Identification of endoplasmic reticulum molecular chaperones to determine antigen presentation to cytotoxic T lymphocytes

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06631
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Saitama Medical University
• Principal Investigator: Matsui Masanori 埼玉医科大学, 医学部, 准教授 (50199741)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 細胞傷害性T細胞 / HLAクラスI / 抗原提示 / 分子シャペロン / 小胞体 / アジュバント / TAPBPR

Outline of Final Research Achievements

The HLA-A2 mutant molecule HLA-A2-H74L with one amino acid substitution from Histidine to Leucine at position 74 fails to present antigen to cytotoxic T cells because it does not bind to endogenously processed antigenic peptides. This phenomenon is thought to be due to the lack of the interaction between HLA-A2-H74L and an unknown molecular chaperone in the ER, which may assist to exchange from self-peptides to antigenic peptides.
We attempted to identify this molecule using immunoprecipitation and mass spectrometry, but we failed. At that time, a new molecular chaperone, TABPPR, was identified. Due to its properties, it is highly possible that the molecular chaperone in question is TABPPR. The analysis of a human cell line in which TABPPR was knocked out by the CRISPR/Cas9 method revealed the antigen-presenting ability of the cell line was slightly reduced, suggesting a critical role of TAPBPR in the antigen presentation associated with HLA class I.

Free Research Field

免疫学　ウイルス学

Academic Significance and Societal Importance of the Research Achievements

細胞傷害性T細胞 (CTL)は、がん細胞やウイルス感染細胞の排除に極めて重要な役割を果たしている。従って、その誘導を行う抗原提示機構を理解する事は重要である。本研究では、新規小胞体分子シャペロン、TAPBPRの抗原提示における重要性が示唆された。この分子シャペロンは抗原提示能を促進すると考えられるので、がんやウイルス感染症に対する新しいCTL誘導型ワクチンに利用できるであろう。さらに、治療薬・治療法の標的分子となりえる。このように、本研究結果は学術的に高い意味を持つとともに、ワクチンなど臨床応用も期待でき、社会的に大きな意義を持つと思われる。