T follicular regulatory cells: Guardians of the germinal centre?

It is a central tenet of the clonal selection theory, that lymphocyte repertoires are tolerized to self-antigens during their ontogeny. Germinal centres are the sites in secondary lymphoid tissues where B cells undergo affinity maturation and class-switching to produce high-affinity antibodies. This process is crucial, both in our ability to mount protective humoral responses to infections and to vaccinations, but it is also involved in untoward reactions to self-antigens, which underlie autoimmunity. The process of affinity maturation poses a significant challenge to tolerance, as the random nature of somatic hypermutation can introduce novel reactivities. Therefore, it has been a long-standing idea that mechanisms must exist which limit the emergence of autoreactivity at the germinal centre level. One of these mechanisms is the requirement for linked recognition, which imposes on B cells a dependence on centrally tolerant T follicular helper cells. However, as linked recognition can be bypassed by adduct formation of autoantigenic complexes, it has been an appealing notion that there should be an additional layer of dominant mechanisms regulating emergence of autoreactive specificities. About a decade ago, this notion was addressed by the discovery of a novel subset of T regulatory cells localizing to the germinal centre and regulating germinal centre B-cell responses. Here, we detail the progress that has been made towards characterizing this T follicular regulatory cell subset and understanding the functions of these 'guardians of the germinal centre'.