T _fr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1–dependent activation of T _fh cells

Abstract

Follicular regulatory T (T) cells from lymph node germinal centers control follicular helper T (T) cell-dependent B cell activation. These scarce cells, often described and purified as CD25 cells, are thought to be derived from thymic regulatory T (T) cells. However, we observed that mouse T cells do not respond to interleukin-2 (IL-2), unlike T cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that T cells are actually CD25, in mice and humans. Moreover, T cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25 cells resulted in contamination with T cells. Transcriptome studies of CD4CXCR5PD-1Bcl6Foxp3CD25 T cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas T cells express the IL-1R1 agonist receptor. IL-1 treatment expanded T cells in vivo and activated their production of IL-4 and IL-21 in vitro. T cells suppressed the IL-1-induced activation of T cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the T cell control of B cell responses and an IL-2/IL-1 dichotomy for T cell control of effector T cells versus T cell control of T cells.

Control of Germinal Center Responses by T-Follicular Regulatory Cells

“…Interestingly, while microscopy suggested that essentially all the Tfr in the B-cell follicle and GC itself were CD25 + , flow cytometry analysis in the same report demonstrates that PD-1 hi Tfr express significantly less CD25 than PD-1 int or negative Tfr (CD25 MFI 616 ± 96 vs. 1101 ± 121.4, p = 0.0074 unpaired t -test), and also display a bimodal expression of CD25 with a significant fraction appearing to be CD25 lo/− (34). This is in keeping with two previous reports that suggested that the most highly-differentiated PD-1 hi CXCR5 hi BCL6 + Tfr in human tonsils also downregulate CD25 (25, 26). Importantly, however, while PD-1 hi Tfr do appear to be enriched in the GC itself, they are extremely rare, with only around 3% of Tregs in the mLN matching this description (34).…”

“…In contrast, in the context of a primarily self-antigen-driven response, Tfr may play a more active role directly controlling GC B-cell and Tfh cell numbers. This may be because Tfr have a more self-skewed TCR repertoire, respond better to vaccination with self-antigens rather than foreign antigens, and do not appear to require recognition of the same antigen as a particular Tfh cell in order to suppress it (25, 46, 47). We also previously demonstrated that while short-term depletion of Tregs/Tfr is effective at enhancing antigen-specific Tfh formation following vaccination with a foreign antigen, longer-term depletion of Tregs further increased the total number of Tfh but also reduced the absolute number of antigen-specific Tfh (12).…”

“…Another recently proposed mechanism of Tfr function is expression of the IL-1 decoy receptor IL-1R2 (25). Addition of IL-1 to vaccinated mice enhances the Tfh response and resulting antibody production, while blocking IL-1 has the opposite effect.…”

“…Addition of IL-1 to vaccinated mice enhances the Tfh response and resulting antibody production, while blocking IL-1 has the opposite effect. Tfr have enhanced IL-1R2 expression in comparison to other Tregs and are able to inhibit IL-1 driven enhancement of Tfh cytokine production in a similar manner to blocking IL-1 (25). This suggests that Tfr may be able to engage IL-1 and prevent its interaction with Tfh cells.…”

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…35,69,70 Wing and colleagues showed that following immunization both CD25 − and CD25 + Tfr cells emerge with the CD25 − Tfr cells preferentially locating within GCs. 35,69,70 Wing and colleagues showed that following immunization both CD25 − and CD25 + Tfr cells emerge with the CD25 − Tfr cells preferentially locating within GCs.…”