Understanding the mechanisms of the breakdown of self-tolerance initiated from the thymus

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K19442
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Kyoto University
• Principal Investigator: Hamazaki Yoko 京都大学, iPS細胞研究所, 教授 (10362477)
• Project Period (FY): 2018-06-29 – 2023-03-31
• Keywords: 胸腺 / 中枢性自己寛容 / ハッサル小体 / 胸腺髄質

Outline of Final Research Achievements

Hassall corpuscle (HC) is a characteristic keratinized structure within the thymic medulla, which is crucial for establishing central T-cell self-tolerance. In this study, we found that the medullary thymic epithelial cells constituting HCs undergo cellular senescence in a steady state and constantly express inflammatory cytokines such as CXCL5 and IL-1 family as SASP factors. In addition, a mouse strain exhibiting systemic autoimmune disease (NZB/W F1) shows HC hyperplasia, with high activation levels of neutrophils and pDCs, as well as T cells in the thymus. Administration of anti-Gr-1 antibody and removal of neutrophils, which are assumed to react to CXCL5, suppressed pDC activation and type I IFN production. These results suggest that T cells are activated in the thymus by HC hyperplasia, suggesting a role in initiating autoimmunity.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

HCを構成する髄質上皮細胞を純化しその遺伝子発現の特徴を明らかにすることで、長らく組織学定義にとどまっていた胸腺髄質のHCを分子細胞レベルで定義することができた。また、自己免疫疾患モデルマウスにおいてHCの過形成や低形成が認められること、HCの過形成が胸腺内好中球やpDCを活性化し、おそらくはそれを介して胸腺内でＴ細胞が活性化している可能性を示唆することができた。本研究は、自己免疫疾患発症メカニズムの解明とその介入方法開発の一助となることが期待される。