  • Journal Title: Eur J Immunol Volume: 47 Issue: 2 Pages: 305-313
  • DOI: 10.1002/eji.201646631
  • Peer Reviewed
• [Journal Article] Oral CD103-CD11b+ classical dendritic cells present sublingual antigen and induce Foxp3+ regulatory T cells in draining lymph nodes (2017)
  • Author(s): Tanaka Y, Nagashima H, Bando K, Lu L, Ozaki A, Morita Y, Fukumoto S, Ishii N, Sugawara S
  • Journal Title: Mucosal Immunol Volume: 10 Issue: 1 Pages: 79-90
  • DOI: 10.1038/mi.2016.46
  • Peer Reviewed
• [Journal Article] Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1) modulates antigen presenting cell-mediated T helper cell type 1 responses (2016)
  • Author(s): Akhter N, Takeda Y, Nara H, Araki A, Ishii N, Asao N, Asao H
  • Journal Title: J Biol Chem Volume: 291 Issue: 45 Pages: 23672-23680
  • DOI: 10.1074/jbc.m116.742353
  • Peer Reviewed
• [Journal Article] TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development (2016)
  • Author(s): Nagashima, H., Okuyama, Y., Hayashi, T., Ishii, N., So, T.
  • Journal Title: J Immunol Volume: 196 Issue: 10 Pages: 4082-4089
  • DOI: 10.4049/jimmunol.1501610
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] OX40 ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia. (2016)
  • Author(s): Hirano T, Kikuchi T, Tode N, Santoso A, Yamada M, Mitsuhashi Y, Komatsu R, Kawabe T, Tanimoto T, Ishii N, Tanaka Y, Nishimura H, Nukiwa T, Watanabe A, Ichinose M.
  • Journal Title: EMBO Mol Med. Volume: 8 Issue: 4 Pages: 422-436
  • DOI: 10.15252/emmm.201506154
  • NAID: 120006845618
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mesenteric lymph nodes contribute to proinflammatory Th17-cell generation during inflammation of the samall intestine in mice. (2016)
  • Author(s): Kawabe, T., Suzuki, N., Yamaki, S., Sun, S. L., Asao, A., Okuyama, Y., So, T., Iwakura, Y., and Ishii, N.
  • Journal Title: Eur. J. Immunol. Volume: 46 Issue: 5 Pages: 1119-1131
  • DOI: 10.1002/eji.201545907
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TNF receptor-associated factor-2 and -5 differentially regulate the instructive IL-6 receptor signaling that requires for Th17 development (2016)
  • Author(s): Nagashima H, Okuyama Y, Hayashi T, Ishii N, and So T
  • Journal Title: J Immunol Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Local convection-enhanced delivery of an anti-CD40 agonistic monoclonal antibody induces antitumor effects in mouse glioma models. (2016)
  • Author(s): Shoji T, Saito R, Chonan M, Shibahara I, Sato A, Kanamori M, Sonoda Y, Kondo T, Ishii N, and Tominaga T
  • Journal Title: Neuro-Oncology Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TIGIT marks exhausted T cells, correlates with disease progression, and serves as target for immune restoration in HIV and SIV infection (2016)
  • Author(s): Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS, Hammond KB, Clayton KL, Ishii N, Abdel-Mohsen M, Liegler T, Mitchell BI, Hecht FM, Ostrowski M, Shikuma CM, Hansen SG, Maurer M, Korman AJ, Deeks SG, Sacha JB, Ndhlovu LC.
  • Journal Title: PLoS Pathol Volume: 12 Issue: 1 Pages: e1005349-e1005349
  • DOI: 10.1371/journal.ppat.1005349
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes (2015)
  • Author(s): Takanori So, Hiroyuki Nagashima, Naoto Ishii
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 236 Issue: 2 Pages: 139-154
  • DOI: 10.1620/tjem.236.139
  • NAID: 130005075699
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations and prolongs survival in intracranial glioma- and glioma-initiating cell-isografted tumor models (2015)
  • Author(s): Chonan M, Saito R, Shoji T, Shibahara I, Kanamori M, Sonoda Y, Watanabe M, Kikuchi T, Ishii N, and Tominaga T
  • Journal Title: Neuro-Oncology Volume: 17 Issue: 11 Pages: 1453-1462
  • DOI: 10.1093/neuonc/nov090
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] TRAF2 and TRAF5 binding to the signal transducing receptor gp130 inhibit JAK1 activation in the IL-6-receptor signaling complex (2017)
  • Author(s): Masanobu Kimura, Hiroyuki Nagashima, Naoto Ishii, Takanori So
  • Organizer: 日本免疫学会学術集会
• [Presentation] Early activation of group 2 innate lymphoid cells in the lung is critically controlled by the TNFR superfamily molecule GITR (2017)
  • Author(s): Takanori So, Hiroyuki Nagashima, Yuko Okuyama, Yasutaka Motomura, Kazuyo Moro, Lishomwa C. Ndhlovu, Carlo Riccardi, Naoto Ishii
  • Organizer: 日本免疫学会学術集会
• [Presentation] A new regulator of OX40 co-signaling controls autoimmune neuroinflammation mediated by CD4+ T cells (2017)
  • Author(s): Yuko Okuyama, Hiroyuki Nagashima, Masuko Ushio-Fukao, Michael Croft, Naoto Ishii, Takanori So
  • Organizer: 日本免疫学会学術集会
• [Presentation] TNF receptor-associated factors 5 expressed in non-hematopoietic cells augments acute colonic damage induced by dextran sulfate (2017)
  • Author(s): HAI T PHUNG, Hiroyuki Nagashima, Yuko Okuyama, Shuhei Kobayashi, Atsuko Asao, Naoto Ishii, Takanori So
  • Organizer: 日本免疫学会学術集会
• [Presentation] A novel regulatory role for TRAF2 and TRAF5 in the IL-6-driven Th17 development. (2017)
  • Author(s): NAGASHIMA Hiroyuki, OKUYAMA Yuko, HAYASHI Takaya, ISHII Naoto, SO Takanori
  • Organizer: 2017 Japan-NIH Joint Symposium
  • Place of Presentation: 星陵オーディトリアム、仙台
  • Int'l Joint Research
• [Presentation] TRAF2 and TRAF5 have redundant but unequal inhibitory roles in Th17 differentiation mediated by IL-6 (2016)
  • Author(s): NAGASHIMA Hiroyuki, OKUYAMA Yuko, HAYASHI Takaya, ISHII Naoto, SO Takanori
  • Organizer: 45th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 沖縄コンベンションセンター、宜野湾
  • Year and Date: 2016-12-05
• [Presentation] CD4+ T cell-intrinsic TRAF5 negatively regulates Th17 cell-dependent experimental autoimmune encephalomyelitis (2016)
  • Author(s): Hiroyuki Nagashima, Yuko Okuyama, Takaya Hayashi, Atsuko Asao, Takeshi Kawabe, Satoshi Yamaki, Hiroyasu Nakano, Michael Croft, Naoto Ishii, Takanori So
  • Organizer: International congress of immunology (ICI) 2016
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] International Congress of Immunology 2016 (2016)
  • Author(s): So, T., H. Nagashima, Y. Okuyama, T. Hayashi, A. Asao, T. Kawabe, S. Yamaki, H. Nakano, M. Croft, N. Ishii.
  • Organizer: TRAF adaptors limit IL-6 receptor signaling through an unexpected binding to the signaling transducer receptor gp130
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Traf2とTraf5を介したインターロイキン６（IL-6）シグナル制御 (2016)
  • Author(s): 長島宏行、石井直人
  • Organizer: 第5回 Multidisciplinary meeting on atherosclerosis
  • Place of Presentation: 仙台トラストシティ カンファレンスルーム、宮城県仙台市
  • Year and Date: 2016-01-09
• [Presentation] Role of mesenteric lymphnodes in CD4 T cell homeostasis (2015)
  • Author(s): Naoto Ishii
  • Organizer: 1st Symposium of Creation and Future Trends in Food and Agricultural Immunology
  • Place of Presentation: Multimedia Education and Research Complex, Tohoku University, Miyagi、Sendai
  • Year and Date: 2015-12-12
  • Int'l Joint Research / Invited
• [Presentation] IQGAP1 regulates OX40 co-signaling in CD4+ T cells (2015)
  • Author(s): 奥山祐子、長島宏行、Masuko Ushio-Fukai、Michael Croft、石井直人、宗孝紀
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、北海道札幌市
  • Year and Date: 2015-11-18
• [Presentation] TRAF2 and TRAF5 limit the differentiation of Th17 cells mediated by IL-6 (2015)
  • Author(s): 長島宏行、奥山祐子、林隆也、石井直人、宗孝紀
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、北海道札幌市
  • Year and Date: 2015-11-18
• [Presentation] OX40-mediated susceptibility to imiquimod-induced psoriasis-like skin inflammation is dependent on IL-13 (2015)
  • Author(s): 浅尾敦子、藤田剛、宗孝紀、星野友昭、石井直人
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、北海道札幌市
  • Year and Date: 2015-11-18
• [Presentation] Hepatocyte growth factor-regulated tyrosine kinase substrate is required for T cell development and survival (2015)
  • Author(s): 鈴木信、村田和子、奥山祐子、浅尾敦子、宗孝紀、田中伸幸、石井直人
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、北海道札幌市
  • Year and Date: 2015-11-18
• [Presentation] Oral classical dendritic cells induce sublingual antigen-specific regulatory T cells in draining lumph nodes (2015)
  • Author(s): 田中志典、長島宏行、石井直人、菅原俊二
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、北海道札幌市
  • Year and Date: 2015-11-18
• [Presentation] Investigating the Role of the Immune Checkpoint Receptor TIGIT in T cells during HIV Disease Progression and as Target for Immune Restoration (2015)
  • Author(s): Glen M. Chew, Tsuyoshi Fujita, Gabriela Webb, Benjamin J. Burwitz, Kiera L. Clayton, Naoto Ishii, Mohamed Abdel-Mohsen, Teri Liegler, Fredrick M. Hecht, Mario Ostrowski, Mark Maurer, Alan J. Korman, Steven G. Deeks, Jonah B. Sacha and Lishomwa C. Ndhlovu
  • Organizer: 8th Conference of International AIDS association
  • Place of Presentation: Vancourver, Canada
  • Year and Date: 2015-07-17
  • Int'l Joint Research
• [Remarks] 東北大学大学院医学系研究科免疫学分野
  • URL: http://www.immunol.med.tohoku.ac.jp/