Targeted checkpoint control of B cells undergoing positive selection in germinal centers by follicular regulatory T cells

• 成果类型: Article
• 署名作者: Ke, Fang; Benet, Zachary L.; Shelyakin, Pavel; V. Britanova, Olga; Gupta, Neetu; Dent, Alexander L.; Moore, Bethany B.; Grigorova, Irina L.
• 署名单位: Pirogov Russian National Research Medical University; Russian Academy of Sciences; Pushchino Scientific Center for Biological Research (PSCBI) of the Russian Academy of Sciences; Institute of Bioorganic Chemistry of the Russian Academy of Sciences; University of Kiel; Cleveland Clinic Foundation; Indiana University System; Indiana University Bloomington
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8666
• DOI: 10.1073/pnas.2304020121
• 发表日期: 2024-01-30
• 关键词: transcription factor; dynamic regulation; myc; expression; generation; responses; receptor

摘要

Follicular regulatory T cells (Tfr) can play opposite roles in the regulation of germinal center (GC) responses. Depending on the studies, Tfr suppress or support GC and B cell affinity maturation. However, which factors determine positive vs. negative effects of Tfr on the GC B cell is unclear. In this study, we show that GC centrocytes that express MYC up- regulate expression of CCL3 chemokine that is needed for both the positive and negative regulation of GC B cells by Tfr. B cell-intrinsic expression of CCL3 contributes to Tfr- dependent positive selection of foreign Ag-specific GC B cells. At the same time, expression of CCL3 is critical for direct Tfr- mediated suppression of GC B cells that acquire cognate to Tfr nuclear proteins. Our study suggests that CCR5 and CCR1 receptors promote Tfr migration to CCL3 and highlights Ccr5 expression on the Tfr subset that expresses Il10. Based on our findings and previous studies, we suggest a model of chemotactically targeted checkpoint control of B cells undergoing positive selection in GCs by Tfr, where Tfr directly probe and license foreign antigen-specific B cells to complete their positive selection in GCs but, at the same time, suppress GC B cells that present self- antigens cognate to Tfr.