Lipopeptide Immunity: A novel approach to autoimmunity

• Project/Area Number: 21K07078
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kyoto University
• Principal Investigator: Morita Daisuke 京都大学, 医生物学研究所, 助教 (40706173)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: MHCクラス1 / HLA / リポペプチド / ミリスチン酸修飾 / エイズ / 自己免疫

Outline of Research at the Start

ウイルス蛋白質へのN末端ミリスチン酸（C14脂肪酸）修飾反応は、その蛋白質の機能、及びウイルスの病原性に深く関わっている。サルエイズモデルを活用した詳細な免疫解析から、このミリスチン酸修飾を受けたウイルスペプチド、すなわち「リポペプチド」がMHCクラス1分子によってキラーT細胞へと提示される新しい獲得免疫応答の存在が明らかとなった。本研究では、1) ヒトにおけるリポペプチド免疫応答の解析基盤を確立し、2) リポペプチド免疫と自己免疫応答との因果関係を探索する。

Outline of Final Research Achievements

We have identified a novel subset of MHC class I molecule, LP1 that presents virus-derived lipopeptides to T cells and have elucidated their structures and functions. On the other hand, lipopeptide immunity is theoretically difficult to distinguish between self and non-self due to its ambiguous antigen specificity, suggesting its potential involvement in the exacerbation of human autoimmunity associated with viral infection. Therefore, based on the structural information from the known LP1 molecules, we identified HLA-A*2402 and HLA-C*1402, which are the most frequent alleles in the Japanese population, as LP1 candidates, and determined their X-ray crystal structures at a high resolution. Furthermore, we have established mouse lines that recapitulate lipopeptide immunity. Utilizing these unique animal models, we are investigating the relationship between viral infection and autoimmunity.

Academic Significance and Societal Importance of the Research Achievements

病原体抗原と自己抗原の間に構造類似性がある時、両者の間に免疫学的な交差反応が起こり、自己反応性が生じ得る。従来、この概念は蛋白やペプチド抗原に対する免疫の枠組みの中で理解されてきたが、リポペプチド抗原を特異的に認識するT細胞は、自己と非自己の識別が本質的に困難であることから、自己免疫病態の発露に関わっている可能性が高い。本研究が成就すれば、自己免疫の新概念が生み出され（学術的意義）、リポペプチドを標的とした新しい治療法・予防法・診断法の開発に繋がる（社会的意義）。

Research Products

• [Journal Article] Engagement with the TCR induces plasticity in antigenic ligands bound to MHC class I and CD1 molecules (2023)
  • Author(s): Daisuke Morita, Minori Asa, Masahiko Sugita
  • Journal Title: International Immunology Volume: 35 Issue: 1 Pages: 7-17
  • DOI: 10.1093/intimm/dxac046
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Crystal structures of N-myristoylated lipopeptide-bound HLA class I complexes indicate reorganization of B-pocket architecture upon ligand binding (2022)
  • Author(s): Minori Asa, Daisuke Morita, Jin Kuroha, Tatsuaki Mizutani, Naoki Mori, Bunzo Mikami, Masahiko Sugita
  • Journal Title: Journal of Biological Chemistry Volume: 298 Issue: 7 Pages: 102100-102100
  • DOI: 10.1016/j.jbc.2022.102100
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] N-myristoylated lipopeptide-specific T cell development independently of TAP transporters. (2024)
  • Author(s): Hiromu Suzuki, and Daisuke Morita.
  • Organizer: The 52nd Annual Meeting of the Japanese Society for Immunology
• [Presentation] リポペプチドを提示するMHCクラスI分子の構造と機能 (2022)
  • Author(s): 麻実乃莉、森田大輔、杉田昌彦
  • Organizer: 第33回日本生体防御学会
• [Presentation] A molecular basis for specific recognition of lipopeptides by TCRs (2022)
  • Author(s): Daisuke Morita, Masahiko Sugita
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Dynamic B-pocket remodeling is a basis for HLA class I molecules to bind peptides and lipopeptides. (2022)
  • Author(s): Minori Asa, Daisuke Morita, Masahiko Sugita
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Crystal structure of the ternary complex of TCR, MHC class I and lipopeptides (2021)
  • Author(s): 森田大輔、杉田昌彦
  • Organizer: 第50回日本免疫学会学術集会