Interleukin-10 from CD4 ⁺ follicular regulatory T cells promotes the germinal center response

Abstract

CD4+ follicular regulatory T cells (Tfr cells) suppress B cell responses through modulation of follicular helper T cells (Tfh cells) and germinal center (GC) development. We found that Tfr cells also can promote the GC response through provision of IL-10 following acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing of IL-10 by B cells was necessary for optimal development of the GC response. GC B cells formed in the absence of Treg-cell derived IL-10 displayed an altered dark zone state and decreased expression of the transcription factor FOXO1. IL-10 promoted nuclear translocation of FOXO1 in activated B cells. These data indicate that Tfr cells play a multifaceted role in the fine-tuning of the GC response and identify IL-10 as an important mediator by which Tfr cells support the GC reaction.

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

“…118 Interestingly, GC B cells displayed an enhanced light zone gene signature in the absence of IL-10 secretion by Foxp3 + T cells, suggesting IL-10 production by Treg cells may promote humoral responses in some conditions. 118 Indeed, CD40L expression (critical for GC B-cell proliferation, differentiation, and isotype switching) was observed in human lymph node Tfr cells. 30,46 Tfr cells also express granzyme B (although in lower levels than Treg cells), thus granzyme B-mediated cytolysis might be another regulatory mechanism employed by Tfr cells, as it was already described for Treg cells.…”

“…118 But while Tfr cells were found to be major producers of IL-10 in IL-10-reporter mice, the impact of selective absence of IL-10 secretion by Tfr cells was not conclusive. 118 Interestingly, GC B cells displayed an enhanced light zone gene signature in the absence of IL-10 secretion by Foxp3 + T cells, suggesting IL-10 production by Treg cells may promote humoral responses in some conditions. 118 Indeed, CD40L expression (critical for GC B-cell proliferation, differentiation, and isotype switching) was observed in human lymph node Tfr cells.…”

Follicular regulatory T cells: a novel target for immunotherapy?

“…Tfr cells were analysed initially by total Treg depletion, adoptive transfer along with other T cells, and then mice with deletion of Roquin and NFAT2, but these studies may manifest nonspecific effects or nonphysiological function of Tfr cells . Recently, a novel model using Bcl6 fl/fl Foxp3 cre mice has been under investigation, and the findings about Tfr‐cell function are sharply distinct from previous studies . Nevertheless, Bcl6 fl/fl Foxp3 cre mouse model has its limits, and a more recent study has used a Cxcr5 IRES‐LoxP‐STOP‐LoxP‐DTR Foxp3 IRES‐CreYFP mouse strain .…”

“…Furthermore, Tfr cells help maintain high levels of high‐affinity antigen‐specific antibodies and regulate the isotype switch of antibodies . They also promote the GC response through the secretion of IL‐10 and the suppression of cytotoxic Tfh cells . Thus, Tfr cells might play a complicated role in the fine‐tuning of GC response and act as ‘helper cells’ in certain scenarios.…”

“…56 Nonetheless, another study found that Tfr cell-derived IL-10 promotes B-cell differentiation and GC responses by inducing nuclear FOXO1 translocation in activated B cells, contributing to the dark zone phenotype and affinity maturation during acute viral infection. 57…”