Expression of Ly6C/6G defines a novel Aire-dependent subset of medullary thymic epithelial cells with tolerogenic function

• Project/Area Number: 26460577
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokushima
• Principal Investigator: MORIMOTO Junko 徳島大学, 先端酵素学研究所(次世代), 助教 (20451396)
• Co-Investigator(Kenkyū-buntansha): 松本 満 徳島大学, 先端酵素学研究所(次世代), 教授 (60221595)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己免疫疾患 / 自己寛容 / 胸腺髄質上皮細胞 / 中枢性寛容 / 自己抗原 / 胸腺 / Aire

Outline of Final Research Achievements

Medullary thymic epithelial cells (mTECs) are a heterogeneous population in terms of the spectrum of tissue-restricted antigens (TRAs) expressed from each cell for ensuring the elimination of autoreactive T-cells. Because of these heterogeneities, it is unclear whether mTECs are composed of any particular subsets possessing unique properties for their developmental pathway and/or immunological function. Here, we report a distinct mTEC subset characterized by expression of Ly6 family protein. Ly6C/6G+ mTECs, constituting 5-15% of mature mTECs, were preferentially localized at the cortico-medullary junction, and expressed high levels of TRAs. Remarkably, Ly6C/6G+ mTECs were absent in Aire-deficient mice, suggesting that this subset requires Aire and/or Aire+ mTECs for its production. We suggest that Ly6C/6G+ mTECs serve as an important source of TRAs for efficient cross-presentation during establishment of self-tolerance.

Research Products

• [Journal Article] Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program. (2015)
  • Author(s): Kawano H, Nishijima H, Morimoto J, Hirota F, Morita R, Mouri Y, Nishioka Y, Matsumoto M.
  • Journal Title: Journal of Immunology Volume: 195 Issue: 11 Pages: 5149-5158
  • DOI: 10.4049/jimmunol.1501000
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ectopic Aire expression in 1 the thymic cortex reveals inherent properties of Aire as a tolerogenic factor within the medulla (2015)
  • Author(s): Nishijima H, Kitano S, Miyachi H, Morimoto J, Kawano H, Hirota F, Morita R, Mouri Y, Masuda K, Imoto I, Ikuta K, Matsumoto M.
  • Journal Title: J Immunol Volume: 195 Issue: 10 Pages: 4641-4649
  • DOI: 10.4049/jimmunol.1501026
  • Peer Reviewed / Open Access
• [Journal Article] Syndecan 4 Regulation of the Development of Autoimmune Arthritis in Mice by Modulating B Cell Migration and Germinal Center Formation. (2015)
  • Author(s): Endo T, Ito K, Morimoto J, Kanayama M, Ota D, Ikesue M, Kon S, Takahashi D, Onodera T, Iwasaki N, Uede T.
  • Journal Title: Arthritis Rheumatology Volume: 67 Issue: 9 Pages: 2512-2522
  • DOI: 10.1002/art.39193
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NIK in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells (2014)
  • Author(s): Mouri, Y., Nishijima, H., Kawano, H., Hirota, F., Sakaguchi, N., Morimoto, J., Matsumoto, M.
  • Journal Title: J. Immunol. Volume: 193 Issue: 9 Pages: 4356-4367
  • DOI: 10.4049/jimmunol.1400389
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor-a9b1 integrin-mediated signaling induces breast cancer growth and lymphatic metastasis via the recruitment of cancer-associated fibroblasts. (2014)
  • Author(s): Ota D, Kanayama M, Matsui Y, Ito K, Maeda N, Kutomi G, Hirata K, Torigoe T, Sato N, Takaoka A, Chambers AF, Morimoto J, Uede T.
  • Journal Title: Journal of Molecular Medicine Volume: 92 Issue: 12 Pages: 1271-1281
  • DOI: 10.1007/s00109-014-1183-9
  • Peer Reviewed
• [Journal Article] Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program (2014)
  • Author(s): Nishikawa, Y., Nishijima, H., Matsumoto, M., Morimoto, J., Hirota, F., Takahashi, S., Luche, H., Fehling, H.J., Mouri, Y., Matsumoto, M.
  • Journal Title: J. Immunol Volume: 192 Issue: 6 Pages: 2585-2592
  • DOI: 10.4049/jimmunol.1302786
  • Peer Reviewed / Open Access
• [Journal Article] Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress (2014)
  • Author(s): Ito K, Morimoto J, Kihara A, Matsui Y, Kurotaki D, Kanayama M, Simmons S, Ishii M, Sheppard D, Takaoka A, Uede T
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 8 Pages: 3080-3085
  • DOI: 10.1073/pnas.1311022111
  • Peer Reviewed / Open Access
• [Journal Article] α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis. (2014)
  • Author(s): α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis.
  • Journal Title: Rheumatology (Oxford). Volume: 53 Issue: 3 Pages: 415-424
  • DOI: 10.1093/rheumatology/ket371
  • Peer Reviewed / Open Access
• [Presentation] Expression of Ly6 family protein defines a novel Aire-dependent subset of medullary thymic epithelial cells with tolerogenic function (2017)
  • Author(s): Morimoto Junko
  • Organizer: 第19回武田振興財団生命科学シンポジウム
  • Place of Presentation: 大阪府吹田市武田薬品研修所
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] Novel Aire-dependent tolerogenic lineage(s) of medullary thymic epithelial cells expressing Ly6 family protein (2016)
  • Author(s): Junko Morimoto
  • Organizer: The Fifth Bizan Immunology Symposium
  • Place of Presentation: 徳島大学（徳島県・徳島市）
  • Year and Date: 2016-03-03
  • Int'l Joint Research
• [Presentation] A novel Aire-dependent subset of medullary thymic epithelial cells that express Ly6 family protein (2015)
  • Author(s): Junko Morimoto, Yumiko Nishikawa, Hiroshi Kawano, Yasuhiro Mouri, Hitoshi Nishijima, Mitsuru Matsumoto
  • Organizer: 日本免疫学会
  • 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