Study of functional characteristics of cytotoxic Tfh cells and their pathological significance

2021 Fiscal Year Final Research Report

• Project/Area Number: 18H02632
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Ichimiya Shingo 札幌医科大学, 医学部, 教授 (30305221)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 濾胞ヘルパーT細胞 / 記憶B細胞 / DP-Tfh細胞 / 細胞傷害性Tfh細胞 / IgG4関連疾患 / 異所性リンパ組織 / Eomes / CD70

Outline of Final Research Achievements

This study aimed to characterize the functional features of T follicular helper cells (Tfh cells) in ectopic lymphoid tissues with chronic inflammation. The analysis of fibroinflammatory lesions of IgG4-related disease (IgG4-RD) revealed that the Tfh cell population contained double-positive Tfh cells (DP-Tfh cells), which expressed both CD4 and CD8 and presented cytotoxicity-related molecules, including Eomes, granzymes, perforin, CRTAM, and GPR56. Studies of clinical parameters and co-culture experiments using autologous T and B cells suggest that DP-Tfh cells would regulate memory B cells. Further in vitro experiments showed that normal Tfh cells could differentiate into DP-Tfh cells under the stimulation with IL-2 and IL-7, which was highly expressed in the tissue lesions of IgG4-RD. Taken together, DP-Tfh cells may play a possible role in inhibiting memory B cell function to control the antibody production program within a persistent inflammatory environment.

Free Research Field

病理学、免疫学

Academic Significance and Societal Importance of the Research Achievements

Tfh細胞はリンパ濾胞胚中心の形成を調節し、抗原特異的な抗体の産生と液性免疫記憶の成立に関わるヘルパーT細胞である。臨床検体を用いた本研究から、異所性リンパ濾胞の形成を伴う３次免疫リンパ組織において細胞傷害活性を有するDP-Tfh細胞が多く検出され、B細胞による免疫記憶を調節する新たなメカニズムが示された。本研究は慢性炎症病態のさらなる理解につながり、また重症ウイルス感染症では細胞傷害性Tfh細胞が高頻度に認められるため、免疫関連疾患の病態背景のみならず、感染防御機構の研究においても意義ある成果と考えられる。