Mechanisms and meanings of phenotypic alteration of naive CD4 T cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19393
• 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: National Center for Global Health and Medicine
• Principal Investigator: Sekiya Takashi 国立研究開発法人国立国際医療研究センター, その他部局等, 免疫応答修飾研究室長 (80519207)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 免疫学 / CD4T細胞 / 制御性T細胞

Outline of Final Research Achievements

Naive CD4+ T (TN) cells differentiate into helper T- or regulatory T (Treg)-cell subsets upon encountering antigens, supporting properly directed immune responses. Although all TN cells can differentiate into any Th- and Treg-cell subsets, recent studies revealed heterogeneity among TN cells. Using novel reporter mice to detect ongoing T cell receptor (TCR) signaling, we identified IL-1b signaling as a novel factor that affected TN cell characteristics, independent of tonic TCR signaling that alter TN cells. IL-1b attenuated the differentiation potential of TN cells toward Treg cells. IL-1b signaling was elevated in the splenic TN cells, attenuating their differentiation potential toward Treg cells. Aberrant elevation of IL-1b signaling augmented colitogenic activities of TN cells. Furthermore, TN cells in patients with colitis exhibited elevated IL-1b signaling. Our work revealed the phenotypic alteration of TN cells by IL-1b as a novel regulatory mechanism for immune response.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

TN細胞の不均一性は、その重要性が証明されていないために、注目を集めていない状況にあった。しかし本研究は、疾患マウスモデルを用いた検討やヒト疾患検体データのマイニングにより、TN細胞の不均一性形成の病態生理学的意義を解明した点に、社会的意義を有する。また、免疫研究における激戦分野の一つであるヘルパーT細胞(Th)/制御性T細胞(Treg)分化の研究は急速に進められてきた一方で、TN細胞を均一な集団と捉えると説明のつかない現象も多々見出されてきていた。本研究は、TN細胞の不均一性という新たな切り口からTh/Treg分化のさらなる理解を深めた点に、一つの学術的意義を有する。