Differentiation of follicular helper T cells induced by lung dendritic cells in asthma

• Project/Area Number: 16K09577
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Furuhashi Kazuki 浜松医科大学, 医学部附属病院, 助教 (70759935)
• Co-Investigator(Kenkyū-buntansha): 鈴木 勇三 浜松医科大学, 医学部, 助教 (00758435) ; 須田 隆文 浜松医科大学, 医学部, 教授 (30291397) ; 榎本 紀之 浜松医科大学, 医学部附属病院, 講師 (50436961)
• Research Collaborator: Sakurai Shogo ; Kemeny David Michael
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 濾胞性ヘルパーT細胞 / マウス喘息モデル / 肺樹状細胞 / ダニ抗原喘息モデル / 気管支喘息 / アレルゲン特異的抗体

Outline of Final Research Achievements

We found that follicular helper T cells (Tfh) increased in mediastinal lymph node and spleen using asthma mouse model with house dust mite (HDM) and ovalbumin (OVA) antigen. The antigen specific IgE and IgG1 antibodies were produced in those asthma models. We identified and purely isolated two lung dendritic cells (LDCs) subsets, which were conventional DC1 (cDC1) and DC2 (cDC2). Subsequently, we established co-culture assay with each LDC subset from OVA asthma mouse model and naive T cells from OT-II mice having OVA specific T cell receptors. As a result, we found that cDC2 induced greater frequencies of Tfh than cDC1.

Academic Significance and Societal Importance of the Research Achievements

本課題によって、喘息肺における所属リンパ節におけるTfh細胞の増加やアレルゲン特異的IgE抗体産生を確認し、さらにTfh細胞は、抗原提示細胞である肺樹状細胞サブセットの中のcDC2によって、より効率よく誘導されていることが確認できた。これらの結果は、気管支喘息の病態にTfh細胞が深く関わっていることを示唆し、気管支喘息において従来から重要と考えられていたTh2細胞などのヘルパーT細胞の他に、Tfh細胞が関与する気管支喘息の新たな病態の解明につながると考えられる。また将来、Tfh細胞の誘導を制御するようなTfh細胞をターゲットにした治療戦略が開発できる可能性も考えられる。

Research Products

• [Journal Article] IL-17A Attenuates IFN-λ Expression by Inducing Suppressor of Cytokine Signaling Expression in Airway Epithelium (2018)
  • Author(s): Niwa Mitsuru、Fujisawa Tomoyuki、Mori Kazutaka、Yamanaka Katsumasa、Yasui Hideki、Suzuki Yuzo、Karayama Masato、Hozumi Hironao、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suzuki Tetsuro、Maekawa Masato、Suda Takafumi
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 8 Pages: 2392-2402
  • DOI: 10.4049/jimmunol.1800147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differences in airway structural changes assessed by 3-dimensional computed tomography in asthma and asthma?chronic obstructive pulmonary disease overlap (2018)
  • Author(s): Niwa Mitsuru、Fujisawa Tomoyuki、Karayama Masato、Furuhashi Kazuki、Mori Kazutaka、Hashimoto Dai、Yasui Hideki、Suzuki Yuzo、Hozumi Hironao、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Annals of Allergy, Asthma & Immunology Volume: 121 Issue: 6 Pages: 704-710.e1
  • DOI: 10.1016/j.anai.2018.08.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Respiratory impedance is correlated with airway narrowing in asthma using three-dimensional computed tomography (2018)
  • Author(s): Karayama M, Inui N, Mori K, Kono M, Hozumi H, Suzuki Y, Furuhashi K, Hashimoto D, Enomoto N, Fujisawa T, Nakamura Y, Watanabe H, Suda T.
  • Journal Title: Clin Exp Allergy Volume: 48 Issue: 3 Pages: 278-287
  • DOI: 10.1111/cea.13083
  • Peer Reviewed
• [Journal Article] Prior exposure to inhaled allergen enhances anti-viral immunity and T cell priming by dendritic cells (2018)
  • Author(s): Lee DCP, Tay NQ, Thian M, Prabhu N, Furuhashi K, Kemeny DM.
  • Journal Title: Plos One Volume: 13 Issue: 1 Pages: e0190063-e0190063
  • DOI: 10.1371/journal.pone.0190063
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-13 regulates IL-17C expression by suppressing NF-κB-mediated transcriptional activation in airway epithelial cells (2018)
  • Author(s): Yamanaka K, Fujisawa T, Kusagaya H, Mori K, Niwa M, Furuhashi K, Kono M, Hamada E, Suda T, Maekawa M.
  • Journal Title: Biochem Biophys Res Commun Volume: 495 Issue: 1 Pages: 1534-1540
  • DOI: 10.1016/j.bbrc.2017.11.207
  • Peer Reviewed / Open Access
• [Journal Article] Persistent impairment on spirometry in chronic eosinophilic pneumonia: a longitudinal observation study (Shizuoka-CEP study) (2017)
  • Author(s): Suzuki Y, Oyama Y, Hozumi H, Imokawa S, Toyoshima M, Yokomura K, Nakamura H, Kuroishi S, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Koshimizu N, Yamada T, Mori K, Masuda M, Shirai T, Hayakawa H, Sumikawa M, Johkoh T, Suda T
  • Journal Title: Ann Allergy Asthma Immunol Volume: 119 Issue: 5 Pages: 422-428
  • DOI: 10.1016/j.anai.2017.08.009
  • Peer Reviewed
• [Journal Article] Relationship between fraction of exhaled nitric oxide and airway morphology assessed by three-dimensional CT analysis in asthma (2017)
  • Author(s): Nishimoto K, Karayama M, Inui N, Mori K, Kono M, Hozumi H, Suzuki Y, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Watanabe H, Suda T
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 10187-10187
  • DOI: 10.1038/s41598-017-10504-w
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Utility of YKL-40 in Polymyositis/dermatomyositis-associated Interstitial Lung Disease (2017)
  • Author(s): Hozumi H, Fujisawa T, Enomoto N, Nakashima R, Enomoto Y, Suzuki Y, Kono M, Karayama M, Furuhashi K, Murakami A, Inui N, Nakamura Y, Mimori T, Suda T
  • Journal Title: J Rheumatol Volume: 44 Issue: 9 Pages: 1394-1401
  • DOI: 10.3899/jrheum.170373
  • Peer Reviewed
• [Journal Article] Blomia tropicalis allergen 5 (Blo t 5) T-cell epitopes and their ability to suppress the allergic immune response. (2017)
  • Author(s): Wong KH, Zhou Q, Prabhu N, Furuhashi K, Chua YL, Grotenbreg GM, Kemeny DM
  • Journal Title: Immunology Volume: 152 Issue: 2 Pages: 344-355
  • DOI: 10.1111/imm.12772
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Priming with high and low respiratory allergen dose induces differential CD4+ T helper type 2 cells and IgE/IgG1 antibody responses in mice. (2017)
  • Author(s): Furuhashi K, Chua YL, Wong KHS, Zhou Q, Lee DCP, Liong KH, Teo GH, Hutchinson PE, Kemeny DM.
  • Journal Title: Immunology Volume: 印刷中 Issue: 2 Pages: 227-238
  • DOI: 10.1111/imm.12726
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Respiratory impedance is correlated with morphological changes in the lungs on three-dimensional CT in patients with COPD. (2017)
  • Author(s): Karayama M, Inui N, Mori K, Kono M, Hozumi H, Suzuki Y, Furuhashi K, Hashimoto D, Enomoto N, Fujisawa T, Nakamura Y, Watanabe H, Suda T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 41709-41709
  • DOI: 10.1038/srep41709
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of soluble CD163 in polymyositis-related or dermatomyositis-related interstitial lung disease (2017)
  • Author(s): Enomoto Y, Suzuki Y, Hozumi H, Mori K, Kono M, Karayama M, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suzuki D, Ogawa N, Nakashima R, Mimori T, Iwashita T, Suda T
  • Journal Title: Arthritis Res Ther Volume: 19 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s13075-016-1214-8
  • NAID: 120005973333
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Soluble hemoglobin scavenger receptor CD163 (sCD163) predicts mortality of community-acquired pneumonia (2016)
  • Author(s): Suzuki Y, Enomoto Y, Yokomura K, Hozumi H, Kono M, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T
  • Journal Title: J Infect Volume: 73 Issue: 4 Pages: 375-377
  • DOI: 10.1016/j.jinf.2016.07.004
  • Peer Reviewed / Int'l Joint Research