Balance of Tfh/Tfr cell is critically important for the maintenance of immune tolerance, as evidenced by the fact that T follicular helper (Tfh) cells are central to the autoantibodies generation through providing necessary help for germinal center (GC) B cells, whereas T follicular regulatory (Tfr) cells significantly inhibit autoimmune inflammation process through restraining Tfh cell responses. However, signals underlying the regulation of Tfh and Tfr cells are largely undefined. Regulatory B cells (Bregs) is a heterogeneous subpopulation of B cells with immunosuppressive function. Considerable advances have been made in their functions to produce anti‐inflammatory cytokines and to regulate Th17, Th1, and Treg cells in autoimmune diseases. The recent identification of their correlations with dysregulated Tfr/Tfh cells and autoantibody production makes Bregs an important checkpoint in GC response. Bregs exert profound impacts on the differentiation, function, and distribution of Tfh and Tfr cells in the immune microenvironment. Thus, unraveling mechanistic information on Tfh-Breg and Tfr-Breg interactions will inspire novel implications for the establishment of homeostasis and prevention of autoantibodies in diverse diseases. This review summarizes the dysregulation of Tfh/Tfr cells in autoimmune diseases with a focus on the emerging role of Bregs in regulating the balance between Tfh and Tfr cells. The previously unsuspected crosstalk between Bregs and Tfh/Tfr cells will be beneficial to understand the cellular mechanisms of autoantibody production and evoke a revolution in immunotherapy for autoimmune diseases.
Potential Pathways Associated With Exaggerated T Follicular Helper Response in Human Autoimmune Diseases