The multifaceted functions of follicular regulatory T cells

Abstract

The immune system is capable of generating robust antibody responses to foreign antigens during infection and vaccination, while simultaneously limiting antibodies to self-antigens. T follicular regulatory (Tfr) cells are a subset of follicular T cell with specialized roles in regulating humoral immunity. Although Tfr cells have been studied for the past 10 years, their roles have remained elusive. In this review we discuss the current understanding of Tfr cell functions in autoimmunity and how Tfr cells simultaneously control foreign and autoantigen specific antibody responses. We highlight new tools that enable in-depth study of Tfr cells in vivo and recent data suggesting an important role for Tfr cells in limiting participation of autoreactive B cells in germinal centers.

Figure 1.. Integrated paradigm for regulation of antibody responses by Tfr cells.

Tfr cell differentiation is initiated by DCs upon interaction with nTreg cells. The Tfr transcriptional program forms, including expression of CXCR5 which, in part, directs Tfr cells to the B cell follicle. While crossing the T cell zone Tfr cells may inhibit Tfh cell differentiation. In the B cell follicle Tfr cells interact with B cells which strengthens the Tfr phenotype, enhancing and strengthening the Tfr transcriptional program. In the B cell follicle, Tfr cells can attenuate foreign vaccine-specific Tfh cell cytokine production and B cell responses, thereby preventing initial GC formation. At the same time, Tfr cells prevent autoreactive B cells from being activated through similar mechanisms. If Tfh and B cells are able to escape suppression in the B cell follicle and form a GC, Tfh and B cells in GCs become activated which induces heightened IL-21 production by Tfh cells and enhanced costimulation/antigenic signals from B cells. IL-21 production by Tfh cells inhibits Tfr cells, preventing Tfr cell expansion. The lower concentration of Tfr cells results in more substantial Tfh and GC B cell interactions and expansion, resulting in more IL-21 and more suppressed Tfr cells, and leading to a positive feedback loop in which Tfr cells are no longer able to suppress foreign antigen-specific GC B cells. In situations where autoreactive B cells stray into GCs, Tfr cells may be able to suppress autoreactive GC B cells because of lower BCR signaling in these cells and/or less substantial Tfh cognate recognition, even in the presence of high IL-21 levels. (inset) Tfr cells control activation thresholds in B cells. In settings of high Tfr cells, small amounts of foreign antigen-specific antibody can be made, but it will be high affinity since only B cells with the highest affinity BCR can escape Tfr cell suppression. In settings with intermediate levels of Tfr cells, moderate amounts of antibody with moderate affinity can be made because Tfr cells impose a moderate activation threshold allowing foreign-antigen specific antibody to be made but preventing autoreactive B cells from being activated. In settings of low Tfr cells, high amounts of low affinity foreign-specific antibody can be made since signaling thresholds to overcome Tfr suppression are extremely low and even low affinity BCRs can overcome suppression. In this setting, even autoreactive antibody can be made even with relatively low affinity BCRs and lack of Tfh help.