A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

Abstract

Significance T-follicular regulatory (Tfr) cells, a subset of Foxp3-expressing regulatory T (Treg) cells, have a critical role in the control of antibody responses. Whereas Treg cells express CD25 and are dependent on IL-2, Tfr cells also express the transcription factor BCL6 that is inhibited by IL-2 in T-follicular helper (Tfh) cells. In this report, we find that mature Tfr cells in the germinal centers or circulating in human blood down-regulate CD25 and gain a transcriptional signature mixed between Tfh cells and Treg cells while retaining their regulatory function. These cells represent an IL-2–independent branch of effector Treg cells losing CD25 expression but gaining increased expression of Tfh-related markers, such as BCL6 and CXCR5, in both mice and humans.