Regulation of antibody responses against self and foreign antigens by Tfr cells: implications for vaccine development

The production of antibodies can constitute a powerful protective mechanism against infection, but antibodies can also participate in autoimmunity and allergic responses. Recent advances in the understanding of the regulation of germinal centres (GC), the sites where B cells acquire the ability to produce high-affinity antibodies, offered new prospects for the modulation of antibody production in autoimmunity and vaccination. The process of B cell affinity maturation and isotype switching requires signals from T follicular helper (Tfh) cells. In addition, Foxp3(+) T follicular regulatory (Tfr) cells represent the regulatory counterpart of Tfh in the GC reaction. Tfr cells were identified one decade ago and since then it has become clear their role in controlling the emergence of autoreactive B cell clones following infection and immunization. At the same time, Tfr cells are essential for fine-tuning important features of the humoral response directed to foreign antigens that are critical in vaccination. However, this regulation is complex and several aspects of Tfr cell biology are yet to be disclosed. Here, we review the current knowledge about the regulation of antibody responses against self and foreign antigens by Tfr cells and its implications for the future rational design of safer and more effective vaccines.