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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-01, Vol.121 (5), p.e2304020121
• Main Authors: Ke, Fang, Benet, Zachary L, Shelyakin, Pavel, Britanova, Olga V, Gupta, Neetu, Dent, Alexander L, Moore, Bethany B, Grigorova, Irina L
• Format: Article
• Language: English
• Subjects: AIRE protein; Antigen presentation; Autoantigens; Autoimmune diseases; B-Lymphocytes; Biological Sciences; CD4 antigen; Chemokine CCL3; Clonal selection; Damage tolerance; Differentiation; Epitopes; Germinal Center; Germinal centers; Immunological tolerance; Immunoregulation; Interphotoreceptor retinoid-binding protein; Lymphocytes; Lymphocytes B; Lymphocytes T; Negative selection; Positive selection; Retina; T cell receptors; T-Lymphocytes, Regulatory; Thymocytes; Thymus; Transgenic mice; Uvea; Uveitis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2304020121

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 expression on the Tfr subset that expresses . 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.