Browsing by Author "Grigorova, Irina L."

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    Germinal center B cells that acquire nuclear proteins are specifically suppressed by follicular regulatory T cells
    (eLife Sciences, 2023-03-02) Ke, Fang; Benet, Zachary L.; Maz, Mitra P.; Liu, Jianhua; Dent, Alexander L.; Kahlenberg, Joanne Michelle; Grigorova, Irina L.; Microbiology and Immunology, School of Medicine
    Follicular regulatory T cells (Tfr) restrict development of autoantibodies and autoimmunity while supporting high-affinity foreign antigen-specific humoral response. However, whether Tfr can directly repress germinal center (GC) B cells that acquire autoantigens is unclear. Moreover, TCR specificity of Tfr to self-antigens is not known. Our study suggests that nuclear proteins contain antigens specific to Tfr. Targeting of these proteins to antigen-specific B cells in mice triggers rapid accumulation of Tfr with immunosuppressive characteristics. Tfr then exert negative regulation of GC B cells with predominant inhibition of the nuclear protein-acquiring GC B cells, suggesting an important role of direct cognate Tfr-GC B cells interactions for the control of effector B cell response.
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    Targeted checkpoint control of B cells undergoing positive selection in germinal centers by follicular regulatory T cells
    (National Academy of Science, 2024) Ke, Fang; Benet, Zachary L.; Shelyakin, Pavel; Britanova, Olga V.; Gupta, Neetu; Dent, Alexander L.; Moore, Bethany B.; Grigorova, Irina L.; Microbiology and Immunology, School of Medicine
    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.